Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[CH2:21][CH2:20][N:19]3[C:12](=[CH:13][C:14]4[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]=43)[C:11]2=[O:24])[C:7]=1[CH:8]=[O:9].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)[C:27]1=[O:58].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][N:26]1[C:27](=[O:58])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:21][CH2:20][N:19]4[C:12](=[CH:13][C:14]5[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]=54)[C:11]3=[O:24])[CH:5]=[N:4][CH:3]=2)=[CH:31]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cncc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 35 %

Procedure:
A sealed tube was charged with 107f (200 mg, 0.51 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (240 mg, 0.51 mmol), PdCl2(dppf) (42 mg, 0.05 mmol), K3PO4 (230 mg, 1 mmol), and NaOAc (80 mg, 1 mmol) in CH3CN (5 mL) and H2O (1.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 107g in 35% yield (120 mg) as a brown solid. MS: [M+H]+ 649.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[C:9]2[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=2[N:11]=[CH:12][N:13]=1.B1([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)OC(C)(C)C(C)(C)O1.O>O1CCOCC1.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>[CH3:17][C@H:16]1[C:9]2[C:8]([C:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCc2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Yield: 67 %

Procedure:
A solution of Na2CO3 (0.36 mL, 2M) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (101 mg, 0.60 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacol ester (204 mg, 0.66 mmol) in 1,4-dioxane (1.8 mL). The mixture was sparged with N2 for 2 minutes. The catalyst Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) was added in one portion. The mixture was heated at 110° C. under N2 for 8 hours. Water (20 mL) was added to the mixture and extracted with DCM (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (first with 0-50% EtOAc/hexane, then with 0-4% MeOH/DCM gradient elution) to give (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (127 mg, 67%). 1H NMR (CDCl3, 500 MHz) δ 8.91 (s, 1H), 6.31 (s, 1H), 3.64-3.55 (m, 1H), 3.10-3.03 (m, 2H), 2.98-2.90 (m, 2H), 2.83-2.78 (m, 1H), 2.42-2.34 (m, 2H), 1.77-1.69 (m, 2H). 1.49 (s, 9H), 1.19 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][O:10]C(OCC)C)(=[O:3])[CH3:2].Cl>C(OCC)(=O)C(C)O>[C:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CCOC(C)OCCCC[C@@H](C)OC(C)=O
Agent: Cl
Solvent: CCOC(=O)C(C)O
Product: CC(=O)O[C@H](C)CCCCO
Reaction time: 4 h
Yield: 84.4 %

Procedure:
Alternatively, a solution of 5-(R)-acetoxy-1-ethoxyethoxyhexane (80 g, 0.34 mole) in ethyl lactate (150 ml) was stirred with 1M of aqueous hydrochloric acid solution (100 ml). After 4 hours, the layers were separated and the aqueous layer was saturated with sodium chloride and then extracted with ethyl lactate (4×75 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (2×100 ml), dried over magnesium sulfate and the solvent evaporated under vacuum to give 5-(R)-acetoxy-1-hydroxyhexane (46 g, 83% yield).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1)=O.Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27](/[CH:30]=[C:31]2/[C:32]([NH:37][CH2:38][C:39]#[CH:40])=[N:33][C:34](=[O:36])[S:35]/2)[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[O:36]=[C:34]1[N:33]=[C:32]([NH:37][CH2:38][C:39]#[CH:40])/[C:31](=[CH:30]/[CH:27]2[CH2:26][CH2:25][N:24]([CH2:8][C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=3)[CH2:29][CH2:28]2)/[S:35]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of triethylamine (1.38 mL) and 4-formyl-2-(trifluoromethyl)benzonitrile (593 mg) in DMF (10 mL) was added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (800 mg). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (2.1 g) was added. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (250 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[N:3]=[CH:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:34])=CC=1>C1COCC1.O>[S:34]=[C:2]1[NH:3][C:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:5][NH:1]1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: N#Cc1ccc(-c2ccccc2Cc2c[nH]cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2Cc2c[nH]c(=S)[nH]2)cc1
Reaction time: 16 h

Procedure:
A solution of 2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Intermediate D3) (0.36 g, 1.4 mmol) in THF (11 mL) and water (10 mL) was treated with NaHCO3 (1.2 g) at rt for 5 m. Phenyl chlorothionoformate (0.95 mL, 7.0 mmol) was added and stirring was continued for 16 h. The mixture was diluted with water (10 mL) and extracted with ether (4×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (15 mL) and treated with NEt3 (2.0 mL) for 18 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 and pentane to give a solid 2′-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Compound 6) in 40% yield. 1H NMR (300 MHz, DMSO-d6): δ 11.8 (s, 1H), 11.6 (s, 1H), 7.92 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.44-7.19 (m, 4H), 6.14 (s, 1H), 3.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CCOCC1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:20]([C@@H:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:6]([CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[C:2]([NH:1][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:3]=3)[N:7]=2)=[O:31])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared in example 58, 110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Ethanesulfonyl chloride (21 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was warmed to 80° C. for 4 h. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 60% ethyl acetate/methylene chloride) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 50% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-ethanesulfonylamino-benzyl)-1H-pyrazol-3-yl]-propionamide (14 mg, 11%) as a white powder: ESI-LRMS m/e calcd for C27H33ClN4O5S2 [M+] 592.2, found 593.7 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.16 (m, 2H, CH2), 1.14 (t, J=7.3 Hz, 3H, CH3), 1.37-1.83 (m, 8H, 4×CH2), 2.01-2.16 (m, 1H, CH), 3.03 (q, J=7.3 Hz, 2H, SO2CH2), 3.32 (s, 3H, SO2CH3), 3.84-3.92 (m, 1H, CH), 5.15 (s, 2H, NCH2), 6.46 (d, J=2.2 Hz, 1H, Ar), 6.88 (d, Jo=7.7 Hz, 1H, Ar), 7.01 (t, Jm=1.6 Hz, 1H, Ar), 7.06-7.14 (m, 1H, Ar), 7.24 (t, Jo=7.7 Hz, 1H, Ar), 7.56 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.66 (d, Jm=1.6 Hz, 1H, Ar), 7.69 (d, J=2.2 Hz, 1H, Ar), 7.98 (d, Jo=8.2 Hz, 1H, Ar), 9.75 (s, 1H, NH), 10.78 (s, 1H, NH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1>CN(C=O)C>[NH:33]1[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:31]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:8]([C:5]3([CH3:11])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:10])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1
Reactant: CN1CCC(C)(C(=O)O)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCC(C)(C(=O)Nc2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1,4-Dimethylpiperidine-4-carboxylic acid (3 mg, 0.019 mmol), HOBt (4 mg, 0.029 mmol), EDC (5.5 mg, 0.028 mmol) and sodium bicarbonate (1.6 mg, 0.019 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (6.4 mg, 0.019 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (3.5 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1H), 7.77 (m, 1H), 7.71 (m, 2H), 7.38 (m, 2H), 7.29 (m, 2H), 5.94 (d, 1H, J=8.0 Hz) 4.00 (m, 1H), 3.85 (m, 1H), 3.46 (m, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 2.56 (m, 1H), 2.15 (m, 3H), 1.86 (m, 3H), 1.72 (m, 3H), 1.46 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18](Br)[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl>[OH:7][CH:6]([CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:10][O:9][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC(O)CNC(C)C)cccc32)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) and triethylamine (143 parts) in dichloromethane (1500 parts) is dropwise added a solution of stannic chloride (80 parts) in dichloromethane (500 parts) at -60° C. with stirring. The mixture is warmed to room temperature, stirred for 5 hours, concentrated and shaken with aqueous 5N-sodium hydroxide and ethyl acetate. The ethyl acetate layer is separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give crude product (73 parts) in 87.9% yield. This is triturated in ethyl acetate to give pure 4-(2-hydroxy-3-isopropylaminopropoxy)-1-p-toluenesulfonylindole (56 parts) as amorphous solid in 67% yield. NMR: δCD3SOCD3 0.97d(6.5 Hz)6H, 2.29s3H, 2.56-2.90m3H, 3.76-4.20m3H, 6.71-7.92m9H.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[CH:19]=[N:18][C:17](S)=[N:16]1.[F:21][C:22]([F:26])=[C:23]([F:25])[F:24].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[CH:19]=[N:18][C:17]([C:23]([F:25])([F:24])[CH:22]([F:26])[F:21])=[N:16]1
Reactant: FC(F)=C(F)F
Reactant: FC(F)(F)c1cc(Cl)c(-n2cnc(S)n2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)c1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sixty percent oily sodium hydride (40 mg, 1 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-mercapto-1,2,4-triazole 0.31 g, 1 mmol) in N,N-dimethylformamide (10 ml) at room temperature in a nitrogen atmosphere. After stirring at room temperature for 15 minutes, the atmosphere in the reaction vessel (20 ml volume) was replaced with tetrafluoroethylene gas, and the mixture was heated at 80° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product was subjected to silica gel chromatography to give 0.21 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,1,2,2-tetrafluoroethyl)-1,2,4-triazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:37])[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)([OH:29])[C:25]([F:28])([F:27])[F:26])=[C:19]([Cl:38])[CH:18]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:37])[C:24]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=3)([OH:29])[C:25]([F:26])([F:27])[F:28])=[C:19]([Cl:38])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorosulfonyl-benzoic acid ethyl ester (CAS Reg. No. 10486-51-8, 15 mg) was added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 68 step 4, 20 mg) in pyridine (0.8 ml). The solution was stirred for 30 min at room temperature. The mixture was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (18 mg) as a light yellow foam. MS (m/e)=577.1 [M+H+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:29])([CH3:28])[CH2:20][NH:21][S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:27][N:25]([CH3:26])[S:22]([NH:21][CH2:20][C:19]([F:29])([C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)=[CH:18][CH:17]=1)[CH3:28])(=[O:23])=[O:24]
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 0 °C

Procedure:
In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 285 mg of methanesulfonyl chloride is added dropwise to 350 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine (prepared in example 38) and 380 mg of DBU in THF (125 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and then stirred overnight at this temperature. In the morning, the reaction is concentrated under reduced vacuum. The resulting material is taken into ethyl acetate and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum. This crude material is purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=4)=[O:29])[CH:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28](=[O:29])[NH:27][CH2:26][C:22]2[CH:21]=[C:20]([NH:19][C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)=[O:39])[CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:33]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3cccc(CNC(=O)Nc4ccc(C#N)cc4)c3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)NCc2cccc(NC(=O)c3ccc4c(c3)CCNC4)c2)cc1
Reaction time: 2 h
Yield: 48 %

Procedure:
3,4-Dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (50 mg, 0.18 mmol), EDC (38.3 mg, 0.2 mmol) and HOBt (24.3 mg, 0.18 mmol) were combined in a reaction vial, and DMF (1 mL) was added. To the solution thus formed, N-methylmorpholine (0.22 mL, 0.2 mmol) was added and the reaction mixture was agitated for 1 hour. The urea, 1-(3-amino-benzyl)-3-(4-cyano-phenyl)-urea (40 mg, 0.15 mmol), prepared as described above, was then added as a solution in DMF (0.3 mL), and the reaction mixture was agitated for 48 h. The reaction mixture was diluted to 6 mL with dichloromethane, washed with 1N HCl (3×2 mL), NaHCO3 (satd. aq., 3×2 mL, and brine (1×2 mL), dried and evaporated to 59 mg of an oil (95% yield). This intermediate (6-{3-[3-(4-cyano-phenyl)-ureidomethyl]-phenylcarbamoyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester) was dissolved in dichloromethane (1 mL) and TFA (0.4 mL) was added. The reaction mixture was stirred for 2 h, then the solvents were evaporated and the resulting residue was purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (20 mg, 48% yield), MS analysis electrospray, 426 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=CC=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:35]1CCC(O)C1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH:20]4[CH2:21][CH2:22][O:35][CH2:25]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC1CCOC1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OC1CCOC1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with tetrahydro-3-furanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (14 mg, 0.031 mmol). 1H NMR (CDCl-d) δ 2.07(m, 6H), 3.66(m, 2H), 3.96(m, 7H), 4.13(m, 2H), 4.98(m, 1H), 5.26(s, 2H), 5.40(m, 1H), 6.97(s, 1H), 7.04(s, 1H), 7.08(d, J=8.2 Hz, 1H), 7.26(s, 1H), 8.30(s, 1H), 8.32(s, 1H). LC/MS MH30 =455.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11](N3C[C@H](CNC(=O)C)OC3=O)=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1.[N+:28]([O-:31])(O)=[O:29].O>C(O)(=O)C>[F:14][C:13]1[CH:12]=[C:11]([N+:28]([O-:31])=[O:29])[CH:10]=[C:9]([F:26])[C:8]=1[N:5]1[CH2:4][CH2:3][S:2](=[O:27])(=[O:1])[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a suspension of the product of example 1 (300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. 6 mol, fuming, 90%) is added over 30 min at room temperature. Yellow precipitate is formed within minutes and increases over time. The reaction is kept at room temperature for 18 hours, before it is poured into 6 L of water. After stirred for 2 hours, the yellow suspension is filtered. The precipitate is washed with water (1.5 L×3) and EtOH (0.5 L×2) and dried in oven at 50° C. overnight to give 333 g (94%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[N:9]=[CH:8]1.[Br:20]Br.N.C(O)(C)C.C(Cl)(Cl)Cl>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[C:15]([Br:20])[C:10]=2[N:9]=[CH:8]1
Reactant: COc1cccc(Cn2cnc3cc(N)ccc32)c1
Reactant: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cccc(Cn2cnc3c(Br)c(N)ccc32)c1
Yield: 66 %

Procedure:
To a solution of 1-(3-methoxybenzyl)-5-aminobenzimidazole (0.37 g, 1.3 mmol) in 10 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd Isopropanol/CHCl3) to provide 0.31 g (1.0 mmol, 66%) of the product.