Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)[CH:7]=1.[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:81][C:82]([F:87])([F:86])[C:83]([OH:85])=[O:84]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:50]3[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:9]=2)[CH:7]=1.[C:83]([OH:85])([C:82]([F:87])([F:86])[F:81])=[O:84]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(CN4CCCNCC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (23.59 mg, 0.118 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fibre filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.3 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give N-{[5-chloro-3′-(hexahydro-1H-1,4-diazepin-1-ylmethyl)-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (28.2 mg, 62.3%) as a white solid. LC-MS m/z 763 M+; mp 121-124° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:42]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 4.0 g, 8.0 mmol), 3-(dimethylamino)phenylboronic acid (3.3 g, 20 mmol), bis(triphenylphosphine)palladium(II) dichloride (567 mg, 0.8 mmol) in 1,4-dioxane (40 mL) and an aqueous sodium carbonate solution (2N, 21 mL) was heated in a microwave reactor to 100° C. for 3 h under nitrogen. At this time, the reaction was cooled to 25° C., diluted with ethyl acetate (50 mL) and then washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (60 g, petroleum ether/ethyl acetate 15:1) afforded N,N-dimethyl-3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)but-1-enyl)benzenamine (3.0 g, 83%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (dd, 1H, J1=4.5 Hz, J2=3.6 Hz), 7.85 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.65 (d, 2H, J=7.8 Hz), 7.38-7.36 (m, 1H), 7.31-7.14 (m, 4H), 7.06 (t, 1H, J=8.1 Hz), 6.65-6.48 (m, 3H), 6.14 (d, 1H, J=10.2 Hz), 2.77 (s, 6H), 2.72-2.64 (m, 1H), 1.14 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:34][OH:35].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:34][OH:35])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of compound A (17.9 g, 39.7 mmol), hydroxylamine (3.9 g, 119 mmol), pyridine (200 mL), and water (100 mL) were combined. After stirring overnight, water (50 mL) was added and the precipitate was filtered to yield compound B as an off-white solid (16.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH:12]([O:14]CC)=[CH2:13].C1(=O)O[CH:20](C)[CH2:19]O1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:4]1[CH2:3][C:2]([O:14][CH2:12][CH3:13])([CH:7]=[CH:6][CH:5]=1)[CH:19]=[CH2:20]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: C=COCC
Reactant: CC1COC(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC1(OCC)C=CC=C(C(F)(F)F)C1
Temperature: 120 °C
Yield: 75 %

Procedure:
To 22.5 g (100 ml) of 3-bromo-benzotrifluoride and 80 ml propylene carbonate under argon 20.2 g (200 mmol) triethyl amine, 14.4 g (200 mmol) ethyl vinyl ether, 518 mg (0.5 mmol) bis-(dibenzalacetone)-chloroform-palladium and 525 mg (2 mmol) triphenyl phospine are added. The reaction mixture is heated in an autoclave to 120° C. for 20 hours, cooled to room temperature, filtered and the filtrate extracted twice with 50 ml hexane. The hexane phase is washed twice with 50 ml water, dried with Na2SO4 and the solvent is evaporated. The residue is distilled to give 16 g 3-trifluoromethyl-1-ethoxystyrene (b.p. 113° C./50 mbar, yield 75%). Hydrolysis according to Example 2 results in trifluoromethyl-acetophenone (76% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=O>O1CCCC1>[C:7]([CH:9]=[CH:18][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (24.6 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.18 mL, 0.0258 mol) in tetrahydrofuran (31.40 mL). The reaction was warmed to room temperature and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g, 0.023 mol) in tetrahydrofuran (6.28 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (5.10 g, 92%). LCMS (M+Na) 259.0.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:26]([Cl:27])=[C:25]3[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]3)=[N:19]2)=[CH:14][CH:13]=1)[CH3:7].[OH-].[Na+]>>[ClH:27].[Cl:27][C:26]1[N:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:17][CH:16]=2)[N:19]=[C:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2
Reactant: COC(=O)CCN(C)CCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCOc1ccc(-n2nc3ccccc3c2Cl)cc1)CCC(=O)O
Product: Cl
Yield: 188.5 %

Procedure:
The title compound was prepared from product from step 1 (0.2 g, 0.5 mmol) and NaOH (50% in water, 0.080 g, 1.0 mmol) using the procedure of Step 6 of the Example 4 to provide the title compound (0.2 g, 60%). 1H NMR (400 MHz, DMSO) 7.68-7.59 (m, d, J=8.8 Hz, 4H), 7.42-7.38 (m, 1H), 7.24-7.17 (m, d, J=8.8 Hz, 3H), 4.17 (t, J=6 Hz, 2H), 3.27 (m, 4H), 2.77 (m, s, 5H), 2.18 (m, 2H); LC/MS (ESI+) m/z: 99%.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]([NH:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]3=[N:21][CH:22]=2)=O)[CH:10]([CH2:36][CH3:37])[CH2:9]1)(=[O:6])=[O:5])[CH3:2].O=S(Cl)Cl.CCO>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([N:3]([CH2:38][CH3:39])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]2[N:18]3[C:19]4[CH:25]=[CH:24][NH:23][C:20]=4[N:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH:10]([CH2:36][CH3:37])[CH2:9]1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCC1CC(CS(=O)(=O)N(CC)CC)CC1c1nnc2cnc3[nH]ccc3n12
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a mixture of N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 1.27 mmol) and TEA (0.529 mL, 3.80 mmol) in 1,4-dioxane (12.7 mL) was added SOCl2 (0.185 mL, 2.53 mmol). The reaction mixture was heated at about 80° C. for about 2 h. The reaction mixture was cooled to ambient temperature and partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (30 mL). The aqueous layer was washed with DCM (2×30 mL). The organic layers were combined, concd under reduced pressure, and purified by silica gel (80 g) chromatography eluting with a gradient of 0-60% MeOH in DCM to give a brown solid. The resulting solid was suspended in Na2CO3 (2 M aqueous, 2 mL), EtOH (2 mL) and 1,4-dioxane (2 mL). The reaction mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature and purified by RP-HPLC (Table 1, Method d) to afford N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (0.300 g, 58%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.89 min; MS m/z: 405 (M+H)+. The solid was further purified by using General Procedure AA to give N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=11.8 min, or =negative) (0.021 g, 7%) [Example #1.1]; N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methane-sulfonamide (Table 2, Method 27, Rt=11.1 min, or =positive) (0.018 g, 6%) [Example #1.2]; N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyl)methanesulfonamide (Table 2, Method 27, Rt=10.7 min, or =positive) (0.018 g, 6%) [Example #1.3]; N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 28, Rt=20.1 min, or =negative) (0.031 g, 11%) [Example #1.4]; N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.002 g, 1%) [Example #1.5]; and N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.001 g, 1%) [Example #1.6].
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][C:15]#[N:16].N.[H][H]>CO.[Ni]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: N#CCCNCC1CCc2ccccc2O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCNCC1CCc2ccccc2O1
Yield: 90.8 %

Procedure:
A mixture of intermediate (16-c) (0.12 mol) in methanol saturated with ammonia (500 ml) was hydrogenated with Raney nickel (6 g) as a catalyst After uptake of hydrogen (2 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by distillation, yielding 24 g (90.8%) of (±)-N-[(3,4-dihydro-2H-benzopyran-2-yl)methyl]-1,3-propanediamine (interm. 17-c).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: Fc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 65 °C

Procedure:
A mixture of 2-chloro-6-fluoro-benzothiazole (0.65 g, 3.5 mmol) and 4-bromoaniline (0.61 g, 3.5 mmol) in n-butanol (6 mL) was heated at 60-70° C. under nitrogen to obtain a solution, to which 4 M HCl in dioxane (0.43 mL, 1.73 mmol) was slowly added dropwise. The reaction mixture was then heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with ethanol and collected by filtration. This yielded 0.98 g (88%) of the title compound. LC/MS m/z 323.0 (MH+); retention time 3.74 min. 1H NMR (CD3OD) δ 7.10-7.30 (m, 1H), 7.39 (d, 1H), 7.45 (d, 2H), 7.58-7.61 (m, 3H).
Reaction SMILES: [C:1]([CH:3]([CH3:13])[CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)#[N:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:1]1[N:2]=[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]2=[CH:4][C:3]=1[CH3:13]
Reactant: BrBr
Reactant: CC(C#N)CC1CCCCCC1=O
Solvent: CC(=O)O
Product: Cc1cc2c(nc1Br)CCCCC2
Temperature: 15 °C

Procedure:
The product of step (a) (88 g, 0.5 m) in acetic acid (1 l) was treated with bromine (26 ml, 0.5 m) over 15 minutes, maintaining an internal temperature of ca, 15° C. The mixture was allowed to warm to room temperature overnight. The solvent was evaporated off under reduced pressure and the residue partitioned between water and diisopropyl ether. The organic phase was dried (MgSO4) and evaporated to give a residue which on recrystallising from hexane gave the title compound as white needles, mp 68-70.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[F:13][C:14]([F:40])([F:39])[C:15]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[C:20]([C:29]#[N:30])=[N:19]1>>[F:40][C:14]([F:13])([F:39])[C:15]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](/[CH:27]=[C:4]3/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/3)=[CH:24][CH:25]=2)[C:20]([C:29]#[N:30])=[N:19]1
Reactant: N#Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[2,4-bis(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-carbaldehyde following General Procedure F.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[C:4]([F:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.Cl.C(=O)(O)[O-:25].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:25])=[C:4]([F:13])[CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C#N)c1ccc(Br)cc1F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (2.0 g, 8.3 mmol) in tetrahydrofuran (20 mL) under nitrogen was added 1 N solution of DIBAL-H in tetrahydrofuran (19 mL, 19 mmol) dropwise at −30° C. The resulting solution was stirred at ambient temperature for 3 hours before the addition of 2 N hydrochloric acid aqueous solution (10 mL) at 0° C. After stirred at ambient temperature for 10 minutes, the solution was basified with saturated aqueous sodium bicarbonate solution to pH 8-9, and then extracted with ethyl acetate (3×50 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-2% ethyl acetate in hexane to afford the title compound as a colorless oil. MS ESI: [M+H]+ m/z 245; 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 7.32-7.21 (m, 1H), 7.18-7.03 (m, 2H), 1.41 (s, 6H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]([CH:9]=O)[CH3:8].CN1C2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:22].C([O-])(O)=O.[Na+]>ClCCl.N1C=CC=CC=1>[CH3:8][N:7]1[C:6]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]([CH:13]=[O:22])=[C:9]1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CN1C(=O)Cc2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(Cl)c(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
POCl3 (6 ml) was added dropwise to a mixture of dry DMF (5.9 ml) and dichloromethane (5.9 ml) kept at 0° C. 1-Methyl-5-chloro-1,3-dihydroindol-2-one (4.0 g) dissolved in dichloromethane (20 ml) and pyridine (2.9 ml) was added dropwise at 0° C. over a period of 30 min. Subsequent stirring at room temperature for 3h. The mixture was poured onto icewater (500 ml) neutralized with NaHCO3 whereafter the mixture was stirred overnight. The precipitate was filtered off, washed with water and dried. The crude material (4.45 g) was recrystallized from ethanol yielding 1.27 g (25.4%) of (45). M.p. 165°-167° C.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>O>[CH3:2][NH:3][C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CNC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CNC1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of conc. HCl (15 ml) and water (8 ml) was poured over methyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine (2.1 g, 8.4 mmol) and the mixture was stirred at RT for 5 days. For working up, the reaction mixture was diluted with water (20 ml) and extracted with ether (3×30 ml). The ethereal phase was discarded. The aqueous phase was then rendered basic with 2N NaOH and extracted with methylene chloride (3×30 ml). The organic phase obtained in this way was dried with Na2SO4 and then concentrated on a rotary evaporator. By purification by chromatography on silica gel with ethyl acetate/ethanol (4:1), it was possible to obtain the ketone Ket-15 in a yield of 1.38 g (81%) as a solid with a melting point of 32-38° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:16](=[O:17])[CH2:6][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: NC1CC1
Reactant: O=C(Cl)CCl
Product: O=C(CN1CCNCC1)NC1CC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl-chloride and cyclopropylamine in an analogous manner as described in example 21.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:26]1([C:29]([NH:31][NH2:32])=[O:30])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:32][NH:31][C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)n1
Reactant: NNC(=O)C1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Br)n1)NNC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Bromopyridin-2-yl)acetic acid (Example 235, Step 2) (41% wt, 1.50 g, 2.85 mmol), EDC (1.64 g, 8.54 mmol), HOBT (872 mg, 5.69 mmol), and cyclopropanecarboxylic acid hydrazide (570 mg, 5.69 mmol) were combined in DMF (15 mL), and DIEA (994 μL, 5.69 mmol) was added. The reaction was stirred overnight at room temperature. After evaporation of the DMF, the residue was diluted with water and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The solid residue was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([C:17]#[N:18])=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.BrB(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:13])[CH3:14])[C:5]([C:17]#[N:18])=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: COc1c(Br)c(-c2cccc([N+](=O)[O-])c2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc([N+](=O)[O-])c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
N-(2-Bromo-5-cyano-3-methoxy-6-methyl-3′-nitrobiphenyl-4-yl)-2,2-dimethylpropionamide (I-12) (630 mg, 1.41 mmol) was dissolved in dichloromethane (dewatered, 20 ml) under nitrogen atmosphere, cooled at −70° C. in a dry ice-methanol bath. 1 M tribromoborane (dichloromethane solution) (4.23 ml) was dropwise added to it at −70° C. to −68° C., followed by stirring for 2 hours with heating up to 0° C. The reaction liquid was diluted with cold water, followed by pH control at 6 to 7 by addition of aqueous 10% sodium carbonate solution. The organic matter was extracted with ethyl acetate, washed with saturated brine, dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→3:2) to obtain the entitled compound (503 mg, 82%) as a pale yellow solid.