Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[OH2:28].[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1
Reactant: BrCCSc1ccccc1
Reactant: Oc1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Oc1ccc2c(c1)nc(CC1CCN(CCSc3ccccc3)CC1)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A mixture of 6.48 parts of [(2-bromoethyl)thio]benzene, 6.8 parts of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazol-5-ol, 4.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred for 2 hours at reflux temperature using a water separator. After cooling to room temperature, the reaction mixture was poured into water. The layers were separated. The organic layer was washed with 500 parts of water, dried, filtered and evaporated. The residue was taken up in a mixture of trichloromethane and methanol (95:5 by volume) and 25 parts of silica gel. After stirring for 15 minutes, the whole was filtered, washed with the eluent and the filtrate was evaporated. The residue was boiled in 160 parts of 2-propanone. The mixture was stirred overnight at room temperature. The product was filtered off, washed with 2-propanone and crystallized from 280 parts of 2-propanone. The product was filtered off, washed with 2-propanone and dried in vacuo at 50° C., yielding 2.7 parts (27.8%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(phenylthio)ethyl]-4-piperidinyl]methyl]-1H-benzimidazol-5-ol hemihydrate; mp. 193.8° C. (570).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([NH:45][C:13]([NH:12][C:11]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:46]=[CH:47][CH:48]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 83 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 172B (0.145 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.192 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.74 (s, 1H), 8.69 (d, 1H), 7.78 (s, 1H), 7.45 (m, 6H), 7.35 (s, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 6.85 (s, 1H), 3.99 (s, 6H), 2.41 (s, 3H); LC-MS (ESI) m/z 581 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17]I>CN(C=O)C>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washed with hexanes, then was suspended in dry DMF (230 mL). Solid ethyl indole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over 5-10 mm, allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40-45° C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O (500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL), dried (MgSO4), and concentrated to leave the title compound (27.10 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf=0.39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:27][C:24]3[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: COc1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc(Cl)nc23)cn1
Yield: 59.1 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), 6-methoxypyridin-3-amine (0.155 g, 1.250 mmol) and sodium acetate (0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H2O=1:1) was refluxed for 1 hour. The reaction mixture was diluted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to get 6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (0.085 g, 59%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 3.97 (3H, s), 6.85 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.20 (1H, dd, J=2.8, 8.8 Hz), 8.55 (1H, d, J=2.8 Hz), 8.67 (1H, br s), 8.73 (1H, s).
Reaction SMILES: BrC1C(C)=CC(O)=CC=1[Cl:10].[Br:11][C:12]1[C:26]([CH3:27])=[CH:25][C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:14](OC)[CH:13]=1>>[Br:11][C:12]1[C:26]([CH3:27])=[CH:25][C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:14]([Cl:10])[CH:13]=1
Reactant: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Reactant: Cc1cc(O)cc(Cl)c1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Yield: 83 %

Procedure:
[2-(4-Bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane was prepared in 83% yield from 4-bromo-3-chloro-5-methyl-phenol according to the procedure for [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane. 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.09 (s, 1H), 5.26 (s, 2H), 3.79 (t, 2H, J=8.4 Hz), 2.35 (s, 3H), 0.95 (t, 2H, J=8.4 Hz), 0.02 (s, 9H). Anal. (C13H20ClBrO2Si) C, H. Calculated: C, 44.39; H, 5.73. Found: C, 45.08; H, 5.91.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)CCC>>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[C:13]([C:11]([N:9]2[CH2:10][C:5]3[C:6](=[N:7][C:2]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[CH:3][CH:4]=3)[CH2:8]2)=[O:12])[CH:18]=1)(=[O:21])=[O:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3ccncc3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and 4-tributylstannanylpyridine. White solid. MS (m/e): 492.1 [M+H]+, 100%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>ClCCl>[CH3:31][N:32]([CH3:36])[C:33]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)=[O:34]
Reactant: CN(C)C(=O)Cl
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (9 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (69 μL, 0.754 mmol) in anhydrous dichloromethane (1 mL). After stirring for 3 h at 0° C., the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (80 mg, 32%). 1H NMR (400 MHz, CDCl3) δ7.13 (d, 2H), 6.86 (d, 2H), 3.98 (t, 2H), 3.84 (t, 1H), 3.74 (m, 2H), 3.52 (m, 2H), 3.36 (d, 2H), 2.69 (s, 6H), 2.65 (m, 2H), 2.57 (m, 4H), 2.02-1.95 (m, 4H), 1.84-1.78 (m, 6H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([C:23]#[CH:24])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)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.[Cu]I>[NH2:32][C:27]1[C:26]([C:24]#[C:23][C@H:13]2[O:12][CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1
Reactant: Nc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2cccnc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynylmorpholine-4-carboxylate (1 eq) and 3-bromopyridin-2-amine (1.4 eq) in acetonitrile (0.1M) and triethylamine (25 eq) was flushed with nitrogen for 10 minutes. Then bis(triphenylphosphine)palladium(ii) chloride (0.1 eq) and copper(i) iodide (1.2 eq) were added and the mixture was flushed again with nitrogen for 10 minutes. The reaction mixture was stirred at 60° C. for 2 hours in the dark. It was concentrated to dryness and the residue was purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, 8bromo-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath at 105°-110° C. with formaldehyde gas bubbling through the solution to give 8-bromo-1-(2-hydroxyethyl)-6-(2-pyridyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1COCC1>[N:36]1([C:33]2[CH:32]=[CH:31][C:30]([NH:29][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:35][CH:34]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (55 mg, 0.3086 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 82% yield (0.116 g, 0.2107 mmol).
Reaction SMILES: [CH2:1]([C:11]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1)[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].I[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH:1]([C:2]1[N:6]([CH2:5][CH2:4][CH3:10])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)([C:11]1[N:12]([CH2:2][CH2:1][CH3:11])[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCI
Reactant: c1ccc2[nH]c(Cc3nc4ccccc4[nH]3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1nc2ccccc2n1CCC)c1nc2ccccc2n1CCC
Reaction time: 0.33 h
Yield: 151 %

Procedure:
To a flask were added 0.79 g 2,2′-methylenebis(1H-benzimidazole) and 20 ml N,N-dimethylformamide under nitrogen. 0.42 g sodium hydride were added in portions and the mixture was stirred 20 minutes. 1.74 g 1-iodopropane were added slowly and the mixture was stirred at 22 C for 16 hrs. After quenching with the slow addition of 40 ml water, the product was extracted with ethyl acetate and washed with water. Solvent removal resulted in an oil which was purified by silica gel chromatography using 25% ethyl acetate in hexane to give 0.9 g of a light yellow oil which crystallized on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1)([O-])=O.C(O)(=O)C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)S(=O)(=O)c1ccccc1-2

Procedure:
A 10 g portion of 3-nitrodibenzothiophene S,S-dioxide in 180 ml of dimethylformamide and 20 ml of glacial acetic acid containing 1.0 g of 5% palladium on carbon was hydrogenated for 1.75 hours, then filtered through diatomaceous earth and the filtrate evaporated. The residue was dissolved in 250 ml of acetonitrile, filtered through diatomaceous earth and concentrated to 150 ml. The solid was collected, giving 6.95 g of the desired product mp 261°-264° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC(C)C
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.843 mmol) and isobutyl bromide (115 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (15 mg, 15.7%).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]1=[O:25])C.[OH-].[Li+]>C(O)C.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:26])=[O:3])[C:7](=[O:25])[CH:8]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)C(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 101B (0.77 g, 2.12 mmol) in ethanol/water (1:3, 30 mL) was added lithium hydroxide (0.26 g, 6.37 mmol), and the reaction mixture was stirred at ambient temperature overnight. Then the mixture was concentrated and partitioned in cold 1 N HCl/methylene chloride. The organic layer was separated, dried over MgSO4 and concentrated to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.86 (s, 1H), 7.35 (m, 5H), 5.47 (s, 1H), 4.09 (dd, 2H), 3.90 (d, J=15.26 Hz, 1H), 3.53 (m, 1H), 3.28 (m, 1H), 1.40 (s, 9H); MS/DCI 352 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](I)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17][C:18]1[S:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Br:17][C:18]1[S:22][C:21]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[C:13]([CH3:15])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(I)n1
Reactant: OB(O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-iodo-6-methylpyridine (example A.52) (1.0 g, ca. 80% pure, ca. 2.75 mmol) and commercially available 5-bromthiophene-2-boronic acid (0.568 g, 2.75 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.480 g, 46%). MS (ISP) 397.9 [(M+H)+], 400.0 [(M+2+H)+], 402.1 [(M+4+H)+] and 404.2 [(M+6+H)+].
Reaction SMILES: CC([O-])=O.[K+].[C:6]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])#[N:7].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].O>C(O)(C)C>[NH2:18][C:17]([C:16]([Cl:20])([Cl:19])[Cl:15])=[C:8]([C:6]#[N:7])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: C=CCOC(=O)CC#N
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: C=CCOC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of KOAc (589.4 g, 6.006 mol) in isopropanol (3 L) was added allyl cyanoacetate (429.4 g, 403.2 mL, 3.432 mol) and the reaction mixture was cooled to 5° C. Trichloroacetonitrile (495.5 g, 3.432 mol) was added in 50 mL portions, maintaining temperature below 15° C. The reaction mixture was then allowed to warm to 20° C. and stirred for 3 h. Water (˜4 L) was added to dissolve the inorganic materials and precipitate out the desired product. The mixture was stirred for 20 minutes and the solid was isolated by filtration under vacuum. This solid was filtered, washed with water (2×0.5 L) and dried in a vacuum oven overnight at 40° C. to afford allyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate 2 as an off-white powder (787 g, 85%). 1H NMR (500 MHz, CDCl3) δ 10.17 (br s, 1H), 6.97 (m, 1H), 5.99 (m, 1H), 5.44 (m, 1H), 5.31 (m, 1H), 4.76 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:21][C:22]1[S:26][C:25]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[N:24][C:23]=1[C:35](O)=[O:36])=O)(C)(C)C>>[NH2:21][C:22]1[S:26][C:25]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[N:24][C:23]=1[C:35]([NH:13][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:36]
Reactant: Nc1cnccc1N1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CCCCC1

Procedure:
Following the procedures as described in EXAMPLE 1 and starting with 4-(piperidin-1-yl)pyridin-3-amine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, the title compound was obtained as a white solid (36 mg, 34%). 1H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 9.35 (s, 1H), 8.21 (d, J=5.2, 1H), 7.67 (s, 2H), 7.53 (tt, J=8.3, 6.3, 1H), 7.29 (p, J=2.6, 2H), 7.13 (d, J=5.3, 1H), 2.90-2.80 (m, 4H), 1.76-1.64 (m, 4H), 1.51 (d, J=5.3, 2H). ESIMS m/z=416.1 (M+1).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:38][S:39]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:35])([F:36])[F:37])=[N:32][N:33]=5)[N:30]=4)[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Product: CS(=O)(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 75 %

Procedure:
Obtained in 75% yield by an analogous method to Example 26, starting from 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 32, preparation of starting materials) and methanesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH:22][C:35](=[O:34])[CH2:36][OH:37])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)N)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)NC(=O)CO)c1

Procedure:
Prepared as described in Example 102 using (1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (73 mg, 0.18 mmol) and acetoxyacetyl chloride (0.077 ml, 0.72 mmol). Yield 67 mg (80%).