Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[C:4]([C:16]([NH2:18])=[O:17])=[N:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)[C:7]=1[CH3:8])C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C1(C)C=CC=CC=1.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>[CH3:8][C:7]1[N:6]([C:9]2[CH:10]=[C:11]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([NH2:18])=[O:17])[CH:3]=1
Reactant: CCc1c(C(N)=O)nn(-c2cccc(Br)c2)c1C
Reactant: OB(O)c1ccccc1OC(F)(F)F
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: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: Cc1cc(C(N)=O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 90 °C
Yield: 93.4 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxamide (0.237 g, 0.8 mmol) and 2-trifluoromethoxyphenyl boronic acid (0.262 g, 1.2 mmol) in n-propanol/toluene (1.27 ml:0.42 ml) mixture were added tetrakis(triphenylphosphine)palladium (0.019 g, 0.01 mmol) and 2M sodium carbonate (0.84 ml). The reaction mixture was heated at 90° C. for 16 hours, and then cooled and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate and concentrated. The crude product was purified by silica-gel column chromatography (3.5:1.5 hexanes/acetone) to give the product (0.270 g, 88%) as a solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][N:13]2[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14]2)[CH2:11][CH2:10]1.[Br:34]Br>O1CCCC1>[Br:34][CH:18]1[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:14][N:13]([CH2:12][CH:9]2[CH2:10][CH2:11]2)[C:19]1=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CC2CC2)CC1c1ccccc1
Reactant: BrBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Br)C(=O)N(CC2CC2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (1 M in THF; 2.13 mL, 2.13 mmol) was added to tert-butyl 4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-diazepane-1-carboxylate (0.489 g, 1.42 mmol) in tetrahydrofuran (5 mL) at −78° C. After 30 min, the enolate solution was transferred dropwise via cannula to a solution of bromine (0.36 mL, 7.10 mmol) in tetrahydrofuran (3 mL) at −78° C. over a period of 5 min. After 15 min, the mixture was quenched with aqueous saturated sodium sulfite and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate, washed with saturated 50 aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated. MS 423 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([C:41]5[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCOC[C@@H]5O)cnc4c4ccccc34)cn2)cn1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.095 mmol) in 1 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 N aqueous, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 85° C. for 20 h, and additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %) were added. After 24 h, the reaction was cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 467.53 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J=7.9 Hz, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.80-7.78 (m, 2H), 7.72 (s, 2H), 7.66-7.55 (m, 2H), 7.22-7.19 (m, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.80-4.73 (m, 1H), 4.28-4.15 (m, 1H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 3.61-3.51 (m, 1H), 3.34-3.29 (m, 1H), 2.28-2.18 (m, 1H), 1.99-1.95 (m, 1H).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:4]=2[O:3]1.C([Li])CCC.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.CCCCCC>[Cl:20][C:7]1[C:5]2[O:6][C:2]([F:1])([F:14])[O:3][C:4]=2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(Cl)c2c1OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
7.5 g (0.038 mol) of 2,2-difluoro-1,3-benzodioxole-4-carboxylic acid, prepared according to the process described in European Application 0,333,658, are dissolved, with stirring and under an argon atmosphere, in 75 ml of dry tetrahydrofuran (THF). ml (0.081 mol) of n-butyllithium in solution in hexane are run in dropwise at -70° C. After stirring for 1 hour, 8.9 g (0.038 mol) of hexachloroethane in solution in 50 ml of dry tetrahydrofuran (THF) are run in. After 2 hours at -70° C., the temperature is allowed to return to 10° C. The reaction mixture is hydrolysed with 150 ml of ice-cold water and brought to a pH of approximately 1 by addition of 1N hydrochloric acid. The aqueous phase is extracted with ether, dried over magnesium sulphate and concentrated under vacuum. The solid is washed with heptane to give 3.7 g (0.016 mol) of 7-chloro-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (yield: 42%; melting point: 185° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)nc1
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: C1CCOC1
Product: O=C(c1ccc(Br)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
The mixture of 6-bromonicotinic acid (700 mg, 3.5 mmol), morpholine (391 mg, 4.5 mmol), HATU (220 mg, 0.59 mmol) and DIPEA (0.3 mL) in 10 mL of dry THF was stirred at room temperature for 14 hours. The reaction solution was evaporated to dryness. To the residue was added 20 mL of 0.5N hydrochloride, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated to give (6-bromopyridin-3-yl)(morpholino)methanone (750 mg, 79%). LC-MS: 271, 273 [M+H]+, tR=1.290 min.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.CC([O-])(C)C.[K+].O.Cl>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:8])[CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][C:13](=[O:20])[NH:12][C:4]=2[CH:3]=1
Reactant: COC(=O)CCC(=O)Nc1cc(I)ccc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CC(=O)Nc2cc(I)ccc2C1=O
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 4-iodo-2-[(4-methoxy-4-oxobutanoyl)amino]benzoate (24.6 g, 63 mmol) in THF (240 mL) at 10° C. was added a 1 M solution of KOt-Bu in THF (185 mL, 185 mmol) dropwise over 30 min while maintaining the temperature at 10° C. After 2.5 h, 50 mL of H2O followed by 190 mL of 1N HCl were added to bring the solution to pH=4. The resulting mixture was allowed to stir at rt for 40 min. The organic solution was separated and the aqueous solution was extracted with EtOAc (2×200 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give methyl 8-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate (22 g, 97%).
Reaction SMILES: [C:1]1([S:7]([C:10]2([CH2:13][CH:14]3[CH2:16][O:15]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[CH2:25][NH:26][CH2:27][CH2:28][C:29]=1[CH3:30]>C(#N)C>[C:1]1([S:7]([C:10]2([CH2:13][CH:14]([OH:15])[CH2:16][N:26]3[CH2:25][C:24]([CH3:23])=[C:29]([CH3:30])[CH2:28][CH2:27]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)C1(CC2CO2)CC1
Reactant: CC1=C(C)CNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)CN(CC(O)CC2(S(=O)(=O)c3ccccc3)CC2)CC1

Procedure:
Crude 2-(1-benzenesulphonylcyclopropylmethyl)oxirane (500 mg, 2.1 mmol), potassium carbonate (580 mg, 4.2 mmol) and 3,4-dimethyl-1,2,5,6-tetrahydropyridine (470 mg, 4.2 mmol) in acetonitrile (3 ml) were heated at 60° C. for 18 hours. The mixture was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27].[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([N:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH2:35])[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]
Reactant: NNc1ccccc1
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Product: C[C@H](Nc1nc(N(N)c2ccccc2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Yield: 67.8 %

Procedure:
An ethanolic solution of 0.5 g (1.15 mmol) of sulfone 1 and 0.15 g (1.38 mmol) of phenylhydrazine was refluxed for 14 hours. Cooling, distillative removal of the solvent and chromatography on silica gel (cyclohexane:methyl tert-butyl ether [MTBE] 95:5) gave 0.36 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[OH:29])[CH3:21])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12].Br[CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH3:21])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[O:29][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN2C(=O)c3ccccc3C2=O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 60 °C
Yield: 89.1 %

Procedure:
A mixture of 4-(2-amino-3-nitrophenyl)carbonylamino-N-(2-hydroxy-4-methylphenyl)-3-methoxy-N-methylbenzamide (520 mg), N-(4-bromobutyl)phthalimide (326 mg) and potassium carbonate (160 mg) in N,N-dimethylformamide (10 ml) was heated at 60° C. for 8 hours. The mixture was diluted with ethyl acetate and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude oil was purified by silica gel column (1% methanol in chloroform) to give 4-(2-amino-3-nitrophenyl)carbonylamino-3-methoxy-N-methyl-N-[2-(4-phthalimidobut-1-yloxy)-4-methylphenyl]-benzamide (670 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH:32]3[CH2:34][CH2:33]3)[C:35](=[O:37])[CH3:36])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNCC4CC4)c23)ccc1OCc1ccccn1
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)CC1CC1
Yield: 58 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(cyclopropylmethyl)amino]ethoxy}quinazolin-4-amine and acetyl chloride to give the title compound in 58% yield; NMR spectrum (DMSO-d6) 0.16-0.27 (m, 2H), 0.36-0.52 (m, 2H), 0.97-1.06 (m, 1H), 2.00 (s, 3H), 3.24-3.29 (m, 2H), 3.93-4.02 (m, 2H), 4.33-4.56 (m, 2H), 5.31 (s, 2H), 7.13-7.18 (m, 1H), 7.21-7.29 (m, 1H), 7.31-7.40 (m, 2H), 7.54-7.62 (m, 2H), 7.69-7.79 (m, 1H), 7.86-7.92 (m, 1H), 7.93-7.96 (m, 1H), 8.44 (s, 1H), 8.61 (d, 1H), 9.81 (s, 1H); Mass spectrum MH+ 518.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:17][O:18][C:19](=[O:25])[CH2:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClC(Cl)C>[CH3:17][O:18][C:19](=[O:25])[CH2:20][S:21](=[O:23])(=[O:22])[NH:4][C:3]1[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[F:10]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CS(=O)(=O)Nc1c(F)cc(F)cc1F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
0.76 g (5 mmol) of 2,4,6-trifluoroaniline is dissolved in 40 ml of dichloroethane with exclusion of moisture, 0.4 ml (5 mmol) of pyridine is added, 0.86 g (5 mmol) of chlorosulfonyl acetic acid methyl ester, dissolved in 10 ml of dichloroethane, is instilled at 0° C. and then it is stirred for 1 hour at 0° C. and 12 hours at room temperature. The reaction solution is then shaken out twice with 10 ml of 2N hydrochloric acid each, the phases are separated, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. The residue is crystallized from diethyl ether/pentane 1:1. 790 mg (2.79 mmol)=55.79% of the theoretical yield is obtained as a crystallizate. Melting point 99-100° C.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[CH3:10][OH:11]>>[CH3:10][O:11][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CO
Reactant: CC(C)CC(Br)C(=O)Cl
Product: COC(=O)C(Br)CC(C)C

Procedure:
2-Bromo-4-methylpentanoyl chloride (IV, Example 2) is added dropwise to methyl alcohol (200 ml.) at 0°. After two hours the methanol is removed under reduce pressure and the residual oil is partitioned between chloroform and water. The chloroform is separated from the water and removed under reduced pressure to give a residual oil which is distilled under reduced pressure to give the title compound, b.p. 78°-90°/30 mm.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[F:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (500 mg, 1.107 mmol) in DCM (11 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine (266 mg, 1.107 mmol), HBTU (504 mg, 1.329 mmol), and TEA (0.386 mL, 2.77 mmol). This mixture was stirred at room temperature for 18 h before being purified by CombiFlash chromatography to afford 0.6767 g (96%) of the title compound. LC-MS m/z 637 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:6]([N:17]([C:16]2[CH:18]=[CH:19][C:13]([O:12][CH:11]([F:10])[F:20])=[CH:14][CH:15]=2)[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride in 70 ml of toluene is heated to boiling. A solution of 15.9 g (0.1 mole) of p-difluoromethoxyaniline in 30 ml of toluene is added dropwise to it over 20 minutes with stirring. Thereafter, the resulting solution is refluxed until water is no longer distilled. This requires about 2 hours. The mixture is cooled to room temperature to precipitate crystals. The precipitated crystals are filtered off and washed with hexane to obtain 29.2 g of 2,3-dichloro-N-(p-difluoromethoxyphenyl)maleimide melting at 217.5°-218° C. in the form of light yellow plate crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (S)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((S)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 26a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>ClCCl>[CH3:8][O:7][C:5](=[O:6])[CH:4]=[CH:3][CH2:2][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: COC(=O)/C=C/CBr
Solvent: ClCCl
Product: COC(=O)C=CCN1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 4-bromocrotonate (2 g, 11.2 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0° C. Piperidine (1.11 mL, 11.2 mmol) was added slowly. The mixture was stirred at 0° C. for 1 hour. The solvent was removed in vacuo. The crude material was used as is. MS m/z 184 (M+1).
Reaction SMILES: [Br:1][CH:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[BH4-].[Na+]>CO>[Br:1][CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1
Reactant: O=C1c2ccc(Cl)cc2SCC1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2ccc(Cl)cc2SCC1Br
Temperature: 0.5 °C

Procedure:
Suspend 3-bromo-7-chlorothiochroman-4-one (59.6 gms., 215 mmols) in methanol (500 ml.), cool to 0.5° C., and with stirring add sodium borohydride (8.18 gms., 215 mmols) in three portions. Continue stirring the reaction mixture at room temperature for three hours, then pour into ice water (4 liters) and extract with chloroform (2 liters). Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Triturate the residue with chloroform/hexane to give 3-bromo-7-chlorothiochroman-4-ol, m.p. 141°-142° C.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].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.[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67](O)=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: NCC(F)F
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
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: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCC(F)F)c3)ccc2n1CC1CCOCC1
Yield: 1.6 %

Procedure:
Following the same procedure in Example 31, method B, using 2,2-difluoroethylamine (138 mg, 1.7 mmol), N,N-diisopropylethylamine (0.8 ml, 4.4 mmol), HATU (646 mg, 1.7 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (1.1 mmol) in DMF (15 mL). The crude product was purified on LCMS using high pH column 40-70% acetonitrile gradient to afford 9 mg (2% yield) of the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.51 (m, 3 H), 1.51-1.58 (m, 2 H), 1.60 (s, 9 H), 3.22 (q, J=7.36 Hz, 1 H), 3.33 (d, J=2.93 Hz, 1 H), 3.62 (m, 1 H), 3.68-3.76 (m, 1 H), 3.90 (dd, J=10.64, 3.42 Hz, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 5.90 (m, 1 H), 6.68 (dd, J=3.03, 1.46 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.87 (s, 1 H), 7.90-7.99 (m, 2 H), 8.28 (s, 1 H); MS (APPI) (M+H)+=509.3.