Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O:14][C:15](=O)/[CH:16]=[C:17](/[O:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH2:29][CH3:30])[C:22]=1[F:31])\[CH2:18]Br)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:18][C:17]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH2:29][CH3:30])[C:22]=2[F:31])=[CH:16][C:15]1=[O:14])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)/C=C(\CBr)Oc1c(F)ccc(OCC)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OC)C2)c1F
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a solution of (L)-leucine methyl ester hydrochloride (6.00 g, 0.033 mol) dissolved in acetonitrile (50 mL) was added (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (6.05 g) in acetonitrile (10 mL) and N,N-diisopropylethylamine (7.27 g, 0.056 mol) and the resulting mixture refluxed for 14 h. The reaction mixture was cooled to room temperature and then poured into ethyl acetate. The mixture was filtered to remove salts and the filtrate washed successively with saturated ammonium chloride, water, and brine. The solution was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in tetrahydrofuran (10 mL) and then transferred to an Emry Optimizer microwave reaction vessel and heated at 160° C., for 4 h. The crude product obtained after aqueous work-up, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 100 g, 5% to 60% ethyl acetate/hexanes) to afford (S)-2-[4-(3ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.80 g, 28%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:20])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([Cl:20])=[O:13])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(SC(C)(C)CC(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(SC(C)(C)CC(=O)Cl)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-(4-methoxy-pbenylsulfanyl)-3methyl-butyric acid (20.0 g. 83.2 mmol) in 250 mL of benzene at room temperature was added a solution of oxalyl chloride (15.84 g. 124.8 mmol) in 10 mi of benzene over 30 minutes. After 4 h, the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure) followed by ice cold H2O, and finally saturated aqueous NaCl. The solution was dried (Na2SO4) and concentrated under reduced pressure to give a clear yellow oil. This material (3(4-methoxy-phenylsulfanyl)3-methyl-butyroyl chloride) was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ: 7.45 (2H, d, J=8.8 Hz), 3.84 (3H, s), 3.12 (2H, s, 1.41 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:13][CH:14]=2)=[O:38])=[N:6][CH:7]=1
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(S(=O)c2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
To a stirred solution of 6n (1.0 g, 2.11 mmol) in DCM (50 mL) at 0° C. was added MCPBA (0.364 g, 2.11 mmol) in portions. The resulting mixture was stirred at room temperature for 6 h and then diluted with water and made slightly basic with Na2CO3 solution. The DCM layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried and evaporated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-methanol 5:1) to give 8g, yield 48%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.38 (br, s, 1H), 9.15 (s, 2H), 8.20 (m, 1H), 7.88 (m, 1H), 7.72-7.80 (m, 6H); EI-MS m/z 489 [M]+, 491 [M+2]+; HRMS calculated for C18H12BrN5O5SNa [M+Na]+: 511.9634, found: 511.9632. Anal. (C18H12BrN5O5S) C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([OH:25])=O)[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N.O1CCOCC1.C([N:57](CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:8]([N:15]1[C@@H:20]2[C@H:21]([C:23]([NH2:57])=[O:25])[CH2:22][C@@:16]1([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:29]=1)[CH2:18][CH2:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 24 h
Yield: 56 %

Procedure:
A solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 53; 2.7 mmol) was treated with ammonia solution in dioxane (0.5M, 10 ml, 5 mmol), triethylamine (0.6 ml, 4.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (960 mg, 5.02 mmol), and 4-N,N-dimethylaminopyridine (120 mg, 1 mmol). The mixture was stirred for 24 hours, diluted with ethyl acetate (100 ml), washed with 10% aqueous citric acid, saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (850 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1([NH:18][C:19](=[O:21])[CH3:20])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([NH:18][C:19](=[O:21])[CH3:20])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC(=O)NC1(C)CCCN(c2c([N+](=O)[O-])cnn2C)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)NC1(C)CCCN(c2c(N)cnn2C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of N-(4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (330 mg, 1.11 mmol) in a mixture of EtOH (25 mL) and water (2.5 mL) was added ammonium chloride (300 mg, 5.55 mmol) and iron powder (250 mg, 4.44 mmol). The reaction mixture was heated at 100° C. for 2 hr before being cooled, filtered through Celite® and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and DCM (40 mL) and the organic layer was separated, washed with brine (20 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-yl)acetamide as a brown solid which was used without further purification. Following the procedure for Example 149 using this intermediate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 378 as an off-white foam (54 mg, 19% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.86 (s, 1H), 7.39-7.29 (m, 1H), 7.07-6.99 (m, 2H), 6.15 (s, 2H), 5.38 (s, 1H), 3.74 (s, 3H), 3.30-3.18 (m, 4H), 3.12 (ddd, J=13.6, 6.6, 3.1 Hz, 1H), 2.30-2.19 (m, 2H), 2.00-1.72 (m, 6H), 1.45 (s, 3H). LCMS (ES+) m/z 504 (M+1)
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C\CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC/C=C\COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[I-]>C(C(C)=O)C>[CH2:2]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCCCCOc1ccc(C=O)cc1

Procedure:
A mixture of 11-bromoundec-1-ene (2.02 g), 4-hydroxy-benzaldehyde (1.06 g, 8.6 mmol), potassium carbonate, potassium iodide and tetra-n-butylamomnium iodide was heated at reflux in methyl ethyl ketone (10 ml) for 16 hours. After cooling, the solids were filtered off and washed with acetone. The combined organic fractions were evaporated to dryness. The crude product obtained was filtered through a pad of silica gel which was eluted with petroleum ether (b.p. 40-60° C.) to remove the excess of bromoundecene. The silica gel was then eluted with acetone and the acetone fractions evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [Li+].[BH4-].[CH:3]1([C@H:6]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]([C:18](OC)=[O:19])[C:8](=[O:22])[CH2:7]2)[CH2:5][CH2:4]1>C1COCC1.CCOC(C)=O>[CH:3]1([C@H:6]2[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:9]([CH2:18][OH:19])[CH:8]([OH:22])[CH2:7]2)[CH2:4][CH2:5]1
Reactant: COC(=O)C1C(=O)C[C@@H](C2CC2)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CO)C(O)C[C@H]1C1CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
LiBH4 (0.5 g, 23.3 mmol) was added to a solution of (5S)-1-tert-butyl 2-methyl 5-cyclopropyl-3-oxopyrrolidine-1,2-dicarboxylate (31) (2.2 g, 7.76 mmol) in THF (20 mL). The reaction mixture was stirred at 60° C. for 18 h after which HPLC indicated that the reaction was compete. The resulting solution was diluted with EtOAc (20 mL) and washed with sat. aq. NaHCO3 (20 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-tert-butyl 5-cyclopropyl-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (32). Retention time (min)=1.484 method [1], MS (m/z) 280.2 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:26]=[C:27]([CH2:31]O)[CH:28]=[CH:29][CH:30]=3)=[N:23][CH:24]=2)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:22]4[N:23]=[CH:24][C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)=[CH:20][N:21]=4)[CH:26]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCN(C)CC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
67 mg (0.44 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one and 125 mg (0.44 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}methanol are suspended in 5 ml of DMF with 222 mg (0.67 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g), and the mixture is shaken at room temperature for 30 min. 156 mg (0.67 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 15 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by column chromatography on silica gel, giving 67 mg of “A125”; HPLC: Rt=2.20 min (method B); ESI: 418 (M+H);
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]1)[CH3:2].Br[C:32]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([Cl:47])[CH:38]=2)[S:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[Cl:47][C:39]1[CH:38]=[C:37]([C:35]2[S:34][N:33]=[C:32]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:24]4)[CH:5]=[CH:6][CH:7]=3)[N:36]=2)[CH:42]=[CH:41][C:40]=1[O:43][CH:44]([CH3:45])[CH3:46]
Reactant: CCOC(=O)CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Yield: 30.7 %

Procedure:
A solution of ethyl (4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinyl)acetate (D144) (200 mg, 0.481 mmol), 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (161 mg, 0.481 mmol), tripotassium phosphate (307 mg, 1.444 mmol) and Pd(Ph3P)4 (55.6 mg, 0.048 mmol) in N,N-Dimethylformamide (DMF) (6 mL) and Water (1.500 mL) was heated by Biotage Initiator to 120° C. for 15 min. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by ISCO column chromatography to afford ethyl (4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)acetate (D145) (80 mg). MS (ES): C29H36ClN3O3S requires 541.2. found 542.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A 12 L flask was charged with 4-bromo-3-methyl phenol (428 g, 2.29 mol), CH2Cl2 (7.5 L), triethylamine (480 mL, 3.45 mol), and tert-butyldimethylsilyl chloride (324 g, 2.15 mol). To the solution was added 4-dimethylaminopyridine (15.0 g, 0.123 mol). The reaction mixture was stirred at ambient temperature overnight. The reaction was washed with saturated ammonium chloride (2.2 L) and then DI water (0.9 L). The organic layer was dried (Na2SO4), filtered, and concentrated to crude product (699 g). This material was purified by silica gel chromatography (heptane) to give the title compound (637 g, 98.5%).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1>>[C:2]([C:1]([N:14]([C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:5])(=[O:3])[CH3:4]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Product: CC(=O)C(=O)N(c1ccc(Cl)cc1)[C@H](C(=O)O)C(C)C

Procedure:
Following the procedure of Example 47, the m-phenoxybenzyl ester of N-acetylformyl,N-(4-chlorophenyl)valine [MS m/e 479 (M+, 0.5), 183 (100)] is prepared by the reaction of the acid chloride of pyruvic acid with the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(O)cc1

Procedure:
4-Hydroxybenzoic acid (11.04 g.) was heated under reflux with thionyl chloride (80 ml.) containing dimethylformamide (0.1 ml.) for 2 hours. The solution obtained was evaporated. The residue was dissolved in toluene and the subsequent solution was evaporated. The residue obtained (which contained 4-hydroxybenzoyl chloride) was dissolved in methylene chloride (80 ml.). The solution obtained was treated dropwise with 1,2,3,6-tetrahydropyridine to pH7 with stirring and ice-cooling. The mixture was further stirred at 25° C. after the addition was complete for 2 hours and then evaporated. The residue was stirred with water and the solid was collected by filtration and then washed with water and acetone. After recrystallisation from a mixture of ethanol and ethyl acetate, there was obtained 1-(4-hydroxybenzoyl)-1,2,3,6-tetrahydropyridine (11.3 g.), m.p. 202°-206° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35].C1CCN2C(=NCCC2)CC1>ClCCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2c(C)nc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1
Temperature: 100 °C

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5 ml) and treated with triethylorthoacetate [Aldrich] (2 ml) then heated to 100° C. for 12 h. The mixture was cooled and DBU (0.1 ml) introduced. The solvent was evaporated then the residue purified by flash chromatography on silica gel (eluting with aq. ammonia-methanol-dichloromethane) to obtain the title compound as a white solid;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>N1C=CC=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 50 °C
Yield: 8.6 %

Procedure:
1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.23 mmol) was dissolved in pyridine (1 mL). Dimethylcarbamyl chloride (0.21 mL, 2.3 mmol) was added and the mixture was heated at 50° C. for 18 h. Solvent was removed in vacuum and the residue was purified using reverse phase prep HPLC to afford the title compound as a pale tan solid (10 mg). 1HNMR (500 MHz, DMSO-D6) δ 8.89 (s, 1H), 8.25 (s, 1H), 7.70-7.59 (m, 5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m, 2H), 3.11 (s, 3H), 2.88 (s, 3H). LCMS: m/e 507 (M+H)+, ret time 1.04 min (method 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22]Cl)=[CH:14]1)(=[O:12])=[O:11].[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:14]1)(=[O:12])=[O:11]
Reactant: C1CNCCNC1
Reactant: COc1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)c(Br)c1
Product: COc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3ccccc32)c(Br)c1

Procedure:
Using essentially the same procedure as described in example 127, 1-(2-Bromo-4-methoxybenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15]([OH:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[NH2:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1.[C:15]([NH:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Reactant: O=C(O)c1cccnc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1
Product: O=C(Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1)c1cccnc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.9 g of benzoguanamine and 2.6 g of nicotinic acid are dissolved in 50 ml of pyridine, and the mixture is further mixed with 2.5 g of methanesulfonyl chloride and agitated at 60° C for 3 hours. Following processing as described in Example 4, there is obtained 0.11 g of 2-amino-4-nicotinamido-6-phenyl-s-triazine [mononicotinoylbenzoguanamine] and 1.05 g of 2,4-bis(nicotinamido)-6-phenyl-s-triazine (dinicotinoylbenzoguanamine).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].O=C(Cl)[O:22][C:23](Cl)(Cl)Cl.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>>[CH3:28][N:29]([CH2:30][CH2:31][CH3:32])[C:23]([N:16]1[CH2:17][CH2:18][C:11]2([C:10](=[O:19])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:13][CH2:12]2)[CH2:14][CH2:15]1)=[O:22]
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Reactant: CCCNC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCCN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(CC)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and methyl-propyl-amine. MS (ESI): 358.4 (MH+).