Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH2:28][CH3:29].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH2:28][CH3:29]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCCN
Agent: S
Solvent: CCO
Product: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 120 °C

Procedure:
A mixture of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1 g) and butylamine (1.5 cc) in absolute ethanol (20 cc) is saturated with hydrogen sulphide and then heated for 24 hours to a temperature in the region of 120° C. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with distilled water (10 cc) and ethyl acetate (25 cc). After extraction, the organic phase is separated, washed with distilled water (10 cc) and then with saturated aqueous sodium chloride solution (20 cc), dried over potassium carbonate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Butyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.15 g) is thereby obtained in the form of a viscous yellow oil which is subsequently used as it is.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](=[O:36])C(Cl)(Cl)Cl)=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1.O>O1CCOCC1>[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:1][CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:36])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3)cc1)C2
Yield: 10.6 %

Procedure:
A solution of 0.216 g (0.002 mol) of 3-aminomethylpyridine and 0.508 g (0.001 mol) of 1-[10-(1,1′-biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-2,2,2-trichloroethanone of Step B in 25 mL of 1,4-dioxane was heated overnight under reflux with stirring. The cooled reaction mixture was poured into 200 mL of water. The solid was collected and dried to provide the title compound (0.053 g).
Reaction SMILES: [N:1]1([C:7](=[O:15])[CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[N:35]([C:44](Cl)=[O:45])[C:34]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:33]2)=[CH:28][CH:27]=1.Cl>C(Cl)Cl.O>[ClH:25].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C@H:32]2[C@@H:36]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[N:35]([C:44]([N:12]3[CH2:11][CH2:10][N:9]([CH2:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:15])[CH2:14][CH2:13]3)=[O:45])[C:34]([C:47]3[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:33]2)=[CH:30][CH:31]=1
Reactant: CCOc1cc(C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 191 %

Procedure:
A solution of morpholin-4-yl-2-piperazin-1-yl-ethanone (17 mg, 0.081 mmol, Oakwood Products) and diisopropylethylamine (10 mg, 0.077 mmol) in 0.5 mL of methylene chloride was added to a solution of (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (35 mg, 0.070 mmol, example 29) in 0.5 mL of methylene in a 4-mL vial. The vial was then capped and shaken for 1 h at room temperature. The reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water. The vial was agitated and centrifuged. The organic layer was transferred to a 4-mL vial and concentrated in vacuo. The crude was dissolved in 0.5 mL of acetonitrile, and then 0.6 mL of water and 0.492 mL of 0.5 M hydrochloric acid (2.46 mmol) were added to the sample. The sample was frozen with liquid nitrogen and lyophilized to give 4-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-benzonitrile hydrochloride (47.6 mg, 91% yield). LC-MS: 675.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])(=[O:11])=[O:10]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2Cl)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.24 g of (2-chlorophenyl)methanesulfonyl chloride were initially charged in 30 ml of dichloromethane, and 1.66 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of water, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.93 g) was used in the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:4]2.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].P(C#N)(OCC)(OCC)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:15](=[O:17])[CH:14]=[CH:13][C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)C=CC1=Cc2cnc3cccc(n23)S1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C=CC2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 8 h

Procedure:
While 0.708 g (2.898 mM) of 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylic acid, 0.68 g (3.19 mM) of 1-(tert-butoxycarbonyl)piperidin-4-ylmethylamine, and 0.48 ml (3.48 mM) of triethylamine were stirred together in 10 ml of N,N-dimethylformamide, 0.53 ml (3.48 mM) of diethyl cyanophosphate was added dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[F:23])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=3[F:23])[O:24][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 3-[[5-(3,5-difluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-difluoro-phenol (20 mg, 0.05 mmol, 1.0 eq) in DMF (3 mL) was added Cs2CO3 (26 mg, 0.075 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (11 mg, 0.06 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 1 h then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 30:1) to give the title compound as a colorless oil (23 mg, 92%).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(N(CC)CC)C>ClCCl>[O:30]([C:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=2[CH:16]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)Oc3ccccc3)cc1[C@@H](NC(C)=O)CC2
Yield: 79 %

Procedure:
A solution of N-acetyl colchicinol (0.35 g; 0.98 mmol), phenyl chloroformate (145 μl; 1.08 mmol) and triethylamine (150 μl; 1.08 mmol) in dichloromethane (20 ml) was stirred at ambient temperature for 1 hour. The mixture was washed with water and the organic phase evaporated. The residue was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (80/20) to give N-[(5S)-3-phenoxycarbonyloxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a foam.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38](O)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38]([NH:27][C@H:24]3[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]4[CH2:17][CH2:18][N:13]([C:12]5[C:7]6[O:6][CH2:5][O:4][C:8]=6[CH:9]=[CH:10][CH:11]=5)[CH2:14][CH2:15]4)[CH2:22][CH2:23]3)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (26 mg, 64.6%), MS (ISP) m/z=494.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Product: CC(=O)NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 80 %

Procedure:
The title compound (75 mg, 80%) was prepared from the compound from Example 12, step 2 (100 mg, 0.3 mmol) and acetic anhydride by the procedure described in Example 24 Example 14: MS (ESI) m/z 311 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.58 (m, 2H), 2.08 (m, 2H), 2.84 (dd, J=2.8, 12 Hz, 2H), 3.54 (dd, J=2.8, 12.8 Hz, 2H), 3.93 (m, 1H), 5.35 (d, J=7.2 Hz, 1H), 6.91-6.97 (m, 6H), 7.03 (m, 1H), 7.27-7.31 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:5][C:6]=1[C:7]([OH:9])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[O:58]1[CH2:59][CH2:60][CH:55]([NH:54][C:7]([C:6]2[S:5][C:4]([CH2:10][CH2:11][C:12]3[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:14][O:15][CH:16]=3)=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:56][CH2:57]1
Reactant: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (70 mg, 0.22 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (79 mg, 0.24 mmol), N,N-diisopropyl ethyl amine (190 μL, 1.11 mmol) and 4-aminotetrahydropyran (25 mg, 0.24 mmol). The resulting reaction mixture was stirred overnight and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (84 mg, 95%) as a white solid. S: m/e=399.2 [M+H]+.
Reaction SMILES: [H-].[Na+].C1(S)C=CC=CC=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:22]C)=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([OH:22])=[C:15]([S:17]([NH:20][CH3:21])(=[O:18])=[O:19])[CH:16]=1
Reactant: CNS(=O)(=O)c1cc(Cl)ccc1OC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(Cl)ccc1O
Yield: 64.2 %

Procedure:
To a solution of sodium hydride (60% in mineral oil, 90.24 mg, 2.25 mmol) in dry dimethyl formamide was added thiophenol (0.225 ml, 2.25 mmol) dropwise. To this was then added 5-Chloro-2-methoxy-N-methyl-benzenesulfonamide (531 mg, 2.25 mmol) followed by refluxing for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with a 1N sulfuric acid solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel yielded the above titled compound (320 mg, 53% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([OH:23])[CH:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[F:21])[C:14]([CH3:22])=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC1C=CC=C2C=1N([C@@H](C1C=CC=CC=1)[C@H](O)CO)C=C2C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+]>>[ClH:1].[NH2:2][CH2:3][C@@H:4]([OH:23])[C@@H:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[F:21])[C:14]([CH3:22])=[CH:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cn(C(c2ccccc2)C(O)CN)c2c(F)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1cn([C@@H](c2ccccc2)[C@H](O)CO)c2c(F)cccc12
Agent: Cl
Product: Cc1cn([C@@H](c2ccccc2)[C@H](O)CN)c2c(F)cccc12

Procedure:
In an analogous manner to EXAMPLE 117, step 6 3-amino-1-(7-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol hydrochloride was prepared from (2S,3S)-3-(7-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (EXAMPLE 179, step 4) and para-toluenesulfonic acid followed by ammonium hydroxide as a white solid. MS (ES) m/z 299.0.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19]3)=O)[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2([CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][CH:10]([CH2:8][NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11]3)[CH2:19][CH2:20][CH2:21]2)=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccccc1)C1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(CN3CCCC(CNc4ccccc4)C3)CCC2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A solution of 202 (0.504 mmol, 200 mg) in Toluene (2 mL) at 0° C. was treated with 3.0 M Red-Al (3.5 equiv, 1.76 mmol) under Ar. The reaction mixture stirred for 12 h and returned to 25° C. The reaction mixture was then cooled to 0° C., quenched with 10% aqueous NaOH and extracted with EtOAc (3×25 mL). The organics were dried with NaCl(sat) and Na2SO4 (s). The reaction mixture was purified by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, 2:1 hexane-EtOAc) which provided 203 (170 mg, 186 mg theoretical, 91%) as a colorless oil: Rf 0.61 (SiO2, 2:1 hexane-EtOAc); LRMS m/z 368 (M+, C23H29ClN2, requires 368).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH:24]([OH:42])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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]>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH:24]([OH:42])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:12])=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)[CH:28]=1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: Cc1cn(C)c2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn(C)c2cc(-c3cccc(OCC(O)CN4CCc5ccccc5C4)c3)ccc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 6-bromo-1,3-dimethyl-1H-indole (200 mg, 0.89 mmol), 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (401 mg, 0.98 mmol), K2CO3 (369 mg, 2.67 mmol) and Pd(dppf)Cl2 (50 mg) in dioxane (8 mL) and H2O (2 mL) was stirred at 100° C. for 16 h under N2. The catalyst was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to afford the title compound (38 mg, Yield 10%). 1H NMR (400 MHz, MeOD): δ 8.42 (s, 1H), 7.52-7.50 (m, 2H), 7.37-7.25 (m, 7H), 7.16-7.14 (m, 1H), 6.93-6.89 (m, 2H), 4.48-4.45 (m, 1H), 4.34 (s, 2H), 4.11-4.09 (m, 2H), 3.76 (s, 3H), 3.50-3.47 (m, 2H), 3.36-3.31 (m, 2H), 3.31-3.14 (m, 2H), 2.30 (s, 3H) ppm; ESI-MS (m/z): 427.3 [M+1]+.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:30]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added MeI (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 62 mg (59%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[N:17]4[N:18]=[C:19](/[C:22](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 62 %

Procedure:
The title compound (14.0 mg, 59%) was synthesized from 1-(3-(1-(1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (20.0 mg, 0.06 mmol) and hydrazinecarboxamide (13.97 mg, 0.13 mmol) using the same procedure as described in the synthesis of example 69. 1H-NMR (400 MHz, CDCl3) δ ppm 8.33 (s, 1H), 7.87 (m, 2H), 7.66 (m, 3H), 7.32 (m, 2H), 4.74 (q, 1H), 4.03 (s, 3H), 2.24 (s, 3H), 1.84 (d, 3H). LCMS (method A): [MH]+=377, tR=4.70 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)#[N:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(C#N)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (103 mg), p-cyanophenol (127 mg), triphenylphosphine (126 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (90 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:4) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (118 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:30])([F:29])[F:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccccc2C(F)(F)F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 28.9, 32.0, 42.7, 60.5, 121.9, 126.2, 126.5, 127.1, 128.8, 129.8, 132.0, 132.6, 139.2, 140.2 and 143.1.