Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:16])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][CH:2]([CH3:16])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:13])=[O:14])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)CC#Cc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)CC#Cc1ccccc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 14 h

Procedure:
1 g of 2-(4-hydroxy-pent-1-yn-1-yl)-benzenesulfonamide is dissolved in 9 ml of pyridine and cooled to 5°, and 0.44 ml of acetic anhydride is added. The reaction mixture is stirred under argon at 5° for 14 hours and then at room temperature for a further 24 hours. The reaction mixture is then poured onto 100 ml of ice-cold 1N hydrochloric acid and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are washed twice with 20 ml of 1N hydrochloric acid each time, with 50 ml of water and with 30 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered off and concentrated by evaporation at 15 torr and 40°. The crude product is chromatographed on 80 g of silica gel (Merck ST 60, 40-63 μm). A 1/1 mixture of hexane and ethyl acetate is used as eluant. 2-(4-Acetoxy-pent- 1-yn-1-yl)-benzenesulfonamide is obtained in the form of a colourless oil. 1H-NMR (200 MHz, DMSO-d6): 7.90 (d, d, 1H); 7.48-7.63 (m, 3H); 7.22 (s, 2H); 5.01 (m, 1H); 2.82 (d, 2H); 2.05 (s, 3H); 1.33 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][C:5]=1[OH:26].CNN>>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][NH2:15])=[CH:6][C:5]=1[OH:26]
Reactant: COC(=O)c1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1O
Agent: CNN
Product: COC(=O)c1ccc(OCCCON)cc1O
Yield: 96.2 %

Procedure:
This compound was produced using similar methods as those used in Step 2, example 4, starting with 4-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-propoxy]-2-hydroxy-benzoic acid methyl ester (0.42 g, 1.12 mmol) and methyl hydrazine (0.087 g, 1.88 mmol). The crude material was purified by flash chromatography through silica gel using ethyl acetate/chloroform (10/90) to give 4-(3-aminooxy-propoxy)-2-hydroxy-benzoic acid methyl ester (0.26 g, 96%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 7.51 (d, 1H), 6.23 (s, 1H), 6.21 (d, 1H), 3.85 (t, 2H), 3.69 (s, 3H), 3.62 (t, 2H), 1.86 (m, 2H).
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([C:22]3=[O:29])[CH2:20]1)[CH2:26]2>>[C:1]([O:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([C:22]3=[O:29])[CH2:20]1)[CH2:26]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Product: C=CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Yield: 95 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1-hydroxyadamantane-4-one was used instead of the 1-hydroxyadamantane-2-one, and, as a result, a 1-acryloyloxyadamantane-4-one (yield: 95%, white solid) was obtained.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][NH:2]1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][CH2:16]Br)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][CH2:16][N:2]2[CH2:3][C@H:4]3[C@H:9]([CH2:8][CH:7]=[CH:6][CH2:5]3)[CH2:1]2)=[CH:13][CH:12]=1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Reactant: BrCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Brc1ccc(CCN2C[C@H]3CC=CC[C@H]3C2)cc1
Yield: 42.2 %

Procedure:
A mixture of 0.6 g of cis-3a,4,7,7a-tetrahydroisoindoline, 1.4 g of 4-bromophenethyl bromide, 1.0 g of potassium carbonate and 3 mL of dimethylformamide was stirred and heated in a 90° oil bath for 1 hour. Toluene (20 mL) and water (20 mL) were added and the aqueous layer was extracted with toluene. Addition of 10 mL of 10% hydrochloric acid to the toluene solution resulted in the formation of three layers. The two lower layers were made basic with aqueous sodium hydroxide solution. Extraction with methylene chloride gave 0.89 g of crude product which on short-path distillation gave 0.63 g of cis-2-(4-bromophenethyl)-3a,4,7,7a-tetrahydroisoindoline. 'H NMR (in CDCl3) δ7.4 (d, 2H); 7.0 (d, 2H); 5.8 (m, 2H); 3.0 (m, 2H); 2.6-2.8 (m, 4H); 2.4 (m, 2H); 2.1-2.3 (m, 4H) and 1.9 (d, 2H). The fumarate had m.p. 166°-167° after crystallization from ethanol. Anal. Calcd. for C20H24BrNO4 : C, 56.88; H, 5.73; N, 3.32 Found: C, 56.91; H, 5.64; N, 3.21
Reaction SMILES: C=O.C(=O)C.C(=O)CC.[C:10]1(CC=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:19][C:20]([NH2:22])=[O:21]>>[NH2:19][C:20]([NH2:22])=[O:21].[NH2:19][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCc1ccccc1
Agent: C=O
Agent: CC=O
Agent: NC(N)=O
Solvent: CCC=O
Product: Nc1ccccc1

Procedure:
The amino-series resin is usually obtained by a reaction of an amino group-containing compound with an aldehyde (e.g., an aliphatic aldehyde such as formaldehyde (formic aldehyde), acetaldehyde or propionaldehyde, an aromatic aldehyde such as phenylacetaldehyde). The amino-series resin may include a urea resin (e.g., a urea resin obtained by a reaction of urea with an aldehyde), an aniline resin (e.g., an aniline resin obtained by a reaction of an aniline compound such as aniline, naphthylamine, toluidine, xylidine, N,N′-dimethylaniline or benzidine, with an aldehyde), a melamine resin (e.g., a melamine resin obtained by a reaction of melamine with an aldehyde), a guanamine resin (e.g., a guanamine resin obtained by a reaction of a guanamine compound such as benzoguanamine, acetoguanamine or formoguanamine, with an aldehyde) and the like.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.Cl.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][C@@H:32]([NH2:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)C.C[O-].[Na+].CO>>[CH3:27][O:29][C:30](=[O:40])[CH2:31][C@@H:32]([NH:39][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCOC(=O)C[C@@H](N)c1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Temperature: 140 °C
Yield: 67 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in a CEM microwave tube (10 mL) with (R)-3-amino-3-pyridin-3-yl-propionic acid ethyl ester dihydrochloride (134 mg, 0.5 mmol) (commercially available from AstaTech 46345) and a solution of sodium methoxide in methanol (2 mL, 0.5M, 1 mmol) was added with stirring. The reaction was heated to 140° C. in the CEM microwave apparatus for approximately 90 minutes. The reaction was cooled, concentrated under vacuum and filtered through silica to provide 49 mg of the desired product which was used without additional purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].F[P-](F)(F)(F)(F)F.Br[P+](N(C)C)(N(C)C)N(C)C.C(N(C(C)C)CC)(C)C.[NH2:74][C:75]1([C:78](O)=[O:79])[CH2:77][CH2:76]1>ClCCl>[NH2:74][C:75]1([C:78]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:79])[CH2:77][CH2:76]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: NC1(C(=O)O)CC1
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CC1)C(C)C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
To a solution of #50 (100 mg, 0.15 mmol, 1 eq.), bromotris(dimethylamino)phosphonium hexafluorophosphate (Brop, 70 mg, 0.18 mmol, 1.2 eq.) and diisopropylethylamine (0.08 mL, 0.45 mmol, 3 eq.) in dichloromethane (15 mL, 0.01 M) at 0° C. was added 1-aminocyclopropanecarboxylic acid (18 mg, 0.18 mmol, 1.2 eq.). After 2 hours, the mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #51 (45 mg, 34%). Rf 0.5 (10% methanol in dichloromethane). LC-MS (Protocol L): m/z 741.44 [M+H+]; 1H NMR (300 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.88 (br d, J=8 Hz), total 1H], [8.16 (br d, J=9 Hz) and 8.22 (br d, J=10 Hz), total 1H], [7.77 (d, J=3.5 Hz) and 7.79 (d, J=3.5 Hz), total 1H], [7.63 (d, J=3.5 Hz) and 7.65 (d, J=3 Hz), total 1H], 7.10-7.32 (m, 5H), 5.33-5.60 (m, 1H), 3.16, 3.20, 3.21 and 3.26 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), [1.05 (d, J=6.3 Hz) and 1.10 (d, J=6.3 Hz), total 3H].
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]OS(C)(=O)=O)=[C:6]([F:14])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[CH3:28][N:29]1[CH:33]=[C:32]([NH:34][C:35]2[N:40]=[C:39]3[NH:41][N:42]=[CH:43][C:38]3=[CH:37][N:36]=2)[CH:31]=[N:30]1>>[F:1][C:2]1[C:7]([CH2:8][N:41]2[C:39]3=[N:40][C:35]([NH:34][C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)=[N:36][CH:37]=[C:38]3[CH:43]=[N:42]2)=[C:6]([F:14])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(COS(C)(=O)=O)c2F)CC1
Product: Cn1cc(Nc2ncc3cnn(Cc4c(F)ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4F)c3n2)cn1

Procedure:
tert-butyl 4-(2,4-difluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate was synthesized following the procedure in Example 1 (Step i) then Step (ii) using tert-butyl 4-(2,4-difluoro-3-(((methylsulfonyl)oxy)methyl)phenyl)piperazine-1-carboxylate and N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:24]=[CH:25][C:26]#[N:27])=[CH:5][C:4]=2[N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]#[N:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(N)nc3cc(CCC#N)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.05 g), methanol (20 mL), and 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (100 mg, 0.27 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 18 hours and then cooled to ambient temperature. The reaction mixture was sequentially filtered, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-30% CMA). A final recrystallization from acetonitrile provided 71 mg of 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanenitrile as a white solid, mp 273-275° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[C:33][C:34]([O:36][CH3:37])=[O:35])[N:27]=3)=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]2C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][C:26]3[N:27]=[C:28]([C:32]#[C:33][C:34]([O:36][CH3:37])=[O:35])[CH:29]=[CH:30][CH:31]=3)=[C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C#Cc1cccc(Cc2c(-c3ccccc3)n(C(=O)OC(C)(C)C)c3cc(OC)ccc23)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 6-methoxy-3-(6-methoxycarbonylethynylpyridin-2-ylmethyl)-2-phenylindole-1-carboxylate (100 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added dichloromethane and an aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (75.1 mg). 1H-NMR (CDCl3) δ ppm: 3.84-3.89 (6H, m), 4.45 (2H, s), 6.75 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.04-7.10 (1H, m), 7.31-7.55 (7H, m), 8.09 (1H, br s). ESI-MS (m/z): 397 (M+H)+
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:24](OC)(OC)(OC)[O:25][CH3:26]>C(O)(=O)C>[CH3:24][O:25][C:26]1[O:1][C:2]([CH3:23])([CH3:22])[CH:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: CC(C)(O)C(c1ccc(CCN2CCOCC2)cc1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(CCN3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-[4-(2-morpholin-4-ylethyl)phenyl]propane-1-sulfonamide (44 mg) was stirred with tetramethyl orthocarbonate (1 ml) and glacial acetic acid (0.2 ml) at 80° C. for 17 hours. The solvents were removed under reduced pressure. This gave the crude product with a molecular weight of 382.5 g/mol (C18H26N2O5S), which was used without further purification.
Reaction SMILES: [CH3:1][C@@:2]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[Br-].[Li+].CN1CCCC1=O.[C:25]([O:31][CH:32](Cl)[CH3:33])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(OCC)(=O)C>[OH:10][C:8]1[CH:9]=[C:4]([CH2:3][C@@:2]([CH3:1])([C:12]([O:14][CH:32]([O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:33])=[O:13])[NH2:15])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CC(Cl)OC(=O)C(C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(OC(=O)C(C)(C)C)OC(=O)[C@@](C)(N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 grams (0.047 mole) of α-methyldopa, 4.7 grams of powdered 4A molecular sieves, 6.1 grams (0.070 mole) of lithium bromide and 47 milliliters of N-methylpyrrolidinone were stirred for about one hour at 25° C. To this mixture, 8.1 grams (0.049 mole) of α-chloroethyl pivalate was added and the mixture was aged at 55° C. for 8 hours. At the end of this time, the mixture was cooled to 25° C., diluted with 100 milliliters of ethyl acetate and washed successively with one 200 milliliter and two 100 milliliter portions of saturated sodium bicarbonate solution. The combined sodium bicarbonate washes were extracted with two 100 milliliter portions of ethyl acetate and the combined ethyl acetate extracts concentrated under vacuum to 150 milliliters. The assay yield of α-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate was found to be 14.4 grams or 90 percent of theoretical.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH-:20].[Na+]>>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:20])=[CH:6][N:7]2[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Br)cc21
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(Br)cc21
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-bromo-1-isopropyl-1H-indol-3-yl)-ethanone (3.30 g, 9.88 mmol) in a 20% aqueous sodium hydroxide solution (35 mL) was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (100 mL) and ethyl acetate (100 mL), and treated with a 1N aqueous hydrochloric acid solution (60 mL). The organic layer was then washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (2.63 g, 94%) as a yellow solid: mp 207-209° C.; EI-HRMS m/e calcd for C12H12BrNO2 (M+) 281.0051, found 281.0047.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[CH:20][C:19]=2[CH3:37])=[CH:11][CH:10]=1.[OH-].[Na+]>O.C(#N)C>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[O:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:20][C:19]=2[CH3:37])=[O:38])=[CH:11][CH:10]=1
Reactant: Cc1cc([C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1NC(=O)Nc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cc([C@@H]2CNCCO2)ccc1NC(=O)Nc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a stirred solution of trifluoroacetic acid (233 μl) in water (6 ml) was added a solution of (R)-tert-butyl 2-(4-(3-(6-chloropyridin-3-yl)ureido)-3-methylphenyl)morpholine-4-carboxylate (104 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (R)-1-(6-chloropyridin-3-yl)-3-(2-methyl-4-(morpholin-2-yl)phenyl)urea (41 mg, 51%) as a white solid. MS (ISP): 349.1 ([{37Cl}M+H]+), 347.1 ([{35Cl}M+H]+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C1C=CC=CC=1>[Si:7]([C:5]1[N:1]=[N:2][NH:3][CH:4]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: c1c[nH]nn1
Solvent: c1ccccc1
Product: C[Si](C)(C)c1c[nH]nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-1,2,3-triazole (4.98 g, 72.10 mmol, 1 equiv.) in dry benzene (145 mL) at rt under nitrogen, is added TEA (11.05 mL, 79.31 mmol, 1.1 equiv.) followed by the dropwise addition of TMSCl (9.15 mL, 72.10 mmol, 1 equiv.). A white precipitate develops. Reaction mixture is stirred at rt under nitrogen for 1 hour. The resultant precipitate is removed by filtration and washed thoroughly with dry benzene. The filtrate is gently concentrated to avoid evaporating the highly volatile product to give a quantitative yield of TMS-triazole with a trace of benzene.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Br)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[C:26]=1[O:35][CH3:36].[F-].[Cs+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:35][CH3:36])[C:27]=2[F:34])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1nc(Br)cc(NC(C)=O)c1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OCc1ccccc1
Temperature: 100 °C

Procedure:
Methyl 4-acetamido-3-(benzyloxy)-6-bromopicolinate (prepared as in Kong, L. C. C. et al. U.S. Patent Application Publication 2005/0176767; 1.5 g, 4.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (1.2 g, 5.9 mmol), bis(triphenylphosphine)-palladium(II) dichloride (PdCl2(PPh3)2; 278 mg, 0.4 mmol), cesium fluoride (CsF; 1.2 g, 7.9 mmol), 1,2-dimethoxyethane (DME; 7 mL), and H2O (7 mL) were combined and heated in a Biotage microwave at 100° C. for 15 min. H2O was added to the reaction mixture, and the product was extracted with EtOAc. The combined organic extracts were washed with satd aq NaCl, dried with sodium sulfate (Na2SO4), filtered and concentrated. Flash chromatography (SiO2; 0-45% EtOAc/cyclohexane gradient) afforded methyl 4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate as a yellow solid: mp 115-120° C.; 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 7.59 (dd, J=8.5, 7.7 Hz, 1H), 7.45 (s, 5H), 7.24 (dd, J=8.6, 1.7 Hz, 1H), 5.13 (s, 2H), 4.03 (s, 3H), 3.99 (d, J=1.0 Hz, 3H), 1.88 (s, 3H); ESIMS m/z 459 ([M+H]+).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)=O.[C:13]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][CH2:1][C:3]2[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(C=O)o1
Reactant: NCCCc1ccccc1
Product: CCOC(=O)c1ccc(CNCCCc2ccccc2)o1

Procedure:
Subsequently, ethyl 5-{[(3-phenylpropyl)amino]methyl}-2-furoate (0.64 g) was prepared from ethyl 5-formyl-furan-2-carboxylate (500 mg) and 3-phenylpropylamine (0.85 mL) in the same manner as in Preparation Example 52.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24]>O1CCCC1>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3]
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11-dihydro-11-oxodibenzo[b,f]thiepin as prepared in Example 31, Step 1, in 10 cc. of anhydrous tetrahydrofuran with stirring and add 2 ml. of N,N-dimethylethanolamine. Stir at room temperature for 18 hours and strip the mixture to dryness. Partition the residue between ether and dilute hydrochloric acid and separate the aqueous layer. Basify the aqueous layer with aqueous ammonia and extract with ethyl acetate. Evaporate the organic phase and chromatograph the residue over silica-gel eluting with 90% chloroform in methanol to obtain the title product.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1>>[CH:1]1([C:4]([O:6][C:10]([CH:7]2[CH2:9][CH2:8]2)=[O:11])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(O)C1CC1
Product: O=C(OC(=O)C1CC1)C1CC1

Procedure:
This was prepared from cyclopropanecarboxylic acid (Aldrich) and cyclopropanecarboxylic acid chloride (Aldrich) by the method given (Example IV) for the preparation of the cyclobutyl analogue and purified by vacuum distillation; bp 95°-100° C. at 6 torr (lit.: Castro and Dormoy, Bull. Soc. Chem. Fr. 8, 3034 (1971) bp 102°-104° C. at 8 torr); IR anhydride C=O stretch absorptions at 5.53 and 5.74μ.