Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)CCl.[BH4-].[Na+]>C(Cl)Cl.CC(OC)(C)C.C([O-])([O-])=O.[K+].[K+]>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:30](=[O:31])[C@@H:22]([OH:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: ClCCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)cc1C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (800 mg, 0.27 mmol, prepared as described in example 1, step 3) in CH2Cl2 (3 mL) was added under a nitrogen atmosphere at 0° C. benzoylformic acid (61 mg, 0.41 mmol), EDC (130 mg, 0.68 mmol). After stirring for 1 h, the mixture was concentrated and redissolved in MeOH (3 mL) and treated with NaBH4 (206 mg, 5.44 mmol) and stirring continued for 3 h at ambient temperature. It was diluted with TBME (15 mL) and aqueous K2CO3 (2 M, 15 mL), stirred further for 20 min, the layers separated and the organic layer washed with water (15 mL). The combined aqueous layers were extracted with TBME (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the racemic compound (78 mg, 67%) as a pale yellow oil. MS m/e: 429.2 [M+H]+ which was then separated by chiral HPLC to provide the title compound as an off white solid MS m/e: 429.2 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([Cl:19])[C:15]([CH3:18])=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu].[Zn]>[CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([Cl:19])[C:15]([CH3:18])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)nc2nc(SCc3ccccc3)nn2c1Cl
Agent: [Cu]
Agent: [Zn]
Product: Cc1cn2nc(SCc3ccccc3)nc2nc1Cl
Yield: 32 %

Procedure:
This material was prepared in 32% yield by reduction of 2-benzylthio-5,7-dichloro-6-methyl-1,2,4-triazolo[1,5-a]pyrimidine with zinc-copper couple following the general procedure described in Example 21. The desired product was isolated as a solid, m.p. 179°-181° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [OH-].[K+:2].O.[NH:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[N:7][N:6]=[N:5]1.CCO>>[NH:4]1[C:8]([C:9]([O-:11])=[O:10])=[N:7][N:6]=[N:5]1.[K+:2].[K+:2].[NH:4]1[C:8]([C:9]([O-:11])=[O:10])=[N:7][N:6]=[N:5]1
Reactant: CCOC(=O)c1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1nnn[nH]1
Yield: 128 %

Procedure:
Dipotassium 1H-tetrazole-5-carboxylate was prepared as follows: A solution of potassium hydroxide (1.3 g, 23.2 mmol) in water (4.2 mL, 230 mmol) was added to a solution of ethyl tetrazole-5-carboxylate (1.1 g, 7.7 mmol) in EtOH (24 mL, 410 mmol). The solid product that formed immediately was collected and washed with cold EtOH to yield dipotassium 1H-tetrazole-5-carboxylate (1.5 g).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=O)[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:8]1>C(O)C>[CH3:6][N:7]1[CH2:8][CH:9]=[C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:24])[CH:20]=3)[NH:15][CH:14]=2)[CH2:11][CH2:12]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(N)=O)cc23)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
H2SO4 (0.1 mL) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carboxamide (130 mg, 0.41 mmol) in ethanol (4 mL) and the resulting solution was stirred at room temperature for 1 hour. Filtration and subsequent concentration afforded 20 mg (18.6%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:36]C(C[AlH]CC(C)C)C.C[Zn]C>C1COCC1.CCOC(C)=O>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH3:36])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: CC(C)C[AlH]CC(C)C
Agent: C[Zn]C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 60 °C
Yield: 744.4 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (112 mg, 0.180 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (7.33 mg, 8.98 μmol) in THF (5 ml) at 0° C. was added DIBAL-H (1.0 M solution in dichloromethane) (0.018 ml, 0.018 mmol), followed by dimethylzinc (1.0 M solution in heptane) (0.197 ml, 0.197 mmol), and the reaction mixture was stirred with heating at 60° C. for one hour. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (75 mg, 0.134 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 8.72-8.86 (m, 1H), 7.98 (s, 1H), 7.45 (dd, J=8.6, 1.4 Hz, 1H), 7.30-7.40 (m, 1H), 7.01 (s, 1H), 6.71 (d, 2H), 5.49 (s, 2H), 4.47 (d, 2H), 3.38 (t, 2 H), 2.25 (s, 3H), 0.75 (t, 2H), −0.09 (s, 9H
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:25](/B(O)O)=[CH:26]\[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(C(c2ccc3nccc(Br)c3c2)c2nccs2)cc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(C(c2ccc3nccc(/C=C/c4ccccc4)c3c2)c2nccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (28 mg, 0.0674 mmol), (E)-styrylboronic acid (19.9 mg, 0.135 mmol), Pd(OAc)2 (1.5 mg, 0.00674 mmol), SPhos (5.5 mg, 0.022 mmol) and K3PO4 (28.6 mg, 0.135 mmol) was stirred at room temperature overnight under argon. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc twice. The organic layers combined were concentrated and the crude material was purified by silica column chromatography (25% EtOAc/hexanes) to yield (E)-2-((4-chlorophenyl)(4-styrylquinolin-6-yl)methyl)thiazole.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12]C)=[O:11])[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of 1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid, methyl ester [1.8 g, Reference Example 19(c)] in methanol (60 mL) was treated with sodium hydroxide solution (25 mL, 2N) and the mixture was stirred at room temperature for 2 hours then evaporated. The residue was treated with water (50 mL) and the pH of the mixture was adjusted to 34 by addition of hydrochloric acid. The resulting yellow solid was filtered, then washed well with water and then dried to give the title compound (1.1 g) as a yellow solid.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:18])([CH3:17])[CH2:9]/[C:10]/2=[CH:13]\[C:14](Cl)=[O:15])=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:18])([CH3:17])[CH2:9]/[C:10]/2=[CH:13]\[C:14]([NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: CC1(C)C/C(=C\C(=O)Cl)c2cc(F)ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)C/C(=C\C(N)=O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 95.4 %

Procedure:
A solution of 30% aqueous ammonium hydroxide (10 ml, 76 mmol, Mallinckrodt) was added to the solution of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetyl chloride (0.01363 mol) obtained from Example 41h diluted with dichloromethane (200 ml) and cooled to 0° C. The biphase solution was stirred rapidly and allowed to warm to room temperature over 18 h. The reaction solution was concentrated by spin evaporation in vacuo, diluted with dichloromethane (200 ml), and washed with 1N aqueous hydrochloric acid (McIntosh), a solution of 5% aqueous sodium bicarbonate (Mallinckrodt), dried with magnesium sulfate (Mallinckrodt), and concentrated by spin evaporation in vacuo. The residue was chromatographed on Silica Gel 60 using ethyl acetate-hexanes (1:1), and then ethyl acetate. Fractions containing (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene) acetamide were combined and concentrated by spin evaporation in vacuo. Recrystallization from dichloromethane-hexanes gave 2.85 g (95%) of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetamide as a white crystalline solid, m.p., 167-168° C.:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>>[CH:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)([CH3:30])[CH3:29]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)OC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OC(C)C)nc3cc21
Yield: 42.6 %

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid isopropyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.805 mmol) and isopropyl chloroformate (886 mg, 0.886 mmol). 136 mg (43%) of the title compound were obtained.
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[C:5]=1[CH2:23][CH2:24][CH3:25])=[N+]=[N-]>CO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[C:5]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CCCc1c(N)ncnc1Cn1ccnc1-c1cccc(F)n1
Reaction time: 4 h

Procedure:
Pd/C (10%, 10 mg) is added to a solution of 104 (2 mmol) in MeOH (20 ml). The mixture is stirred under H2 at 30 psi for 4 hours. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The light resulting yellow solid (105) is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=S)[NH:14][C:13]2=[O:18])=[CH:9][C:8]=1[O:21][CH3:22].CS(C)=O.IC.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CCOC(C)=O.CC#N>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[N:14][C:13]2=[O:18])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: CN1CCNCC1
Reactant: COc1cc(CC2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CS(C)=O
Solvent: CI
Solvent: CC#N
Product: COc1cc(CC2SC(N3CCN(C)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reaction time: 3 h
Yield: 34.7 %

Procedure:
To a flask was added 5-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-benzyl]-2-thioxo-thiazolidin-4-one from Step A (140 mg, 282 μmol), DMSO (1 mL) and iodomethane (2 mL). The reaction solution was allowed to stir under N2 for 3 h. The excess iodomethane was removed in vacuo. To the reaction mixture was added MeCN (6 mL) and N-methyl piperazine (95 μL, 850 μmol). The reaction solution was stirred at 55° C. for 2 h. The reaction solution was then diluted with EtOAc (200 mL), washed with aq. NH4Cl and water, dried over Na2SO4 and concentrated. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 90:10) to provide title compound (55 mg, 35% yield). 1H NMR (CDCl3) δ 8.10 (1H, d, J=8.1 Hz), 7.92 (1H, s), 7.83 (1H, d, J=8.1 Hz), 6.83 (1H, s), 6.73 (2H, br s), 5.36 (2H, s), 4.46 (1H, dd, J1=3.6 Hz, J2=10.4 Hz), 3.96 (2H, t, J=4.9 Hz), 3.90 (3H, s), 3.57 (1H, dd, J=3.6 Hz, J2=14.3 Hz), 3.49 (2H, t, J=4.9 Hz), 2.92 (1H, dd, J1=10.4 Hz, J2=14.3 Hz), 2.46 (4H, m), 2.32 (3H, s); MS (ESI) 562 (MH+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:16]([NH:18][O:19][CH3:20])=[O:17].C(N(CC)CC)C>C(#N)C>[C:4]([C:3]1[C:2]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([NH:18][O:19][CH3:20])=[O:17])=[N:9][C:8]([Cl:10])=[C:7]([F:11])[CH:6]=1)#[N:5]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(F)cc2C#N)c1
Temperature: 70 °C
Yield: 20.5 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (830 mg, 4.34 mmol), 3-amino-N-methoxy-4-methyl-benzamide (576 mg, 3.2 mmol) and triethylamine (0.5 mL) in acetonitrile (10 mL) was heated to 70° C. overnight. Then the solvent was removed under reduced pressure and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (220 mg, 21%) was isolated after purification by silica gel chromatography. C15H12ClFN4O2 MS m/e=335 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH:25]=O)=[C:13]3[C:17]4=[C:18]([CH2:20][NH:21][CH2:22][C:23](=[O:24])[N:16]4[CH:15]=[CH:14]3)[CH:19]=2)=[CH:7][CH:6]=1>N1C=CC=CC=1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH:25]=[N:2][OH:3])=[C:13]3[C:17]4=[C:18]([CH2:20][NH:21][CH2:22][C:23](=[O:24])[N:16]4[CH:15]=[CH:14]3)[CH:19]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)cc2c3c1ccn3C(=O)CNC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CNCc2cc(-c3ccc(F)cc3)c(C=NO)c3ccn1c23
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
Hydroxylamine hydrochloride (0.10 g, 0.325 mmol) was added to a solution of 6-(4-fluoro-phenyl)-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-carbaldehyde (56.0 mg, 0.813 mmol) in pyridine (10 mL) and stirred at rt for 20 h. Upon consumption of the aldehyde as indicated by TLC, the solvent was removed in vacuo. The residue was taken up in 2N HCl and extracted with EtOAc several times. The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give 97 mg (92%) of a pale-yellow solid: mp 277-279° C.; 1H NMR (DMSO-d6) δ 3.50 (br s, 2H), 4.12-4.14 (m, 2H), 7.30 (t, 1H, J=6.0 Hz), 7.43 (t, 2H, J=9.0 Hz), 7.57-7.62 (m, 2H), 7.89 (s, 1H), 7.94 (d, 1H, J=9.0 Hz), 8.33 (d, 1H, J=6.0 Hz), 8.41 (t, 1H, J=6.0 Hz), 10.80 (s, 1H). HRMS calcd. for C18H14N3O2F 323.1070 (M+), found 323.1066.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:18]1[CH:23]=CC=C[CH:19]=1.CNC.C1COCC1>C(Cl)Cl>[CH3:19][N:18]([CH3:23])[S:14]([C:12]1[S:13][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: c1ccncc1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1nccc(-c2ccc(S(=O)(=O)N(C)C)s2)n1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A solution of 5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride (200 mg, 0.652 mmol) in 6 mL DCM was treated with pyridine (0.078 mL, 0.97 mmol) and 2 M dimethylamine/THF (0.485 mL, 0.97 mmol). The solution was stirred overnight. Additional 2 M dimethylamine/THF (0.400 mL, 0.8 mmol) was added and the reaction was stirred overnight. The mixture contained <5% starting material by LCMS. The mixture was washed 2×1 N HCl, 1× brine and dried over Na2SO4. 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid dimethylamide (154 mg, 74.9%) was obtained as an off-white solid, >95% pure by LCMS. This material was taken to the next step. MS: m/z 316 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CN(C1CCCCC1)C1CCCCC1.[CH3:27][O:28][CH2:29]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:27][O:28][CH2:29][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([CH3:1])=[CH:3][C:4]([CH:11]=[O:12])=[CH:5]2)=[N:9]1
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Reactant: COCCl
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCn1cc2cc(C=O)cc(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 7-methylindazole-5-carboxaldehyde (8.80 g, 54.9 mmol) and N-methyl-dicyclohexylamine (23.6 mL, 110 mmol) in tetrahydrofuran (200 mL) at 0° C. was added chloromethyl methyl ether (7.50 mL, 1.8 equiv). The reaction was allowed to gradually warm to room temperature overnight. The reaction was concentrated, dissolved in diethyl ether, washed with water, then 1 M hydrochloric acid, then water, then brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was dissolved in ethyl acetate and treated with hexanes until lasting turbidity. The suspension was heated until a clear solution was obtained and the flask placed in the freezer. The resulting crystalline solid was crushed with a spatula to break it up, reheated to dissolve some of the solids, and placed in the freezer. The solids were filtered, washed with very cold diethyl ether (−78° C.), and air-dried to give 5.43 g. The mother liquor was concentrated, redissolved in diethyl ether (ca. 20 mL), cooled to −78° C., and treated with a seed crystal of the product. After 1 h, the resulting solids were filtered, washed with cold diethyl ether (−78° C.), and air-dried to give an additional 1.05 g (total yield=58%). 1H-NMR (CDCl3, 500 MHz) δ 2.66 (s, 3H), 3.44 (s, 3H), 5.73 (s, 2H), 7.59 (s, 1H), 8.09 (s, 1H), 8.32 (s, 1H), 9.97 (s, 1H). Mass spec.: 205.19 (MH)+.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[CH2:23][C:24]1[CH:42]=[CH:41][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([OH:39])[C:31]=2[Cl:40])=[CH:26][CH:25]=1>>[NH2:20][C:16]1[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([OH:39])[C:31]=3[Cl:40])=[CH:41][CH:42]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O
Reactant: CC1(C)COB(c2cccc(-c3ccnc(N)n3)c2)OC1
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(-c4ccnc(N)n4)c3)cc2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described in Example 92 using 4-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-pyrimidin-2-ylamine (327 mg, 1.15 mmol) and 1-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone (400 mg, 1.08 mmol). The title compound is isolated (109 mg, 0.237 mmol) as a yellow solid: 1H NMR (DMSO-d6) δ 2.10 (s, 3H), 4.04 (s, 2H), 5.30 (s, 2H), 6.62 (m, 2H), 6.88 (d, 1H), 7.08 (m, 1H), 7.29 (m, 2H), 7.40 (m, 4H), 7.92 (m, 3H), 8.28 (d, 1H), 13.12 (s, 1H); MS (m/z): 458.2 (M−1).
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:40]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC(C2C=CC(C(C)(C)C(OCC)=O)=CC=2)=O)CC1>>[ClH:1].[OH:40][C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=2)[OH:18])[CH2:13][CH2:14]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Product: CCOC(=O)C(C)(C)c1ccc(C(O)CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
When in the procedure of Example 2 an appropriate amount of ethyl 4-[3-[4-(diphenylmethylene)-1-piperidinyl]-1-oxopropyl]-α,α-dimethylbenzene acetate hydrochloride is substituted for ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, ethyl 4-[3-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxypropyl]-α,α-dimethylbenzeneacetate hydrochloride is obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH3:12][CH:13]([NH2:15])[CH3:14]>C(O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:15][CH:13]([CH3:14])[CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2c(Br)csc12
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ncnc2c(Br)csc12
Yield: 95.5 %

Procedure:
A mixture of compound 65A (0.125 g, 0.5 mmol), and propan-2-amine (0.148 g, 2.5 mmol) in ethanol (10 mL) was heated under reflux for 15 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel eluting with 1:1 EtOAc/hexanes to give 0.13 g of the title compound: 1H NMR (DMSO-d6): δ 8.50 (s, 1H), 8.28 (s, 1H), 7.87 (d, J=7.46 Hz, 1H), 4.40-4.51 (m, 1H), 1.23 (d, J=6.78 Hz, 6H). ESI (+)/MS: 273 (M−H)+.
Reaction SMILES: C(OC(=O)[CH:7]([C:20]#[N:21])[C:8](=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[N+:16]([C:12]1[CH:11]=[C:10]([CH2:9][C:8](=[O:19])[CH2:7][C:20]#[N:21])[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)C(C#N)C(=O)Cc1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#CCC(=O)Cc1cccc([N+](=O)[O-])c1
Yield: 63.2 %

Procedure:
To a solution of 2-cyano-4-(3-nitrophenyl)-3-oxo-butyric acid tert-butyl ester (9.5 g, 31 mmol) in toluene (40 mL) was added TFA (4 mL) and the solution was heated at reflux for 2 h, then the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 4.0 g of 4-(3-nitrophenyl)-3-oxo-butyronitrile (37% over 2 steps).