Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.[CH3:16]O>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1c(C)[nH]c2ccccc12
Yield: 90.7 %

Procedure:
2-(2-Methyl-1H-indol-3-yl)acetic acid (11.7 g, 61.84 mmol) was weighed and added into 100 mL methanol. Concentrated hydrochloric acid 0.7 mL was added dropwise. It was reacted at 70° C. for 4 hours, cooled, rotate evaporated to dryness, extracted with ethyl acetate, washed twice with NaHCO3 aqueous solution. The organic phase was dried and rotate evaporated to dryness to obtain a red brown solid 11.4 g, at a yield of 90.7%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5](F)[CH:4]=1.F[C:15]1C=CC(C=O)=C(C)C=1>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH3:15]
Reactant: Cc1cc(F)ccc1C=O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Product: Cc1cc(S(C)(=O)=O)ccc1CBr

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluoro-2-methyl-benzaldehyde.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 2, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 7.79-7.75 (m, 2H), 7.43-7.39 (m, 2H), 7.25-7.13 (m, 2H), 7.03-6.86 (m, 7H), 5.32 (d, 1H), 5.18 (d, 1H), 4.77 (d, 1H), 3.76-3.70 (m, 1H), 3.36 (t, 1H), 3.08-2.96 (m, 1H), 2.94-2.88 (m, 2H), 2.60-2.53 (m, 1H), 1.82-1.73 (m, 1H). MS (EI) for C28H25ClF2N5O3 found 552 (MH+).
Reaction SMILES: [NH3:1].CO.O=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[NH2:1][C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: N
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CO
Product: CCOC(=O)C1=C(N)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Into 7N-ammonia-methanol solution, 170 g of ethyl 2-oxocyclohexanecarboxylate was added and stirred for an overnight at room temperature. Distilling the solvent off under reduced pressure, the resulting crude crystalline product was recrystallized from ethyl acetate-n-hexane to provide 152 g (90%) of ethyl 2-aminocyclohex-1-enecarboxylate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:30]3[CH:29]=[C:28]([CH3:27])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cc1cc(N2CCNCC2)nc2ccccc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cc1cc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc12

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 4-methyl-2-piperazin-1-yl-quinoline.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[N:29][CH:30]=[C:25]([CH3:24])[CH:26]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1cncc(B(O)O)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-methylpyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 17 mg, 0.123 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.07 min (Method A); M+H=385 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.54-8.48 (m, 1H), 8.45-8.39 (m, 1H), 8.19-8.08 (m, 2H), 7.99-7.92 (m, 1H), 7.71-7.66 (m, 1H), 7.58-7.53 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH2:16]([C:18]1[C:22]([C:23](Cl)=[O:24])=[C:21]([CH3:26])[O:20][N:19]=1)[CH3:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23]([C:22]2[C:18]([CH2:16][CH3:17])=[N:19][O:20][C:21]=2[CH3:26])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCc1noc(C)c1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1noc(C)c1C(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.3 grams (0.120 mole) of m-fluoroaniline and 20.9 ml. (0.150 mole of triethylamine in 120 ml. of toluene is treated by dropwise addition with 22.5 grams (0.129 mole) of 3-ethyl-5-methyl-4-isoxazole carbonyl chloride in 100 ml. of toluene while maintaining the temperature between 30°-35° during addition. The mixture is stirred at room temperature overnight, filtered and the filtrate washed with 2N hydrochloric acid. The toluene is dried and evaporated with the residue recrystallized from toluene to give N-(m-fluorophenyl)-3-ethyl-5-methyl-4-isoxazole carboxamide (m.p. 99.5°-101° C.).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:20][S:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:27][C:25]2[S:26][C:22]([S:21][CH3:20])=[CH:23][CH:24]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSc1ccc(C=O)s1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)s1
Yield: 75.4 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 5-(methylthio)thiophene-2-carboxaldehyde (0.233 g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 2 hours at room temperature to afford 0.293 g (36%) of the title compound as a dark yellow powder, mp 102-104° C.: APCI-MS m/e 397.5 (M++1).
Reaction SMILES: [N:1]1([C:7](=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:7](=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.2 %

Procedure:
Methyl 6-morpholin-4-yl-6-oxohexanoate (4.60 g) obtained in Reference Example 84(1) is dissolved in methanol (20 ml), and thereto is added a solution of sodium hydroxide (1.61 g) in water (8 ml). The mixture is stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure and the residue is neutralized with 2 N hydrochloric acid. The residue is concentrated under reduced pressure and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is concentrated under reduced pressure to give the title compound (4.11 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[CH2:9][N:10]([CH3:12])[CH3:11].Cl.C=O.[C:16](=O)([O-])[O-:17].[Na+].[Na+]>C(O)(=O)C>[CH3:12][N:10]([CH2:9][C:5]1[O:6][C:7]([CH2:16][OH:17])=[CH:8][C:4]=1[CH2:3][O:2][CH3:1])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: COCc1ccoc1CN(C)C
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1cc(CO)oc1CN(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-methoxymethyl-N,N-dimethyl-2-furanmethanamine (7 g), acetic acid (60 ml), concentrated hydrochloric acid (30 ml) and paraformaldehyde (3.7 g) was stirred at ambient temperature for 5 hours. The mixture was basified with sodium carbonate, and extracted with diethyl ether (200 ml). The ethereal extract was dried over anhydrous sodium sulphate and the solvent evaporated in vacuo. The residue was distilled affording the title compound (3.5 g) as an off-white waxy solid, b.p. 90°/5×10-2 mm Hg.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:39])[C@@H:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]([NH:15][C@H:16]([C:26](O)=[O:27])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:40]([S:59][CH2:60][C@@H:61]([C:63]([NH2:65])=[O:64])[NH2:62])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:39])[C@@H:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][C@H:16]([C:26]([NH:62][C@H:61]([C:63]([NH2:65])=[O:64])[CH2:60][S:59][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:27])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[CH:29][CH:30]=1)[CH:2]=[CH2:3]
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.23 g (2.23 mmol) of the compound from example 24A was dissolved in 25 ml dichloromethane. 0.81 g (2.23 mmol) S-Trityl-L-cysteinamide, 0.39 ml (2.23 mmol) N,N-diisopropylethylamine and 0.85 g (2.23 mmol) HATU were added. The reaction mixture was stirred at room temperature for 3 h. From the reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 70 ml silica gel. Solvents used were dicloromethane/methanol 20/1 to dichloromethane/methanol 5/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.38 g (2.03 mmol, 91% of theory, 76% purity) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].Cl>O1CCOCC1.C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC1CC1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1nc(C(=NOC2CC2)C(=O)O)cs1
Temperature: 33 °C
Reaction time: 1.5 h
Yield: 157.2 %

Procedure:
To a solution of ethyl 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(1.88 g) in 1,4-dioxane (16.7 ml) was added 1N sodium hydroxide (16.7 ml). The mixture was stirred for 1.5 hours at 33° C. After the mixture was cooled under ice-bath, 1N hydrochloric acid (16.7 ml) was added to the mixture. The mixture was concentrated in vacuo to give a residue. The residue was suspended in ethanol, concentrated in vacuo and triturated with ethyl acetate to give crude 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetic acid (syn isomer)(2.63 g). This compound was used for Preparation 33 without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH:20]=[CH2:19])=[CH:17][C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCBr
Reactant: Oc1ccc2c(CCc3ccccc3)csc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(CCc3ccccc3)csc2c1
Reaction time: 2.5 h

Procedure:
A stirred solution of the product from Step E (4.651 grams) in dry DMF (40 mL) was exposed to allyl bromide (1.66 mL) followed by cesium carbonate (6.26 grams). After 2.5 hours at ambient temperature, the reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Evaporation gave a residue which, when chromatographed over silica gel (3:1 hex/CH2Cl2), gave the title compound, a clear oil.
Reaction SMILES: C([O:4][C@H:5]1[CH:9]=[CH:8][C@@H:7]([OH:10])[CH2:6]1)(=O)C.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:19]([Si:16]([CH3:18])([CH3:17])[O:4][C@H:5]1[CH2:6][C@@H:7]([OH:10])[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C=C[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-(+)-4-cyclopentene-1,3-diol 1-acetate (1.0 g, 7.03 mmol) (Aldrich) and imidazole (960 mg, 14.06 mmol) (Aldrich) in tetrahydrofuran (35 mL) was added tert-butyldimethylsilyl chloride (1.27 g, 8.44 mmol) (Aldrich). The mixture was allowed to warm slowly to room temperature, stirred overnight and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was dissolved in methanol (45 mL). To this solution was added potassium carbonate (1.17 g, 8.44 mmol) and the mixture stirred overnight. The next morning the reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by silica gel column chromatography with a 0–30% diethyl ether in hexanes gradient to give (−)-(1R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol as a colorless oil. (Yield 1.29 g, 85%).
Reaction SMILES: [C:1]([CH2:7][C:8]([O:10]CC)=O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].O.[NH2:14][NH2:15].O>C(O)C>[C:2]([CH:1]1[CH2:7][C:8](=[O:10])[NH:15][NH:14]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CC(=O)NN1

Procedure:
1.0 kg of ethyl pivaloylacetate was dissolved in 2.5 liters of ethanol and 320 g of hydrazine hydrate was added dropwise thereto while cooling with water. After the addition, the whole was reacted for one night at room temperature and then 5.0 liters of water was added thereto and the system stirred. The crystals precipitated out were filtered out under reduced pressure, washed fully with water, then with a small amount of methanol and then dried with air. Yield: 812 g, 98.5%.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9](OC(C)(C)C)=O)#[N:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.[Cl-].[NH4+]>C(OCC)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:9]2[NH:2][C:1]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[C:3]3[C:4]=2[CH2:5][CH2:6][CH2:7][CH2:8]3)=[CH:19][CH:18]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCC[C@@H]1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Fc1ccc(-c2[nH]c(-c3ccc(F)cc3)c3c2CCCC3)cc1
Reaction time: 2 h

Procedure:
A solution of 14.75 g of the compound of Step A diluted with 30 ml of ethyl ether is added dropwise, at 35° C., to 80 ml of a 2M solution of 4-fluorophenylmagnesium bromide in ethyl ether. After 2 hours, the reaction mixture is cooled and hydrolysed with 20 ml of a saturated ammonium chloride solution. After filtration and washing with ethyl ether, the organic phases are combined and dried over calcium sulphate and then concentrated. The product is isolated by chromatography on silica gel (eluant: cyclohexane/ethyl acetate:97.5/2.5). Crystallisation yields 2 g of the product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14](=[O:15])[CH2:13][CH2:12][Cl:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl benzene (31 ml, 200 mmol) and 3-chloro-propionyl chloride (19 ml, 200 mmol) in methylene chloride (75 ml) was added dropwise to a suspension of aluminum chloride (29.33 g, 220 mmol) in methylene chloride (300 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 hours, and quenched with water dropwise. The reaction mixture was washed with water, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound which was used without further purification in the next step.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH3:13])[CH2:10][CH2:11][SH:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:12][CH2:11][CH2:10][CH:9]([CH3:13])[CH3:8])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 47.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 3-methylbutane-1-thiol (1 ml, 8.0 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (120 mg, yield 48%).
Reaction SMILES: O[CH:2]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5].S(Cl)([Cl:15])=O>>[Cl:15][CH:2]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5]
Reactant: CCC(=O)NC(O)C(Cl)(Cl)CCl
Reactant: O=S(Cl)Cl
Product: CCC(=O)NC(Cl)C(Cl)(Cl)CCl

Procedure:
5.8 gm of N-(1-hydroxy-2,2,3-trichloropropyl)-propionamide were admixed with 20 ml of thionyl chloride, and the mixture was refluxed for 30 minutes. Subsequently, the reaction mixture was evaporated in vacuo. The crude N-(1,2,2,3-tetrachloro-n-propyl)-propionamide thus obtained was dissolved in 30 ml of tetrahydrofuran, and, while stirring, the solution was added to a solution of 1.75 gm of 1,2,4-triazole and 4.2 ml of triethylamine in 30 ml of tetrahydrofuran. After standing for 3 hours at room temperature, the reaction solution was admixed with water, and the tetrahydrofuran was distilled off in vacuo. A quickly solidifying oil was obtained, and the crystallizate was recrystallized from methanol/water. Yield: 4.6 gm; m.p. 167° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Na+].S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.26 mmol) of ethyl 4-(2-(tert-butoxycarbonylamino)ethyl)benzoate in 40 mL of dry THF under a nitrogen atmosphere was added dropwise, 4.7 mL (4.7 mmol) of NaHMDS (1.0 M in THF) at 0° C. After stirring for 10 min, 0.50 mL (5.3 mmol) of dimethyl sulfate was added and the reaction was warmed to 22° C. and stirred for about 16 h. The reaction was quenched by adding 25 mL of saturated NaHCO3 and the mixture was extracted with DCM (2×25 mL). The combined organic extracts were dried (Na2SO4) and evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 10% ethyl acetate/hexane to give ethyl 4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate as a colorless oil.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:34][CH:33]([CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.4 min, 97.7% purity.