Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]=[C:14]=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:5])=[O:4].[F:18][C@@H:19]1[CH2:23][NH:22][C@@H:21]([C:24]([OH:26])=[O:25])[CH2:20]1>O1CCCC1>[Cl:17][C:8]1[C:7]([NH:6][S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])=[CH:12][C:11]([NH:13][C:14]([N:22]2[CH2:23][C@@H:19]([F:18])[CH2:20][C@@H:21]2[C:24]([OH:26])=[O:25])=[O:15])=[C:10]([F:16])[CH:9]=1
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: O=C(O)[C@H]1C[C@H](F)CN1
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C[C@H](F)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide (120 g, 401 mmol) was dissolved in 400 mL of dry tetrahydrofuran. 55.8 g (420 mmol) of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic acid was added in a single portion and the mixture was stirred overnight at room temperature. The mixture was then filtered and the tetrahydrofuran was evaporated under reduced pressure. The residue was dissolved in 800 mL of ethyl acetate, a solution of 86.0 g of sodium bicarbonate in 870 mL of water was added and then solid sodium chloride was added to saturate the aqueous layer. The aqueous layer was separated, washed with 250 mL of ethyl acetate, and then with diethyl ether (twice with 250 mL). The aqueous layer was then added slowly to a stirred mixture of 120 mL of concentrated hydrochloric acid, 240 mL of water, and 800 mL of tetrahydrofuran. Solid sodium chloride was then added to saturate the aqueous layer, the layers were separated, and the aqueous layer was extracted with 100 mL of tetrahydrofuran. The tetrahydrofuran layers were combined, dried over magnesium sulfate, and evaporated under reduced pressure to afford 173.43 g of the title compound as a glassy solid, suitable for use in the next step. 1H NMR (DMSO-d6): δ2.0-2.3 (m, 1H), 2.5-2.6 (m, 1H), 3.66 (m, 1H), 3.86 (m, 1H), 4.97 (s, 2H), 5.40 (d, J=54 Hz, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 8.48 (s, 1H), 10.10 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CCO>[C:15]1([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2ccc(N3CCCC(c4ccccc4)C3)nn12
Temperature: 70 °C
Yield: 60.2 %

Procedure:
A solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (49 mg, 0.22 mmol) in EtOH (1.0 mL) was added to a mixture of 3-phenylpiperidine (53 mg, 0.33 mmol) and DIPEA (57 μL, 0.33 mmol) in EtOH (1.0 mL). The reaction mixture was heated to 70° C. overnight and the crude product was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 5% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(3-phenylpiperidin-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (46 mg, 61%).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)[CH:9]=1>CCOC(C)=O.[Pd]>[CH3:37][Si:34]([CH3:35])([CH3:36])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Int-9e, 5.05 g) and 10% Pd/C (300 mg) in EtOAc was stirred at 45° C. under hydrogen (balloon pressure) for three hours. After filtration and concentration, tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxy late (Int-9f) (5.1 g) was obtained as an oil. LC/MS: m/z=578.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][C:12](=O)[CH2:13][C:14]([F:17])([F:16])[F:15])=[C:4]([F:19])[CH:3]=1.B.O1CCCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH:11][CH2:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[C:4]([F:19])[CH:3]=1
Reactant: O=C(CC(F)(F)F)Nc1c(F)cc(Cl)cc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: Nc1cc(Cl)cc(F)c1NCCC(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-6-nitrophenyl)-3,3,3-trifluoropropanamide (350 mg, 1.1 mmol) in 15 mL of THF was added borane-tetrahydrofuran solution (25 mL, 1 M). The mixture was heated to 70° C. and stirred overnight. The reaction was quenched with MeOH and the solvents were removed by evaporation to give 4-chloro-6-fluoro-N-(3,3,3-trifluoropropyl)benzene-1,2-diamine (300 mg, yield: 82%) as crude oil. MS obsd. (ESI+) [(M+H)+] 257.
Reaction SMILES: [Na:1].COC1O[CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[O:31]1[C:35]2(CCC(O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[Na:1].[O:31]1[C:35]2([CH2:36][CH2:37][CH:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[O:20])[C:13]=3[CH3:30])[CH2:7][CH2:8]2)[O:34][CH2:33][CH2:32]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: Cc1c(OC2CCC3(CC2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 7.3 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,4-dioxaspiro[4.5]decan-8-ol obtained in the step (27a) to obtain the title compound (230 mg, total yield: 7.3%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.F[C:18](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:18][O:15][C:14]([C:3]1[C:2]([NH2:1])=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)=[O:16]
Reactant: Nc1cnc(-c2ccccc2)nc1C(=O)O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(-c2ccccc2)ncc1N
Temperature: 25 °C

Procedure:
To 4.0 g (0.0186 mole) of 5-amino-2-phenyl-pyrimidine-4-carboxylic acid in an ice bath was slowly added 48 mL of trifluoroacetic anhydride and the mixture was heated to 50° C. for 5 h. The reaction mixture was filtered, washed with a little trifluoroacetic anhydride and dried. To a suspension of the resulting product in 50 mL of methanol, was added 0.1 mL of 0.5M sodium methoxide in methanol. The mixture was refluxed for 15 minutes, cooled to room temperature, and HCl gas was bubbled in for one hour. After cooling and filtering, the solid was treated with 200 ml of 1N NaOH and 200 ml ether. The organic layer was dried over magnesium sulfate, filtered, evaporated to yield 2.43 g of 5-amino-2-phenyl-pyrimidine-4-carboxylic acid methyl ester, as a yellow solid.
Reaction SMILES: Cl.C([O:4][C:5](=[O:19])[CH2:6][C:7]1[C:8]([NH2:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[OH-].[Na+].O>CCO>[NH2:18][C:8]1[C:7]([CH2:6][C:5]([OH:19])=[O:4])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)Cc1c(N)n[nH]c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(-c2ccccc2)c1CC(=O)O
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A solution of 4.1 g (0.014 mole) of 3-amino-5-phenyl-1H-pyrazole-4-acetic acid ethyl ester (Example I free base) in 50 ml of absolute EtOH was treated with 1.23 g (0.016 mole) of 50% NaOH and 10 ml of water, and the mixture was refluxed for 4 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was dissolved in water (10 ml). The pH was adjusted to approximately 6.5 with glacial acetic acid, and a solid precipitated. The solid was collected by filtration to give 1.6 g of product, mp 214°-216° C. with effervesence (50% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC([C@@H]2C(=O)[N:39]([C@@H:42]([C@H:55]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH3:56])[C:43]([NH:45][C:46]3[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=3)=[O:44])C(=O)N2)=CC=1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:17][CH:18]=1)[C:10](=[O:12])[NH:39][C@H:42]([C:43](=[O:44])[NH:45][C:46]1[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=1)[C@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:56])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCN2CCOCC2)cc1
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
(R)-tert-butoxycarbonylamino-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetic acid (≈2.93 mmol) was dissolved in tetrahydrofuran (60 mL) and (2S,3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (500 mg, 1.58 mmol) (prepared as described in example 4) was added followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (600 mg, 3.12 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 5.5 hours the reaction mixture was partitioned between ethyl acetate and brine, the organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting residue purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. {(R)-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-[(1S,2S)-2-phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-methyl}-carbamic acid-tert-butyl ester was obtained as a white solid (146 mg, 14%).
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N:35]#[C:36]Br>O.O1CCOCC1>[C:36]([NH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:35]
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CNC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of [S--(R*,R*)] and [R--(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-[4-(trifluoromethyl)phenyl]urea (0.3 g, 0.75 mmol) in water (5 mL) and 1,4-dioxane (5 mL) is added solid sodium bicarbonate (0.06 g, 0.75 mmol) followed by cyanogen bromide (0.1 g, 0.75 mmol). The resulting mixture is stirred 1.5 hour at room temperature before diluting with water and filtering. The solid product is washed with water (2×) and t-butyl-methyl ether (2×). Dry in vacuo at 43° C. for 2 hours, mp 153° C. -154° C. IR (KBr) 3350, 2225, 1674, 1554, 1326, 1115, 699 cm-1 ; NMR (DMSO-d6), 4.61 (m, 1H), 5.04 (m, 1H), 7.19 (m, 10H), 7.57 (m, 6H), 9.04 (s, 1H). Analysis calculated for C23H19F3N4O.0.31H2O: C, 64.24; H, 4.60; N, 13.03. Found: C, 64.24; H, 4.60; N, 12.67.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([Cl:11])[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])[N:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[N:3][C:4]([CH:12]1[CH2:14][CH:13]1[C:15]#[N:16])=[N:5]2
Reactant: NCc1ccccn1
Reactant: N#CC1CC1c1nc(Cl)c2c(Cl)ccn2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#CC1CC1c1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (±)-2-(4,5-dichloropyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (60.0 mg, 0.237 mmol) in THF (1 mL) was added 2-(aminomethyl)pyridine (0.0290 mL, 0.284 mmol) followed by DIPEA (0.124 mL, 0.711 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 4 g, 10% EtOAc/petroleum ether) to afford (±)-2-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (50.0 mg, 59.1%) as off-white solid. LCMS Condition B-41: retention time 0.67 min, [M+1]=325.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.34 (m, 1H), 1.48-1.51 (m, 1H), 1.92-1.96 (m, 1H), 2.45-2.49 (m, 1H), 4.76 (t, J=4.8 Hz, 2H), 6.72 (d, J=2.8 Hz, 1H), 7.29 (q, J=4.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.77 (q, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.53 (dd, J=1.2 Hz, J=3.2 Hz, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:7]=1)=[O:5].[CH3:24][CH2:25][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:7]=1)(=[O:5])[CH2:24][CH3:25]
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of N-methoxy-N-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (1.20 g, 3.52 mmol) in THF (20 mL) was added EtMgBr (1.0 M in THF, 7.04 mL, 7.04 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was warmed to room temperature, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (767 mg, 74% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.06 (3H, t, J=7.2 Hz), 2.99 (2H, q, J=7.2 Hz), 6.73 (1H, d, J=8.3 Hz), 7.79-7.88 (2H, m), 8.06-8.17 (2H, m), 8.97 (1H, d, J=8.3 Hz).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:18]([CH2:25][CH2:26][OH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:27][CH2:26][CH2:25][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCCOc1ccccc1
Product: N=C(OCCOc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-phenoxyethanol, there is obtained 2-phenoxyethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 358 (20), 265 (7), 237 (65), 194 (100);
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:11]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.N>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]([NH:9][C@H:10]2[C@@H:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N[C@@H](C)c1ccccc1
Reaction time: 20 h
Yield: 94 %

Procedure:
The product of Example 61A (62.3 g, 0.167 mol). NaBH(OAc)3 (150.0 g, 0.708 mol), and powdered 4 Å molecular sieves (133.0 g) in toluene (730 mL) in a 3-neck round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel at 0° C. was treated with acetic acid (191 mL, 3.30 mol) dropwise. After the addition was complete, the ice-bath was removed and the mixture was stirred for 20 hours, filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1000 mL) and quenched by slow addition of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to provide the product as a ˜1:1.5 mixture of the two (cis) isomers (60.0 g, 0.159 mol, 94% yield). MS (DCI/NH3) m/z 377 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[S:7][C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][NH:24][NH2:25])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15]4[C:14](=[N:25][N:24]([CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[C:2]=4[CH:3]=[CH:4][C:5]=3[CH3:18])[C:13]=2[CH:12]=1
Reactant: Cc1ccc(Cl)c2c(=O)c3cc(Cl)ccc3sc12
Reactant: CCN(CC)CCNN
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccc(Cl)cc1-2

Procedure:
By condensation of 1,7-dichloro-4-methyl-9-thioxanthenone with 2-(diethylamino)ethyl hydrazine was obtained 9-chloro-2-(2-(diethylamino)ethyl)-5-methyl-2H-(1)benzothiopyrano[4,3,2-cd]indazole. To 0.13 g. of this base in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.2 ml.). After 18 hours at room temperature the solution was evaporated to dryness under reduced pressure and the residue crystallized from acetone to give 9-chloro-2-(2-diethylamino)ethyl)-5-methyl-2H(1)-benzothiopyrano[4,3,2-cd]indazole N-oxide monohydrate, m.p. 134° - 135° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH:26](Cl)[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH:26]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=2)[CH2:11][CH2:10]1)[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(CN2CCNCC2)c1
Reactant: Clc1ccc(C(Cl)c2cccc(OCc3ccccc3)c2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cccc(CN2CCN(C(c3ccc(Cl)cc3)c3cccc(OCc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
The crude piperazine derivative from above (11.0 g, 56 mmole) was dissolved in 150 ml of toluene and added to 19.2 g (56 mmole) of 3-benzyloxy-4'-chlorobenzhydryl chloride (see U.S. Pat. No. 4,757,074) and heated to reflux for 40 hours. The reaction was cooled to room temperature, diluted to 600 ml with diethyl ether, and washed with 100 ml of 1.0M sodium hydroxide followed by three 200 ml portions of water and 100 ml of saturated sodium chloride. The product was dried over sodium sulfate and the solvent removed to give 27.0 g of crude product as a dark oil. The material was purified by chromatography on silica gel (Waters Prep 500) with 0.1% triethylamine in dichloromethane to give 14.7 g (53%) of 1-(3-benzyloxy-4'-chlorobenzhydryl)-4-(3-methylbenzyl)piperazine as a dark oil. A 5.0 g portion of the oil was dissolved in 300 ml of 2:1 ethanol:methanol and treated with an excess of ethanolic hydrochloric acid to produce the dihydrochloride salt of the product. Addition of 150 ml diethyl ether and cooling provided 1.74 g of the salt as white crystals, mp. 204°-208° C. Calc. for C32H33ClN2O 2HCl: C, 67.43; H, 6.19; N, 4.91; Cl, 18.66. Found: C, 67.15; H, 6.14; N, 4.87; Cl, 18.58.
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23](=O)[CH2:24]Br)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].[NH2:27][C:28]([NH2:30])=[S:29]>CN(C)C(=O)C>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:30][C:28](=[NH:27])[S:29][CH:24]=1)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)ON=C(C(=O)CBr)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=N)[nH]1
Yield: 43 %

Procedure:
In 20 ml of N,N-dimethylacetamide there were dissolved 26.5 g of benzhydryl 2-acetoxyimino-4-bromo-3-oxobutyrate and, under ice-cooling and stirring, 4.81 g of thiourea was added. The mixture were stirred at room temperature for 3 hours and 15 minutes, after which it was washed well with 80 ml of ether. The ether was discarded after being removed by decantation. The above procedure was carried out once again and the mixture was poured into 100 ml of water, whereupon crystals separated out. After loosening, the crystals were recovered by filtration and washed with ether, a small amount of ethyl acetate and ether in the order mentioned. By the above procedure there were obtained 10.738 g of crystals of the captioned compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl>[OH:46][C:39]1[C:38]([CH2:37][NH:36][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][CH:11]=2)=[C:43]([CH3:44])[CH:42]=[C:41]([CH3:45])[N:40]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: COC(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(c1ccccc1)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
A mixture of 4-(methoxy(phenyl)methyl)benzoic acid (0.26 g, 1.07 mmol), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (309 mg, 1.61 mmol), 1-hydroxybenzotriazole (218 mg, 1.61 mmol), triethylamine (0.45 mL) and dichloromethane (15 mL) was stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (163 mg, 1.07 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(methoxy(phenyl)methyl)benzamide (Compound I-53) as a white solid (80 mg, 20%). LRMS (M+H+) m/z: calcd 376.18. found 376. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.25 (t, J=3.6 Hz, 1H), 7.30 (d, J=6.9 Hz, 2H), 7.41-7.18 (m, 7H), 5.95 (s, 1H), 5.83 (s, 1H), 4.27 (d, J=3.6 Hz, 2H), 3.31 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H).