Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>CO.O.[Fe]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Temperature: 90 °C

Procedure:
To a mixture of 6-fluoro-3-nitro-2-phenylaminobenzoic acid methyl ester (2.1 g, 7.24 mmol) in a mixture of MeOH (50 mL) and water (15 mL) were added NH4Cl (2.23 g, 43.4 mmol) and iron powder (1.61 g, 28.9 mmol) and the reaction mixture heated at 90° C. for 3 h. After cooling to RT, the suspension was filtered through a pad of Celite® washing with additional MeOH. The filtrate was concentrated in vacuo to remove the organic solvent and the resulting aqueous residue extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as an orange oil which solidified on standing (2.0 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.23-7.18 (2H, m), 7.13 (1H, br s), 6.89-6.80 (3H, m), 6.69-6.64 (2H, m), 3.83 (3H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](OC)(OC)OC>CO.C1(C)C=CC=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of (3-bromo-phenyl)-acetic acid (10.4 g, 48.5 mmol), in methanol (80 mL), was treated with trimethyl orthoformate (6.5 mL, 59.4 mmol). HCl gas was bubbled through the stirred solution for 10 minutes. The HCl addition was exothermic. After stirring for 15 minutes HPLC analysis of the solution showed complete conversion to product. After stirring for 16 hrs at ambient temperature the solution was diluted with toluene (100 mL) and concentrated under reduced pressure to afford a biphasic mixture. This liquid was diluted with toluene and concentrated under reduced pressure to afford (3-bromo-phenyl)-acetic acid methyl ester (11.2 g, quantitative yield) as a pale yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.46-7.38 (2H, m), 7.23-7.18 (2H, m), 3.71 (3H, m), 3.60 (2H, m).
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:32]1[CH2:33][CH2:34][O:30][C:31]1=[O:35])=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Reactant: O=C1NCCO1
Product: COc1ccc2c(CN3CCOC3=O)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in the example 369d was used, starting from Methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester and Oxazolidin-2-one to give 5 mg of 3-[6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylmethyl]-oxazolidin-2-one as a yellow solid. LC-MS m/e 354 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:24])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)=[CH:19][C:18]=2[O:24][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(O)cc2O)CC1
Reactant: N#Cc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(OCc3ccc(C#N)cc3)cc2OCc2ccc(C#N)cc2)CC1
Yield: 70.5 %

Procedure:
{2-[1-(2,4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester (1.13 g, 3.1 mmol) and 4-bromomethyl-benzonitrile (2.43 g, 12.4 mmol) and other reagents as described in Example 75(a) were used to afford 1.3 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (8H, s), 2.1 (4H, s), 2.9 (3H, m), 4.55 (4H, d), 5.25 (3H, s), 5.5 (2H, t), 6.8 (1H, m), 7.3 (1H, d), 7.4 (1H, d), 7.5 (4H, d), 7.66 (1H, d), 7.8 (3H, m), 7.86 (2H, m).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:48])[CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]([CH2:45][CH2:46][Cl:47])[CH2:42][CH2:43][Cl:44])=[CH:37][CH:36]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].O1CCOCC1>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:48])[CH2:32][CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N:41]([CH2:42][CH2:43][Cl:44])[CH2:45][CH2:46][Cl:47])=[CH:39][CH:40]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCOC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCOC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% palladium on carbon (320.7 mg) was placed into an eggplant type flask (100 ml), followed by dropwise addition of 1,4-dioxane (15 ml) at 0° C. To this mixture was added a 1,4-dioxane (15 ml) solution of 1-[3-benzyloxy-1,3,5(10)-estratriene-17β-oxy]-2-[4-[p-[bis(2-chloroethyl)amino]-phenyl]-butyryloxy]ethane (I-5) dropwise at 0° C. The mixture was heated to room temperature and stirred under hydrogen gas for one hour. The reaction mixture was filtered through filter paper while washing with 1,4-dioxane, and the filtrate was concentrated under reduced pressure to produce an oily substance (0.27 g). It was purified by silica gel chromatography (hexane/ethyl acetate =3:1) to obtain 1-[3-hydroxy-1,3,5(10)-estratriene-17β-oxy]-2-[4-[p-[bis(2-chloroethyl)-amino]phenyl]butyryloxy]ethane (0.26 g) (Rf: 0.25, hexane/ethyl acetate=3:1) as oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11])=[O:6].[C:20]1([S+:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:39]([O-:44])(=[O:43])[C:40]([CH3:42])=[CH2:41].[Na+].[I-].[Na+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1>ClCCl.O.CN(C)C=O>[F:14][C:9]([F:15])([S:10]([O-:13])(=[O:12])=[O:11])[CH:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][O:44][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41])[C:16]([F:19])([F:18])[F:17].[C:33]1([S+:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C=C(C)C(=O)[O-]
Reactant: O=C(CCCCl)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCCC(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To 20 g of dimethylformamide were added 5.4 g (9.0 mmol) of triphenylsulfonium 2-(4-chlorobutyryloxy)-1,1,3,3,3-pentafluoropropane-1-sulfonate synthesized in Synthesis Example 1-20, 1.2 g (11 mmol) of sodium methacrylate, 0.20 g (1.4 mmol) of sodium iodide, and 1 mg of 2,2′-methylenebis(6-t-butyl-p-cresol). The mixture was heated and stirred at 90° C. for 12 hours. The reaction solution was allowed to resume room temperature, after which 50 g of water and 80 g of dichloromethane were added. The organic layer was separated and washed with water whereupon dichloromethane was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with water whereupon methyl isobutyl ketone was distilled off under vacuum. The residue was purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(4-methacryloyloxy-butyryloxy)-propane-1-sulfonate was obtained as brown oil (4.2 g, yield 72%). The compound has the following structure.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6](=[O:12])[CH:5]=1.[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21]Cl)(=[O:15])[CH3:14].[Cl-].[Na+]>CS(C)=O>[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][N:7]1[C:6](=[O:12])[CH:5]=[C:4]([NH2:3])[N:9]([CH3:10])[C:8]1=[O:11])(=[O:15])[CH3:14]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirring suspension of sodium hydride (5.52 g, 230 mmol) in anhydrous dimethylsulfoxide (500 ml) was added 6-amino-1-methyluracil (28.2 g, 200 mmol). After stirring at room temperature under argon for 2 hours, (R)-5-Acetoxy-1-chlorohexane (37.5 g, 210 mmol) was added neat and the mixture was stirred at 80° C. for 16 hours. After cooling to room temperature, the mixture was poured into saturated aqueous sodium chloride solution (1500 ml) and extracted with ethyl acetate (9x 200 ml). The combined extracts were washed with water (2x 50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting oil was treated with ethyl ether (400 ml). After stirring overnight at room temperature, the precipitate was filtered and rinsed with ether (2x 50 ml) to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (44.0 g, 78% yield) as a beige powder.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:13][C:12](=[O:14])[CH2:11][N:10]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)phenylglycine was esterified with thionyl chloride in methanol to give N-(toluene-4-sulfonyl)phenylglycine methyl ester. This was then taken up in dry acetone (50 mL) with iodomethane (1.1 eq, 1.88 mL) and K2CO3 (1.1 eq, 4.10 g). The solution was refluxed overnight. The solvent was evaporated under reduced pressure. EtOAc was added and the organic layer was washed with brine. The organic layer was dried over MgSO4. The solvent was evaporated under reduced pressure. The resulting ester was hydrolyzed using the procedure described in Method 6 to yield N-(Toluene-4-sulfonyl)-N-methylphenylglycine, which was coupled with L-phenylalanine ethyl ester using the procedure described in Method 3 to yield the title compound.
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH3:24])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
7.44 grams of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 12.53 g of yellow liquid. MS: m/e 360(M+′), 315(M+—OCH2CH3), 287(M+—CO2CH2CH3), 276, 241(M+−CH3C6H4CO), 225(M+—CH3C6H4CO2), 195, 185, 151, 140, 119 (base), 91, 77.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][OH:16])[CH2:20][CH2:21]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(CC2CN(Cc3ccccc3)CCO2)CC1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
4-Benzyl-2-chloromethylmorpholine (15 g) and 4-(2-hydroxyethyl)piperazine (25 ml) are mixed, and the mixture is heated with stirring at 130° C. for five hours. After the reaction is complete, the mixture is extracted with chloroform, and the extract is dried over magnesium sulfate. The residue thus obtained is concentrated under reduced pressure to give 4-benzyl-2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (16 g).
Reaction SMILES: ClC1N2[C:8](=[O:11])NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45](NCC)(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][CH2:8][O:11][CH2:45][CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=2)=[CH:33][CH:32]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CCOCC3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.306 min, [M+H]30 =470.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12].N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:9]([CH3:8])=[CH:10][C:11]([CH3:12])=[C:4]([C:5]#[N:6])[C:3]1=[O:7]
Reactant: CNC(=O)CC#N
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)n(C)c(=O)c1C#N
Reaction time: 3 h
Yield: 77.4 %

Procedure:
N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol (250 ml.) are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(OCC)(=O)C>C(Cl)Cl>[CH2:9]([O:8][C:6]([NH:4][CH2:3][CH2:1][OH:2])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To ethanolamine (9.0 ml, 149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chlorformate (10.0 ml, 70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide 12.91 g (94%) of the desired compound as a white solid. 1H NMR (CDCl3, TMS) 7.47 (m,5H), 5.11 s,2H), 3.73 (m,2H), 3.38 (m,2H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(N(CC)CC)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C)C=O.O.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>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](/[CH:22]=[CH:21]/[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: C=Cc1ccncc1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncc(/C=C/c3ccncc3)cc2C(=O)N(C)c2cccnc21
Temperature: 125 °C
Yield: 73.6 %

Procedure:
A mixture containing 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]-diazepin-6-one (0.7 g, 1.9 mmol), 4-vinylpyridine (0.3 mL, 2.9 mmol), bis(triphenylphosphine)palladium(II) chloride (60 mg, 0.09 mmol), triethylamine (1.8 mL, 12.8 mmol), and 1 crystal of 2,6-di-tert-butyl-4-methylphenol in 4 mL of N,N-dimethylformamide was heated at 125° C. under argon for 3 hours. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and concentrated to give a yellow oil. Purification by flash chromatography, eluting with ethyl acetate/hexanes, and recrystallization (ethyl acetate/hexanes) provided the 0.5 g of the title compound as yellow crystals, m.p. 150° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].O>CC(C)=O>[N:1]1([S:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 0 °C
Yield: 46.4 %

Procedure:
(prepared according to an analogous procedure described in U.S. Pat. No. 5,755,873) Step A: Pyrrolidine (16 ml, 0.1925 mol) was dissolved in acetone (40 ml) and cooled to 0° C.; 4-acetylaminobenzenesulfonyl chloride (15 g, 0.065 mol) was added over 10 min. Additional acetone (13 ml) was added and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was added to water (350 ml) and the resulting precipitate collected by filtration, the precipitate was washed with water until the washings were at pH 7. The solid was dried under vacuum to give 8.1 g of N-[4-(pyrrolidine-1-sulfonyl)phenyl]acetamide. Step B: The compound from step A (8.1 g) was suspended in water (37.5 ml) and treated with concentrated HCl (19 ml). The mixture was heated at reflux for 1 h. After cooling to rt, NH4OH (23 ml) was added with stirring. The resulting precipitate was collected by filtration and washed with water until the washings were pH 7. The solid was dried to give 6.0 g of 4-(pyrrolidine-1-sulfonyl)phenylamine. 1H NMR (DMSO) δ 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.02 (s, 2H), 3.03 (m, 4H), 1.61 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12](OS(C)(=O)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([NH:26][CH:12]1[CH2:13][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OC1CN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
Methanesulfonic acid 1-(4-nitro-phenyl)-azetidin-3-yl ester (which was obtained in Example 397) (14.32 g, 52.6 mmol) was added to neat benzyl amine (56 mL, 526 mmol) and stirred at 100° C. for 2 days. Water (200 mL) was added and the resultant precipitate was collected and partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was washed with ethyl acetate (2×50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was washed with diethyl ether and dried to give 12.1 g of the desired product as an orange solid; 1H NMR (300 MHz, CDCl3) δ1.66 (brs, 1H), 3.72 (m, 2H), 3.82 (s, 2H), 3.89 (m, 1H), 4.19 (t, 2H, J=7.77 Hz), 6.29 (d, 2H, J=9.12 Hz), 7.34 (m, 5H), 8.07 (d, 2H, J=9.18 Hz); MS (ES) m/z: 283.8 (MH+); Anal. Calcd. for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.59; H, 6.04; N, 14.79.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([CH:18]=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].Cl>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16](/[CH:18]=[CH:21]/[C:20]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyl phosphonoacetate (1.9 mL; 9.72 mmol) was dissolved in tetrahydrofuran (30 mL). Potassium tert-butoxide (1.1 g; 9.72 mmol) was added portionwise. 3-Formylazetidine-1-car-boxylic acid tert-butyl ester (1.0 g; 5.40 mmol) was dissolved in tetrahydrofuran (6 mL) and added to the reaction mixture. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate (100 mL) and hydrochloric acid (100 mL; 1 N) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 1.0 g of 3-((E)-2-ethoxycarbonylvinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.O>[Br:23][C:6]1[C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[C:2]([Br:1])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)c1cc(Br)c(C(=O)O)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(Br)c(C(=O)O)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
step 3—To a solution of 120 (1.0 eq, 2.27 mmol, 621 mg) in DCM (10 mL) at RT was added in three portions NBS (2.0 eq, 4.55, 809 mg). The mixture was stirred RT for 30 min. The reaction was diluted with water, the organic layer was separated, dried (MgSO4) and concentrated to afford 767 mg of 2,6-dibromo-4-tert-butyl-3-hydroxybenzoic acid (122) as a light brownish solid.