Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:55][C@@H:56]1[C:62](=[O:63])[N:61]([CH2:64][C:65]2[C:74]3[C:69](=[CH:70][C:71]([Br:75])=[CH:72][CH:73]=3)[CH:68]=[CH:67][C:66]=2[O:76][CH3:77])[C:60]2[CH:78]=[CH:79][CH:80]=[CH:81][C:59]=2[NH:58][CH2:57]1>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[N:1]([C@H:2]([C:4](=[O:6])[NH:55][C@@H:56]1[C:62](=[O:63])[N:61]([CH2:64][C:65]2[C:74]3[C:69](=[CH:70][C:71]([Br:75])=[CH:72][CH:73]=3)[CH:68]=[CH:67][C:66]=2[O:76][CH3:77])[C:60]2[CH:78]=[CH:79][CH:80]=[CH:81][C:59]=2[NH:58][CH2:57]1)[CH3:3])[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Yield: 90.2 %

Procedure:
Boc-N-Me-Ala-OH (650 mg, 3.19 mmol), HATU (1.32 g, 3.48 mmol) and DIPEA (1.52 mL, 8.72 mmol) were added to a solution of (S)-3-amino-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (1.6 g, 2.90 mmol) in DMF (10 mL). After 18 the mixture was evaporated and the mixture diluted with ethyl acetate. The mixture was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography to afford the title compound (1.6 g, 88%) as a yellow solid. LC-MS: 611 (M+H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15].O.C1(C)C=CC=CC=1>C(O)(=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[N:15]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride (22.8 g, 150 mmol), 2-fluoro-5-nitroaniline (23.4 g, 150 mmol) in glacial acetic acid is heated at reflux for 23 hours, cooled and poured into a water/toluene mixture. The organic phase is separated, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried and concentrated in vacuo to obtain a yellow solid. Recrystallization of the solid from ethanol gives the title compound as off-white plates (26.6 g, mp 154°-156° C.) which are identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.COCCO>CO>[ClH:11].[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:15][CH:12]2[CH2:14][CH2:13]2)[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: NC1CC1
Solvent: COCCO
Solvent: CO
Product: Cl
Product: Nc1nc(NC2CC2)c2nc[nH]c2n1
Temperature: 70 °C
Yield: 23 %

Procedure:
A solution of 2-amino-6-chloropurine (4.6 g, 27.5 mmole) and cyclopropylamine (12.5 g, 220 mmole 8 equiv) in MeOH (100 ml) was heated at 50° C. for 18 hours. Then 2-methoxyethanol (50 ml) was added, and the reaction was heated at 70° C. for an additional 6 hours. After cooling, a small amount of unreacted starting material was filtered off, and the filtrate was evaporated and purified on a silica gel column eluting with CHCl3 : 5% to 10% MeOH. The product was then recrystallised twice from MeOH and once from EtOH as a hydrochloride salt to give 1.45 g, (23%) of product; m.p. 253°-257° C.,
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][C@@:4]1([OH:12])[CH:9]2[CH2:10][CH2:11][NH+:6]([CH2:7][CH2:8]2)[CH2:5]1.[Cl-].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[N:29][C:28]([N:36]=[C:37]=[S:38])=[CH:27]2>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[N:29][C:28]([NH:36][C:37]([NH:2][CH2:3][C@@:4]1([OH:12])[CH:9]3[CH2:8][CH2:7][N:6]([CH2:11][CH2:10]3)[CH2:5]1)=[S:38])=[CH:27]2
Reactant: [NH3+]C[C@]1(O)C[NH+]2CCC1CC2
Reactant: COc1cc2cnc(N=C=S)cc2cc1Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2cnc(NC(=S)NC[C@]3(O)CN4CCC3CC4)cc2cc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirring suspension of (S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride (111 mg, 0.484 mmol) in DMF (3 mL) was added Hunig's Base (0.5 mL, 2.86 mmol) and the resulting mixture was stirred at room temperature for 35 minutes. Then was added a suspension of 6-chloro-3-isothiocyanato-7-methoxyisoquinoline (106 mg, 0.423 mmol) in DMF (3 mL) and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated in vacuo and the residue subjected to a silica gel column in 1% NH4OH/9% MeOH/90% CHCl3 to give 140.3 mg (82%) as a white solid, (S)-1-(6-chloro-7-methoxyisoquinolin-3-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea. LCMS RT 1.28 min, MH+=407.1, 409.0, 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.85 (1H, t, J=5.2 Hz), 9.15 (1H, br. s.), 8.63 (1H, s), 7.76 (1H, s), 6.92 (1H, s), 6.89 (1H, s), 4.14 (1H, dd, J=13.9, 5.6 Hz), 3.99 (2H, s), 3.90 (1H, dd, J=14.0, 5.2 Hz), 3.46 (3H, s), 2.89-3.01 (2H, m), 2.75-2.88 (3H, m), 2.03-2.15 (1H, m), 1.89-1.96 (1H, m), 1.77-1.88 (1H, m), 1.63 (1H, ddd, J=13.4, 6.1, 3.4 Hz), 1.32-1.45 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O-:14])=[O:13]>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH:11][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])=[O:26])[N:3]=1
Reactant: Cc1nc(N)nc2c1CCC2
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc2c1CCC2
Yield: 60.9 %

Procedure:
To a dry, stirred solution of 10 g of 6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-amine in 800 ml of methylene chloride at ambient temperature and pressure was added 14.9 g of 2-nitrobenzenesulfonylisocyanate. The resulting mixture was stirred at reflux temperature (42°) for 2 hours after which the methylene chloride was removed under reduced pressure. The resulting solid was triturated with methanol or 1-chlorobutane and filtered to yield 15 g of N-[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]-2-nitrobenzene-sulfonamide, m.p. 202°-205°. The product showed characteristic absorption bands in the infrared spectrum at 1675 cm-1 and at 1.7, 3.2 and 7.7 to 8.5 ppms by nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: C1C2CCC3C=CC=CC=3N(C(Cl)=O)C=2C=CC=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[Cl:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1)[NH2:43].C1(C)C=CC=CC=1>C(O)C>[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[Cl:39][C:40]1[CH:41]=[C:42]([NH:43][C:37]([NH:36][C:34]([N:24]2[C:25]3[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=3[CH2:27][CH2:28][C:29]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]2=3)=[O:35])=[S:38])[CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N1c2ccccc2CCc2ccccc21
Agent: O=C(N=C=S)N1c2ccccc2CCc2ccccc21
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4c5ccccc5CCc5ccccc54)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was prepared using commercially available 10,11-dihydro-5H-dibenzo(b,f)azepin-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 10,11-Dihydro-5H-dibenzo(b,f)azepine-5-carbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 50%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21]([C:24]1[CH:25]=[C:26]([CH2:33]O)[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[CH:32]=1)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:4][CH2:33][C:26]1[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[CH:32]=[C:24]([S:21]([C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])(=[O:23])=[O:22])[CH:25]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C)cc1S(=O)(=O)c1cc(CO)c2occc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1S(=O)(=O)c1cc(CCl)c2occc2c1

Procedure:
Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dry DCM (2 mL) and DMF (0.9 mL, 1.1 mmol) was added (very exothermic reaction). {5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methanol (370 mg, 1.1 mmol; Intermediate 68)
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:34]=[CH:35][N:36]([CH2:39][C:40]#[CH:41])[C:37]=1[Cl:38]>N(CC)CC.CN(C=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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][N:36]4[C:37]([Cl:38])=[C:33]([Cl:32])[N:34]=[CH:35]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCn1cnc(Cl)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCn3cnc(Cl)c3Cl)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.1 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) and anhydrous DMF (10 mL) is added 4,5-dichloro-1-prop-2-ynylimidazole (104.8 mg). The reaction is sonicated and stirred at room temperature for 2 days. The reaction is condensed to afford a residue. The residue is adsorbed onto silica and chromatographed (eluant 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined and condensed to afford 20 mg of the title compound as a white solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11].[C:14]1([C:20]2[S:24][C:23]([S:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]3[C:34]([NH:36][O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[O:35])(=[O:27])=[O:26])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]1([C:20]2[S:24][C:23]([S:25]([N:28]3[CH2:33][CH2:32][N:31]([S:10]([CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)(=[O:12])=[O:11])[CH2:30][C@@H:29]3[C:34]([NH:36][O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[O:35])(=[O:26])=[O:27])=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCc1ccccn1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)[C@H]1CN(S(=O)(=O)CCc2ccccn2)CCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
2-(2-Pyridyl)ethanesulfonyl chloride hydrochloride (214 mg) was added to a solution of (2R)-1-(5-phenylthiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (200 mg) and triethylamine (188 mg) in CHCl3 (3 ml) with cooling on an ice bath. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by SiO2 column chromatography eluted with MeOH in CHCl3 (1%) to give 184 mg of (2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[2-(2-pyridyl)-ethanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: C([Mg]Cl)(C)C.[Si:6]([O:13][C@H:14]([CH3:21])[CH2:15][C:16]([O:18]CC)=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:22][NH:23][O:24][CH3:25].Cl>C1COCC1>[Si:6]([O:13][C@H:14]([CH3:21])[CH2:15][C:16]([N:23]([O:24][CH3:25])[CH3:22])=[O:18])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
A solution of 2M isopropylmagnesium chloride in THF (800 mL, 1.60 mol) was added dropwise via cannula over 60 min to a stirred solution of (R)-ethyl 3-(tert-butyldimethylsilyloxy)butanoate (131 g, 532 mmol) and N,O-dimethylhydroxylamine/HCl (80 g, 824 mmol) in dry THF (850 mL) while maintaining the internal temperature between −30° C. and −20° C. The suspension was allowed to stir for 3 h between −20 and −10° C., and quenched while cold with saturated aqueous ammonium chloride solution (400 mL). The reaction mixture was partitioned between water (200 mL) and diethyl ether (500 mL) and the aqueous phase was further extracted with diethyl ether (1 L). The combined organic phases were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to yield (R)-3-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylbutanamide. The reaction was repeated 6 times to yield a total of 717 g material. The analytical data complied with data reported in the literature. The material was used without additional purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[OH:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([O:28][CH2:29][CH3:30])=[N:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:16][C:13]1[N:12]=[N:11][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][O:17][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([O:28][CH2:29][CH3:30])=[N:23][CH:24]=[N:25]4)=[CH:20][CH:19]=3)[CH2:5][CH2:6]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reactant: CCOc1ncnc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ncnc2cc(OCCC3CCN(c4ccc(C)nn4)CC3)ccc12
Temperature: 90 °C
Yield: 17.6 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine (76 mg, 318 μmol), 7-hydroxy-4-ethoxyquinazoline (100 mg, 526 μmol), potassium carbonate (109 mg, 789 μmol) and potassium iodide (53 mg, 319 μmol) in DMF (5 mL) was heated at 90° C. overnight in an argon atmosphere. The mixture was concentrated, and the residue partitioned between ethyl acetate (100 mL), and water (20 mL). The organic phase was dried (MgSO4), filtered, concentrated and purified by column chromatography (silica), using gradient elution (ethyl acetate-methanol/EA). The combined fractions gave a white solid (22 mg, 18%). The 1H nmr data are recorded in Table 6 below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[C:31]([O-:34])([O-])=O.[K+].[K+].O.C(Cl)(=O)OC(C)=C.[NH2:45][C@H:46]([CH2:53][O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:47]([OH:52])[C:48]([F:51])([F:50])[F:49]>C1COCC1.CCOC(C)=O>[CH2:55]([O:54][CH2:53][C@@H:46]([NH:45][C:31]([NH:23][C@@:15]([C:4]1[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=1)([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:34])[C@@H:47]([OH:52])[C:48]([F:51])([F:50])[F:49])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C([O-])[O-]
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: N[C@H](COCc1ccccc1)[C@@H](O)C(F)(F)F
Agent: C=C(C)OC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H](COCc1ccccc1)[C@@H](O)C(F)(F)F)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (20 mg, 0.047 mmol), prepared as described in Procedure 3, 4, 5 and 6, in THF (0.5 mL) was added K2CO3 in H2O (10 mg, 2 M in H2O, 0.071 mmol), followed by the addition of prop-1-en-2-yl carbonochloridate (6 μL, 0.052 mmol). The reaction mixture was stirred at rt for 2 h, diluted with EtOAc (25 mL), washed with saturated NaCl (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. To the residue was added (2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol (23 mg, 0.094 mmol), prepared according to the procedure described in J. Org. Chem., 68(19):7545 (2003), TEA (20 μL, 0.14 mmol) in THF (0.5 mL). The reaction mixture was heated at 70° C. for 18 h. The reaction solution was concentrated under reduced pressure and purified by ISCO chromatography (12 g column) using hexane/EtOAc (0-30% over 20 min) to give 1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (Example 236) as a white solid at a retention time of 17 min (19 mg, 59% yield). LCMS: RT=2.138 min [M+H] 701.29 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm); HPLC: RT=4.335 min, Purity 94% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.37 ppm, 3H, m; 7.25 ppm, 3H, m; 7.20 ppm, 1H, t, J=7.03 Hz; 7.13 ppm, 4H, m; 6.97 ppm, 2H, t, J=8.35 Hz; 6.89 ppm, 3H, m; 6.69 ppm, 2H, d, J=7.47 Hz; 5.86 ppm, 1H, m; 5.18 ppm, 1H, d, J=8.35 Hz; 5.13 ppm, 1H, s; 4.44 ppm, 2H, m; 4.26 ppm, 1H, d, J=9.67 Hz; 4.14 ppm, 1H, dd, J=8.13, 3.30 Hz; 3.99 ppm, 1H, m; 3.81 ppm, 2H, m; 3.71 ppm, 1H, m; 3.59 ppm, 1H, m.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]3[CH:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[NH:13][N:12]=[C:11]3[C:5]=2[CH:4]=1.[CH3:23][N:24]1[CH:28]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:27]2[CH2:35][CH2:36][C:37]3[C:42]([C:26]2=[N:25]1)=[CH:41][CH:40]=[CH:39][CH:38]=3>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:5]=2[CH:4]=1.[CH3:23][N:24]1[C:28]([C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[C:27]2[CH2:35][CH2:36][C:37]3[C:42]([C:26]2=[N:25]1)=[CH:41][CH:40]=[CH:39][CH:38]=3
Reactant: CN1N=C2c3ccccc3CCC2C1c1ccncc1
Reactant: COc1ccc2c(c1)C1=NNC(c3ccncc3)C1CCC2
Product: COc1ccc2c(c1)-c1n[nH]c(-c3ccncc3)c1CCC2
Product: Cn1nc2c(c1-c1ccncc1)CCc1ccccc1-2

Procedure:
Following the above procedure but using an equivalent amount of 9-methoxy-3-(4-pyridyl)-2,3,3a,4,5,6-hexahydrobenzo[6,7]cyclohepta[1,2-c] pyrazole or 2-methyl-3-(4-pyridyl)-3,3a,4,5-tetrahydro-2H-naphtho[1,2-c] pyrazole in place of the 3-(4-pyridyl)-2,3,3a,4,5,6-hexahydrobenzo[6,7]cyclohepta[ 1,2-c]pyrazole used therein, there is obtained 9-methoxy-3-(4-pyridyl)-2,4,5,6-tetrahydrobenzo[ 6,7]cyclohepta[1,2-c]pyrazole (m.p. 200°-201°C) or 2-methyl-3-(4-pyridyl)-4,5-dihydro-2H-naphtho[1,2-c]pyrazole (m.p. 124°-217°C).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)[N:9]=1.Cl>CO.O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate (1.09 g, 2.35 mmol) was dissolved in methanol (5 mL) and 4M hydrogenchloride in dioxane (5 mL) was added. The solution was stirred at room temperature overnight, then the mixture evaporated to a dark brown oil and dissolved in ethyl acetate (10 mL). Water (5 mL) was added followed by the addition of sodium bicarbonate solution until neutral pH was achieved (˜2 mL). The phases were separated and the organic phase washed with water (10 mL). The organic layer was dried over magnesium sulphate and evaporated to a pale yellow foam (805 mg).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].C(NC(C)C)(C)C.[Li]CCCC.C(=NC1CCCCC1)CC.CN1C(=[O:38])N(C)CCC1.[C:40]([O:44][C:45]1[C:50]([F:51])=[CH:49][N:48]=[CH:47][C:46]=1[CH3:52])([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([O:44][C:45]1[C:50]([F:51])=[CH:49][N:48]=[C:47]([CH:3]([CH3:4])[CH:2]=[O:38])[C:46]=1[CH3:52])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cncc(F)c1OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Reactant: CN1CCCN(C)C1=O
Agent: CCC=NC1CCCCC1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c(C(C)C=O)ncc(F)c1OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
To a solution of LDA (6.22 mmol, prepared from diisopropylamine (0.81 mL) and n-BuLi (2.5M in hexanes, 2.49 mL) in THF (5.0 mL) at 0° C. was added N-(propylidene)-cyclohexylamine (0.89 mL, 6.47 mmol, prepared in situ from propionaldehyde and cyclohexylamine) dropwise, and the reaction mixture was stirred for 20 minutes. To this solution at 0° C. was added DMPU (6.22 mmol), the mixture was stirred for 10 minutes, then cooled to -78° C. To this solution was added 4-t-butoxy-5-fluoro-3-methylpyridine (0.50 mL, 2.49 mmol) dropwise, and the mixture was warmed to -20° C. and stirred at this temperature for 16 hours. The reaction was then quenched with acetic acid (1M, 15 mL), diluted with hexanes (100 mL) and dilute acetic acid (1M, 85 mL), and stirred vigorously for 1 hour. The organic layer was separated, washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel, eluting with 5% to 10% ethyl acetate in hexanes, to afford the title compound (0.24 g, 49% yield) as an oil. MS 240 (M+H)+ ; 1H NMR (CDCl3) δ1.43 (d, 3H, J=7.0 Hz), 1.43 (d, 9H, J=1.1 Hz), 2.26 (s, 3H), 3.84 (q, 1H, J =7.0 Hz), 8.26 (d, 1H, J=2.2 Hz), 9.78 (d, 1H, J=1.1 Hz).