Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][C:16]([NH2:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>C(O)C>[C:16]([NH:19][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:18])([CH3:17])[CH3:15]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC(C)(C)C
Temperature: 60 °C
Yield: 92 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3 g, 12.89 mmol), 2-methylpropan-2-amine (1.565 mL, 14.83 mmol) and DIEA (2.93 mL, 16.76 mmol) in ethanol (20 mL) was heated at 60° C. overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated to give ethyl 4-(tert-butylamino)-2-(methylthio)pyrimidine-5-carboxylate (3.20 g, 11.86 mmol, 92% yield) as a colorless oil. MS (ESI) m/z. 269.5 [M+1]+.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH2:14]([O:13][C:11]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (15 g, 0.10 mol), benzyl chloroformate (17 ml, 0.12 mol) and sodium bicarbonate (25 g, 0.50 mol in dioxane (120 ml) and water (100 ml) was stirred at room temperature for 48 hours. Water was added and the mixture was extracted with methylene chloride; the organic layer was washed with brine and dried over magnesium sulfate. Upon evaporation, the title compound was obtained as a colorless liquid (21.7 g, 0.093 mol, yield 93%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(pyridin-3-yl)acetamide (0.052 g, 0.12 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.025 g, 0.17 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was heated at 70° C. for 5.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% dichloromethane in ethyl acetate and then 3% methanol in ethyl acetate/dichloromethane (v/v; 8:2). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.022 g, 34%); 1H-NMR (500 MHz, DMSO-d6) 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.72 (br s, 4H, piperazine N(CH2)2), 3.27 (s, 2H, NCH2CO), 6.82 (d, J=9.07 Hz, 2H), and 8.01 (d, J=9.41 Hz, 2H) (3,5-C6H4—NMe2 and 2,6-C6H4—NMe2), 7.34 (dd, J=9.41, 4.70 Hz, 1H, pyridyl 5-H), 8.12 (d, J=8.46 Hz, 1H, pyrid-3-yl), 8.16 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.27 (d, J=4.70, 1H, pyrid-3-yl), 8.85 (s, 1H, pyridyl 2-H), 10.04 (s, 1H, CONH), 13.15 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z): Rt=5.30 min—535, 537 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 535.1596, calculated for C25H28BrN8O (M+H)+: 535.1569.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][C@@H:21]([NH2:23])[CH2:20][CH2:19][C@H:18]2[CH3:24])[N:3]=1.[C:25]([O-:28])(O)=[O:26].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:28][C:25](=[O:26])[NH:23][C@H:21]2[CH2:20][CH2:19][C@@H:18]([CH3:24])[N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:22]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: C[C@@H]1CC[C@H](N)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-{2-amino-6-[(2R,5S)-5-amino-2-methyl-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (170 mg, 0.426 mmol) in THF (4 mL) was added saturated aqueous NaHCO3 (2 mL) followed by phenylmethyl chloridocarbonate (0.07 mL, 0.47 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with 3 mL of water and then extracted with EtOAc (3×30 mL). The organic was then washed with brine, dried over MgSO4, filtered and concentrated. The resulting yellow oil was purified on a Biotage SNAP 10 g column with gradient of 0 to 50% EtOAc in hexane over 30 minutes to afford the title compound (57 mg) as a yellow oil. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:18](=[N:25][NH:26][C:27](=[O:29])[CH3:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO>C(Cl)Cl>[C:19]1([C@H:18]([NH:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:3][CH:2]=[CH2:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Reactant: CC(=O)NN=Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: C=CC[C@@H](NNC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
Enantioselective allylation of acetic acid benzylidene-hydrazide (8) to give (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide: To a cooled (10° C.) solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (9.90 g, 37.0 mmol) in CH2Cl2 (300 mL) was added acetic acid benzylidene-hydrazide (5.00 g, 30.8 mol) as a solid. The resulting solution was stirred for 16 hours and methanol (40 mL) was then added. After 15 min all volatiles were removed by distillation and the residue was diluted with EtOAc (150 mL) and H2O (500 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were washed with H20 and brine, dried (MgSO4), filtered and concentrated. Analysis of the residue by HPLC revealed an ee of 87%. The residue was dissolved in boiling toluene (80 mL) and the solution was then cooled to ambient temperature. Pentane (380 mL) was layered on top of the toluene solution and the resulting biphasic solution was allowed to stand for 16 hours. The resulting crystalline solid precipitate was filtered, washed (pentane:toluene (5:1)) and then dried in vacuo to give 5.04 g (80%) of (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide in 98% ee.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([N:18]([CH3:25])[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[CH:14][CH:13]=1>CN(C)C(=O)C>[CH:19]1([N:18]([CH3:25])[C:16](=[O:17])[C:15]2[CH:26]=[CH:27][C:12]([CH2:11][N:1]3[CH:9]=[C:8]4[C:4](=[N:5][CH:6]=[N:7]4)[N:3]=[CH:2]3)=[CH:13][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Reactant: c1ncc2[nH]cnc2n1
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1ccc(Cn2cnc3ncnc-3c2)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 35.5 %

Procedure:
To a stirred solution of purine (300 mg, 2.5 mmol) in N,N-dimethylacetamide (30 mL) was added 4-bromomethyl-N-methyl-N-cyclohexyl benzamide (852 mg, 2.75 mmol). After stirring at 80° C. for 7 hr, the reaction was stirred at room temperature for 16 hr. The solvent was removed under reduced pressure and the residue (510 mg) chromatographed (silica gel, CH2Cl2 /MeOH/90/10) to give 9 (310 mg, 35%); m.p. 229°-30° C. Anal calcd. for C20H23N5O: C, 68.71; H, 6.61; N, 20.05. Found: C, 68.24; H, 6.79; N, 19.77.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)OCC[O:15]2)=[CH:10][C:9]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6])=[N+]=[N-]>C1COCC1.[Pd].C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:5](=[O:6])[CH2:4][N:1]=[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:9]=3[CH:10]=2)=[O:15])=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=NCC(=O)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Yield: 2.4 %

Procedure:
Intermediate (26) (0.1052 mol) in THF (220 ml) was hydrogenated with Pd/C (0.6 g) as a catalyst at room temperature for 8 h under a 2 bar pressure in a Parr apparatus. After uptake of H2, the catalyst was filtered over celite and the filtrate was evaporated till dryness. The residue (47.9 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1) (35–70 μm). The pure fractions were collected and evaporated and the residue was crystallized from 2-propanone/DIPE giving 14.86 g (31%). A sample (1.35 g) was taken up in hot ethanol and filtered off, yielding 0.93 g (70%) of 7-(4-chlorobenzoyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (intermediate 27), mp. 230° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](O)=[O:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]([CH3:7])[C:3](=[O:4])[CH:2]([Br:1])[CH3:6]
Reactant: CNc1ccccc1F
Reactant: CC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2-Bromopropionic acid (3.4 g, 0.022 mol) and N-methyl-2-fluoroaniline(3 g. 0.024 mol) were dissolved in 50 ml of chloroform and cooled to 0° C. A solution of dicyclohexylcarbodiimide(5 g, 0.024 mol) in 10 ml of chloroform was slowly injected through a syringe. A temperature of the reaction mixture was raised to room temperature and it was stirred for 1 hour. Solid remained during the reaction was filtered out and washed twice with 20 ml of chloroform. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent; ethyl acetate/n-hexane=⅓) to afford 5 g of the target product.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH:21](OCC)=[O:22]>C(Cl)Cl>[C:2]([O:6][C:7](=[O:11])[C@@H:8]([NH:9][CH:21]=[O:22])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC=O)C(=O)OC(C)(C)C

Procedure:
To a suspension of (2S) alanine tert-butyl ester hydrochloride (3.63 g, 20 mmol) in a mixture of ethyl formate (10 mL) and DCM (5 mL) was added diisopropylethylamine (3.83 mL, 22 mmol) and the reaction mixture was refluxed overnight. The solvents were evaporated and the residue was then triturated in Et2O and filtrated. The filtrates were evaporated and the residue was filtered through a short pad of silica using ethyl acetate as eluent. Evaporation of the solvent afforded the sub-title compound as a colorless oil which crystallised upon standing (2.806 g, 81%): 1H NMR (400 MHz CDCl3) δ 1.43 (3H, d), 1.50 (9H, s), 4.55 (1H, m), 6.31 (1H, br s), 8.16 (1H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([NH:62][CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([NH:62][CH3:63])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CCOP(=O)(CC(=O)NC)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)NC
Yield: 89.7 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in the Reference Example 3-1); 4.60 g, 10.0 mmol), dimethyl sulfoxide (1.99 ml, 28.0 mmol), oxalyl chloride (1.28 ml, 15.0 mmol), triethylamine (6.98 ml, 50.0 mmol), 2-(diethylphosphono)-N-methylacetamide (2.32 g, 11.0 mmol) and 60% sodium hydride (420 mg, 10.5 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 100 ml, elution with hexaneethyl acetate 1:2) to give the title compound (4.60 g, 89.7% yield).
Reaction SMILES: O.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:25][OH:26])[CH3:24])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>CO>[Br:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([CH:11]=[N+:25]([CH:23]([CH3:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[O-:26])=[O:10]
Reactant: O=CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(CC(C)NO)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(C)[N+]([O-])=CC(=O)c2cccc(Br)c2)cc1

Procedure:
2.31 g (10 mmol) of 3-bromophenylglyoxal hydrate, 2.175 g (20 mmol) of N-(2-(4-methoxyphenyl)-1-methylethyl)hydroxylamine hydrochloride and 820 mg (10 mmol) of sodium acetate were stirred in 50 ml of absolute methanol at room temperature for 4 hours. After filtration, the fitrate was evaporated, 50 ml of water were added to the residue and the mixture was extracted with methylene chloride (3×25 ml).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3][CH3:4].[NH3:22]>CO>[NH2:22][C:10]1[N:9]=[C:8]([CH3:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: N
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(N)c1[N+](=O)[O-]

Procedure:
177.9 g. of 4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) dissolved in 500 ml. of methanol are heated with 300 ml. of aqueous ammonia (30%) in an autoclave at about 60° for 10 hours. After this time, the solvent is distilled off and the residual 6-amino-4-butylamino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is recrystallized from methanol, yield 135 g.; m.p. 98°-99°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].BrBr.BrC(C1C=CC(S(C)(=O)=O)=C(F)C=1)C(=O)C.[C:34]([NH:37][C:38]([NH2:40])=[S:39])(=[O:36])[CH3:35]>O1CCOCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:39][C:38]([NH:37][C:34](=[O:36])[CH3:35])=[N:40][C:13]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Reactant: CC(=O)NC(N)=S
Agent: BrBr
Agent: CC(=O)C(Br)c1ccc(S(C)(=O)=O)c(F)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (Example 64c) (1.0 g, 4.34 mmol) is dissolved in dioxane (35 ml) and the solution is cooled to 10° C. at which point the mixture is semi frozen. Bromine (0.067 ml, 1.2 mmol, 0.3 eq.) is added slowly and the mixture is stirred for an additional 15 min in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (30 ml) and N-acetylthiourea (0.369 g, 3.1 mmol) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the product crystallised. Filtration affords the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]2[CH2:9][CH2:8]2)[C:3]=1[CH3:10].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:7]1([C:4]2[C:3]([CH3:10])=[C:2]([NH:1][S:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:19])=[O:18])[O:6][N:5]=2)[CH2:9][CH2:8]1
Reactant: Cc1c(C2CC2)noc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1c(C2CC2)noc1NS(=O)(=O)c1ccccc1
Yield: 62 %

Procedure:
This compound was prepared as described in Example 42 from 5-amino-3-cyclopropyl-4-methylisoxazole and benzenesulfonyl chloride in 62% yield. The crude product was preparative HPLC to give a viscous colorless oil.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc(-c2nn[nH]n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3nn[nH]n3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2H-tetrazol-5-yl)benzoic acid (example 412, 4 mmol) and HOAt (4.2 mmol) in DMF (6 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.2 mmol) and the resulting mixture was stirred at room temperature for 1 hour. An aliquot of this HOAt-ester solution (0.45 mL) was mixed with 0.25 mL of a solution of 4-aminobenzoic acid (1.2 mmol in 1 mL DMF). (Anilines as hydrochlorides can also be utilised, a slight excess of triethylamine was added to the hydrochloride suspension in DMF prior to mixing with the HOAt-ester.) The resulting mixture was shaken for 3 days at room temperature. 1N hydrochloric acid (2 mL) was added and the mixture was shaken for 16 hours at room temperature. The solid was isolated by centrifugation (alternatively by filtration or extraction) and was washed with water (3 mL). Drying in vacuo at 40° C. for 2 days afforded the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4]([O:8][C:9]([NH:11][C:12]1[C:17]([C:18]([O:20]C)=O)=[CH:16][C:15]([F:22])=[N:14][CH:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[F:22][C:15]1[N:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[C:17]([C:18](=[O:20])[CH2:2][C:1]#[N:3])[CH:16]=1
Reactant: CC#N
Reactant: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)CC#N
Reaction time: 1 h

Procedure:
To 140 mL of 2.5 M n-butyllithium/hexanes in 300 mL of tetrahydrofuran at −78° C. was slowly added 14.4 g of anhydrous acetonitrile in 100 mL of tetrahydrofuran. After 30 minutes was added 32 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester in 100 mL of tetrahydrofuran. After a further 60 minutes, the reaction was quenched with 35 mL of glacial acetic acid. The reaction was diluted with equal volumes of ethyl acetate and saturated sodium bicarbonate and the aqueous phase was washed twice with ethyl acetate. The pooled organic phases were washed with saturated sodium bicarbonate, dried, and stripped of solvent. This material was further purified by passing through a plug of silica gel with a gradient of 0-5% methanol/chloroform to give a crude product that was used as is for the following step. This material can be further purified by recrystallization from chloroform/hexanes to give a white, crystalline solid: melting point 106-115° C.; mass spectrum (m/e): M+H 279.9.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:10]4[S:11][C:7]([CH2:6][NH:5][CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])=[CH:8][CH:9]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CC(C)CCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCC(C)C)s4)cc23)CC1
Yield: 37 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 46 mg of crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 38.3 mg of the title compound (37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1)[NH2:6].Br[CH:20]([CH2:25][CH2:26][CH2:27]Br)[CH2:21][C:22]([O-:24])=[O:23].C(N(CC)CC)C>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]2[CH2:27][CH2:26][CH2:25][CH:20]2[CH2:21][C:22]([OH:24])=[O:23])[CH:7]=[C:8]([C:10]([CH3:17])([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1
Reactant: O=C([O-])CC(Br)CCCBr
Reactant: CCCCCCC(C)(C)c1cc(N)cc(OC)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cc(OC)cc(N2CCCC2CC(=O)O)c1
Reaction time: 1 h

Procedure:
A mixture of 24.9 g. (0.10 mole) 3-methoxy-5-(1,1-dimethylheptyl)aniline, 34.5 g. (0.12 mole) methyl dl-3,6-dibromocaproate, 15 g. triethylamine and 100 ml. ethyl ether is stirred under nitrogen at room temperature for 20 hours. The ether is evaporated and the residue heated at 90°-120° C. for three hours. Additional methyl dl-3,6-dibromocaproate (5 g.) and triethylamine (5 g.) is added and heating continued at 90° C. for 2 hours and finally at 120° C. for one hour. The reaction mixture is worked up as described in Example 16 to provide the methyl ester of the desired product which is hydrolyzed in methanolic sodium hydroxide by the method of Example 17 to provide the title acid.