Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([O:17][CH3:18])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([O:17][CH3:18])[C:2]([F:1])([F:19])[F:20])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:23][CH:24]=1
Reactant: CO[C@@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CO[C@@H](CN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1)C(F)(F)F

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 335. Product isolated as a pale yellow solid (53 mg, 27%). m.p.=175-177° C.; LCMS (m/e) 591 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.33-7.25 (m, 2H), 7.06 (d, 1H, J=7.8 Hz), 6.86 (s, 1H), 5.46-5.36 (m, 2H), 3.94-3.82 (m, 1H), 3.77-3.66 (m, 1H), 3.62 (s, 3H), 3.30-3.20 (m, 1H), 2.96-2.88 (m, 4H), 2.87-2.72 (m, 6H), 2.80 (s, 3H), 2.28-2.17 (m, 2H), 1.90-1.78 (m, 2H), 1.45-1.37 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[C:14]1[N:15]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH3:29])[CH:24]=[CH:23]3)[C:16]([NH2:19])=[N:17][N:18]=1.Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH:11]([C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:14]2[N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH3:29])[CH:24]=[CH:23]4)[C:16]([NH:19][C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[N:37]=[CH:36][CH:35]=[CH:34]4)=[N:17][N:18]=2)[CH:5]=1)([CH3:13])[CH3:12]
Reactant: Brc1ccc2ncccc2c1
Reactant: COc1cc(OC)c(C(C)C)cc1-c1nnc(N)n1-c1ccc2c(ccn2C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccc3ncccc3c2)n1-c1ccc2c(ccn2C)c1
Temperature: 95 °C
Yield: 87.9 %

Procedure:
A tube was charged with 5-(2,4-bismethoxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-amine (0.25 mmol, 100 mg.), 6-bromoquinoline (0.5 mmol, 100 mg.), tris(dibenzylideneacetone) dipalladium(0), (10 mol %), cesium carbonate (1 mmol, 326 mg.), Xantphos (20 mol %), and dioxane (2 mL). The reaction is place under an atmosphere of nitrogen, and heated to 95° C. for 16 hours. The crude mixture is run directly down a silica gel column for purification, giving N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)quinolin-6-amine (114 mg.)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]1[CH2:30][N:29]([CH2:31][C@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[Cl:59])[N:51]=[CH:52][C:45]=23)[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=2)=[O:34])[CH2:28]1)(C(C)(C)C)(C)C>C1COCC1>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[N:50]1[C:46]2=[N:47][CH:48]=[N:49][C:44]([O:43][C@@H:32]([CH2:31][N:29]3[CH2:28][CH:27]([OH:26])[CH2:30]3)[C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:34])=[C:45]2[CH:52]=[N:51]1
Reactant: Cc1ccc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](CN2CC(O)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (1.515 mL, 1.51 mmol) was added to (2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AD7) (0.9 g, 1.51 mmol) in THF (10 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was quenched with saturated NH4Cl, diluted with DCM and poured onto a phase separator. The organic layer was evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford the product (0.313 g, 43.1%, 98% ee). 1H NMR (400 MHz, CDCl3) δ 2.29 (3H, s), 2.50-2.78 (1H, m), 3.15-3.31 (4H, m), 3.79-3.89 (2H, m), 4.47-4.55 (1H, m), 5.91 (1H, t), 7.42-7.56 (4H, m), 7.59-7.65 (1H, m), 8.08-8.14 (2H, m), 8.37 (1H, s), 8.59 (1H, s), 9.53 (1H, s); m/z (ES+) (M+H)+=480.41; HPLC tR=1.19 min.
Reaction SMILES: CO[C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=[O:4].[CH:40]1(C(Cl)=O)[CH2:42][CH2:41]1>C(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([C:3]([CH:40]3[CH2:42][CH2:41]3)=[O:4])[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:37])([CH3:38])[CH3:36]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)C1CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 109 %

Procedure:
A solution containing amine 50 (197 mg, 0.41 mmol) in DCM (10 mL) was cooled to 0° C. TEA (73 mg, 0.72 mmol) was added followed by cyclopropanecarbonyl chloride (57 mg, 0.55 mmol) and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was diluted with DCM and the resulting organic solution was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 247 mg of 57 as a yellow-colored oil which was used without further purification. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.70 (s, 0.5H), 8.60 (s, 0.5H), 8.25 (dd, J=5.4, 8.7 Hz, 0.5H), 8.10 (dd, J=5.1, 8.7 Hz, 0.5H), 7.03-6.99 (m, 1H), 6.97-6.89 (m, 1H), 6.80 (s, 1H), 5.38 (app t, J=9.3 Hz, 1H), 4.81 (d, J=5.1 Hz, 1H), 4.57-4.50 (m, 2H), 4.37 (app t, J=7.8 Hz, 1H), 4.24 (d, J=10.5 Hz, 1H), 4.16-4.04 (m, 2H), 3.93 (d, J=5.4 Hz, 1H), 3.81-3.73 (m, 1H), 3.54-3.40 (m, 2H), 2.41-2.37 (m, 1H), 1.79-1.60 (m, 8H), 1.45 (s, 9H), 1.21-1.09 (m, 6H), 1.04-1.01 (m, 3H), 0.91-0.86 (m, 1H) ppm. Mass spectrum, m/z [553.4] (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].[CH2:31](O)[CH2:32][OH:33].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:31]1[CH2:32][O:33][C:19]2([CH2:18][CH2:17][C@@:16]3([CH3:21])[C:3](=[CH:4][CH2:5][C@@H:6]4[C@@H:15]3[CH2:14][CH2:13][C@@:11]3([CH3:12])[C@H:7]4[CH2:8][CH2:9][C@@H:10]3[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:2]2([CH3:30])[CH3:1])[O:20]1
Reactant: OCCO
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C2=CC[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC12OCCO2
Yield: 100 %

Procedure:
4,4-Dimethyl-17β-tert-butyldimethylsilyloxyandrost-5-en-3-one (4.0 g) was dissolved in toluene (235 ml). Ethylene glycol (9.3 ml) and PTSA (124 mg) were added and the mixture was refluxed for 7.5 h, removing water with a Dean-Stark trap. After cooling, water was added and the mixture was extracted with EtOAc. The organic phase was washed with 5% NaHCO3, brine then dried over Na2SO4 and evaporated to dryness to give 3,3-(ethylenedioxy)-4,4-dimethyl-17β-tert-butyldimethylsilyloxy-androst-5-ene (4.4 g, 100%) which was used without purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 1-(2-nitro-phenyl)-piperazine (4.53 g) (commercially from Emkachem) and 3,4-dichlorobenzyl bromide (4.6 g) in 100 mL of dichloromethane was treated with triethylamine (3.4 mL). The reaction was stirred at ambient temperature under inert atmosphere overnight. After solvent removal, the crude reaction mixture was subjected directly to flash chromatography using silica. Elution with hexanes, then 20% ethyl acetate in hexanes, and finally 33% ethyl acetate in hexanes furnished the product as an oil (6.4 g), which was carried on as is.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:9]1[CH2:12][N:11]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)#[N:8].O.[OH-].[Na+]>O1CCCC1>[C:14]1([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]2[CH2:12][CH:9]([CH2:7][NH2:8])[CH2:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.7 g (0.15 mole) of lithium aluminum hydride in 200 ml of dry tetrahydrofuran was treated portionwise with 18.6 g (75 mmole) of solid 3-cyano-1-(diphenylmethyl)azetidine. When the addition was complete, the reaction was stirred at room temperature for two hours, refluxed for four hours, and stirred at room temperature for 18 hours. The reaction was decomposed by the successive addition of 6 ml of water, 6 ml of 15% sodium hydroxide, and 18 ml of water, titrating the final water addition to give a granular precipitate. The inorganic precipitate was removed by filtration, washed with tetra hydrofuran and evaporated in vacuo to give 16.9 g of 1-(diphenylmethyl)-3-azetidinemethanamine as a heavy oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:16][C:17]2[C:18]([CH3:24])=[N:19][N:20]([CH3:23])[C:21]=2[CH3:22])[C:11]([C:14]#[N:15])=[N:12][CH:13]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:16][C:17]2[C:18]([CH3:24])=[N:19][N:20]([CH3:23])[C:21]=2[CH3:22])[C:11]([C:14]([NH2:15])=[O:26])=[N:12][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A flask was charged with 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (35.19 g, 88.1 mmol), and sulfuric acid (227.3 g, 2317 mmol) and stirred at ambient temperature overnight. Water (100 mL) was added very slowly to the reaction which was cooled in an ice bath, and then 150 g of ice was added. NaOH (40%) was slowly added until pH was adjusted to about 12. The mixture was extracted ethyl acetate (750 mL×2), and dichloromethane (500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (27.69 g, 77.9 mmol, 89% yield).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[C:21]#[N:22])C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccc2c(C=O)c[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
DMF (0.539 mL) in dry dichloromethane (30 mL) was added dropwise to a solution of oxalyl chloride (0.610 mL) in dry dichloromethane (30 mL) at 0° C. The resulting solution was stirred at 0° C. for 15 min. A solution of 1H-indole-7-carbonitrile (D2) (0.90 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred for 30 min. The solvent was evaporated. THF (20 mL) was added, followed by addition of aqueous NaOH (0.5 M, 50 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (100 mL) and water (70 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-7-carbonitrile (D3) as a light cream solid (0.75 g, 70%). δH (DMSO-d6, 400 MHz): 7.42 (1H, t), 7.79 (1H, dd), 8.43 (1H, dd), 8.48 (1H, s), 10.00 (1H, s), 13.02 (1H, br s). MS (ES): C10H6N2O requires 170; found 171.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10](=[O:20])[C:9]12[CH2:22][CH2:21]1)=[O:4].[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C.O>[F:24][C:2]([F:1])([F:23])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:25]([O-:27])=[O:26])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10](=[O:20])[C:9]12[CH2:22][CH2:21]1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCCN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)ccc21
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(2′-oxo-1′-pentyl-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2.4 g) in acetic acid (20 ml) is added nitric acid (fuming, 0.9 ml) at 15° C. over a period of 3 min. The mixture is stirred at this temperature for 1 h and then diluted with water. The aqueous layer is extracted with Et2O (2×50 ml) The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated. The compound (2.6 g) is obtained as brownish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15]Br)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][O:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2COc2ccc(F)cc2)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a homogeneous solution of 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, Example 194F, (107 mg, 0.246 mmol) and 4-fluorophenol (30.3 mg, 0.270 mmol) dissolved in acetone (4 mL) was added powdered K2CO3 (37.3 mg, 0.270 mmol). The mixture was stirred at 23° C. for 2 hours, filtered through a bed of Celite®, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 3:2) to provide the product (yield: 83 mg, 72%). mp 65-80° C. 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 4.94 (s, 2H), 6.78-6.86 (m, 2H), 6.91-7.00 (m, 2H), 7.15-7.24 (m, 2H), 7.65-7.72 (m, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.93 (s, 1H), 8.08 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 469 (M+H)+. Anal. calc. for C24H18F2N2O4S: C, 61.53; H, 3.87; N, 5.97. Found: C, 61.22; H, 3.63; N, 5.64.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:20]=[O:21])C>>[CH:20]([C:9]1[CH:10]=[CH:11][C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH:8]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: c1ccc(N2CCCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (6.13 g) was added to stirred DMF (7 ml) at 0° C. and the mixture was stirred for 30 minutes at room temperature. The mixture was added dropwise to a solution of 1-phenylpyrrolidine (5.0 g) in DMF (30 ml) at 0° C. and the resulting solution was stirred overnight at room temperature. The reaction mixture was poured into an ice water mixture and extracted with Et2O. The Et2O layer was washed with saturated NaCl solution, dried over MgSO4 and the solution was concentrated in vacuo. The resulting crystalline mass was washed with Et2O-hexane, yielding 1-(4-formylphenyl)pyrrolidine (3.28 g). ##STR6##
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].Cl[C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1>O1CCCC1>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OCC(F)(F)C(F)F
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)C(F)(F)COc1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
2,2,3,3-Tetrafluoropropan-1-ol (5.54 g, 41.31 mmol) was added to a suspension of sodium hydride (2.20 g, 55.08 mmol, 60% in mineral oil) in tetrahydrofuran (50 mL) and reaction mixture was stirred for 30 minutes at room temperature. Then a solution of 2-chloro-3-(trifluoromethyl)pyridine (5.00 g, 27.54 mmol) in tetrahydrofuran (50 mL) was added and mixture was heated at 40° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and then quenched slowly with water. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in heptane to give the title compound as a oil (3.10 g, 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: FCc1cccc(Br)n1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cccc(CF)n1
Yield: 64.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1; from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol, Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 650%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as a white solid.
Reaction SMILES: ClCl.[F:3][C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].II.[Cl:17]S(O)(=O)=O>>[Cl:17][C:12]1[C:4]([F:3])=[C:5]([CH:9]=[C:10]([F:14])[C:11]=1[F:13])[C:6]([OH:8])=[O:7]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: ClCl
Agent: II
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Temperature: 25 °C

Procedure:
A steady stream of chlorine gas was bubbled through a solution of 8.1 g (46 mmol) of 2,4,5-trifluorobenzoic acid, (*Jpn. Kokai Tokkyo Koho JP 58, 150, 543 Sept. 7, 1983.) 0.2 g (catalytic amount) of iodine, and 15 ml of chlorosulfonic acid at 60° C for four hours. The reaction mixture was cooled to room temperature and poured cautiously onto ice with constant stirring. The suspension was extracted with ethyl acetate, and the extracts were combined, washed with water, and dried over magnesium sulfate. The solvent was evaporated to give 9.4 g of the title compound as an orange solid.
Reaction SMILES: Cl.Cl.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3SC(CN5CCNCC5)=CC=3)=CC=CC=4)C)N=C(C3C=C(O)C=C(F)C=3)C=12.[CH3:46][N:47]([CH3:70])[CH2:48][CH:49]=[CH:50][C:51]1[S:55][C:54]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59](=[O:66])[O:58][C:57]=2[CH:67](O)[CH3:68])=[CH:53][CH:52]=1.[CH2:71]([O:78][C:79]1[CH:80]=[C:81]([C:86]2[C:94]3[C:89](=[N:90][CH:91]=[N:92][C:93]=3[NH2:95])[NH:88][N:87]=2)[CH:82]=[C:83]([F:85])[CH:84]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[NH2:95][C:93]1[N:92]=[CH:91][N:90]=[C:89]2[N:88]([CH:67]([C:57]3[O:58][C:59](=[O:66])[C:60]4[C:65]([C:56]=3[C:54]3[S:55][C:51]([CH:50]=[CH:49][CH2:48][N:47]([CH3:70])[CH3:46])=[CH:52][CH:53]=3)=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH3:68])[N:87]=[C:86]([C:81]3[CH:82]=[C:83]([F:85])[CH:84]=[C:79]([O:78][CH2:71][C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[CH:80]=3)[C:94]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)s1
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)s1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Yield: 72432.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 134, step a, from 4-(5-(3-(dimethylamino)prop-1-en-1-yl)thiophen-2-yl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate B40, 220 mg, 0,619 mmol), and 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G18, 125 mg, 0.37 mmol) to give 3-(1-(4-amino-3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-(3-(dimethylamino)prop-1-en-1-yl)thiophen-2-yl)-1H-isochromen-1-one (180 mg, 0,268 mmol, 43.2% yield) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][C:4]=1[CH:5]=[O:6].Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([S:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:24]2[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=[C:21]([C:8]4[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:5]=[O:6])[CH:7]=4)[CH:22]=3)[NH:26][CH:25]=2)[CH2:38][CH2:37]1)(=[O:41])=[O:40])[CH3:43]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(C=O)c4)cc23)CC1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H2O (6.3 mL), was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (963 mg, 2.33 mmol), and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10 min, tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The reaction was heated in the microwave 120° C. for 120 min. Compound was purified by flash chromatography using DCM and MeOH to give 632 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1H-indole-7-carboxamide (58%).