Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O1CCCC1.O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NCCCCO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCCCO
Yield: 100 %

Procedure:
A solution of methyl 2-chloro-3-nitrobenzoate (53.5 g, 248 mmol), triethylamine (41.5 mL, 298 mmol) and 4-amino-1-butanol (45.7 mL, 496 mmol) in tetrahydrofuran (400 mL) was stirred for 60 h at 50° C. The mixture was diluted with water, concentrated in vacuo, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate (short column) to give the title compound as a yellow oil (66.5 g, 248 mmol, 100%).
Reaction SMILES: [C:1](O)([C:3]([F:6])([F:5])[F:4])=O.[NH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]=2)=[CH:12][CH:11]=1)[NH2:9]>>[NH:19]1[CH2:18][CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]3[N:15]([C:1]([C:3]([F:6])([F:5])[F:4])=[N:9][N:8]=3)[N:14]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(NN)nn2)CC1
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(C3=CCNCC3)nn12
Temperature: 70 °C
Reaction time: 24 h
Yield: 20.29 %

Procedure:
TFA (2 mL) was added in one portion to tert-butyl 4-(6-hydrazinylpyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (480 mg, 1.65 mmol) which dissolved with a vigorous effervescence. The solution was stirred for 24 hours at 70° C. The solution was evaporated and the residue was dissolved in methanol. It was run on an SCX cartridge, eluting with 2M ammonia in methanol. Product containing fractions were evaporated to dryness and triturated with ether to afford 6-(1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (90 mg, 20.29%) as a cream solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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].C(Cl)Cl>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1)[CH3:20]
Reactant: CC(C)Cc1ccc(-c2ncc(Br)s2)cc1C#N
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 188.2 %

Procedure:
To a solution of 5-(5-bromo-1,3-thiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D91) (1.1 g), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (443 mg) and Cs2CO3 (1.12 g) in 1,2-dimethoxyethane (DME) (15 mL) and water (3 mL) stirred under nitrogen at room temperature was added PdCl2(dppf)-CH2Cl2 adduct (2.80 g) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 1.5 h. After cooling the reaction, the reaction mixture was filtered through silica gel and the filtrate was washed with aqueous saturated ammonium chloride and saturated brine. The organic phase was collected and dried over anhydrous sodium sulphate. After concentration, the crude product was purified by column chromatography to give 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (1.2 g). MS (ES): C23H22N2OS requires 374. found 375.1 (M+H+).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>>[CH:25]1([N:11]([CH:8]2[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][NH:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)[CH2:10][CH2:9]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)(=[O:13])=[O:14])[CH2:26][CH2:27]1
Reactant: C=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: O=C(CCNC1CCC(O)CC1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 150 °C

Procedure:
N-(1-Acryloyl-piperidin-4-yl)-N-cyclopropyl-3-trifluoromethyl-benzenesulfonamide (1) (125 mg, 0.31 mmol), trans-4-aminocyclohexanol (357 mg, 3.1 mmol) and ETOH (2.5 ml) were mixed together in a sealed tube and heated to 150° C. with microwave equipment for 30 min. After the reaction, the reaction mixture was evaporated in vacuum and the residue was purified by column chromatography on silica gel (CHCl3/MeOH/NH3 aq.=100/10/1) to afford the desired compound as free base, which was dissolved in AcOEt (2 ml), and treated with 4N—HCl in AcOEt (2 ml) solution. The resulting mixture was concentrated in vacuo, and dried under reduced pressure for 24 hours at 60° C. to afford the title compound 3 as a HCl-salt (colorless amorphous, 141 mg, yield 82%) LC: 100%. MS: m/z=517.88, 518.51 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N[C:12]1[CH:13]=[CH:14][C:15](O)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])(=O)C.N1CCOCC1>CO.C(OCC)(=O)C>[NH:1]1[CH2:6][CH2:5][C:4]2([NH:19][C:17](=[O:18])[C:16]3[CH:20]=[CH:12][CH:13]=[CH:14][C:15]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: CC(=O)Nc1ccc(O)c(C(N)=O)c1
Solvent: CO
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: O=C1NC2(CCNCC2)Oc2ccccc21

Procedure:
A mixture of 24 mg (0.077 mmol) of N-[4,8-dimethoxyquinoline-2-yl)carbonyl]-4-piperidone, 15 mg (0.077 mmol) of 5-acetamido-2-hydroxybenzamide, and 0.020 mL of morpholine in 3 mL of methanol is refluxed for 48 hr. The reaction mixture is diluted with ethyl acetate, and washed with water, brine, and dried over Na2SO4. After solvent removal by rotoevaporation, the crude product is purified by preparative TLC to give 11 mg (0.022 mmol, 30% yield) of 6-acetamido-1′-[4,8-dimethoxyquinoline-2-yl)carbonyl]spiro[2H-1,3-benzoxazin-2,4′-piperidin]-4-(3H)-one (Compound 9): 1H NMR (DMSO-d6): δ 2.02 (s, 3H), 3.95 (s, 3H), 4.06 (s, 3H), 7.03 (d, 1H), 8.19 (s, 1H), 7.24 (d of d, 1H), 7.52 (d of d, 1H), 7.67 (m, 2H), 8.02 (d, 1H), 8.82, (s, 1H) and 9.98 ppm (s, 1H). MS m/z: 491.1 (M+H)+, 513.2 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:29])[C@@H:14]([N+:26]([O-])=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(=O)C)[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:29])[C@@H:14]([NH2:26])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1cccc(C[C@@H]([C@H](O)[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)[N+](=O)[O-])c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)COC1(C)C
Reaction time: 0.17 h

Procedure:
Add nickel (II) chloride (6.0 g, 46.1 mmol) to a solution of 4-(R)-[3-(3-acetoxyphenyl)-1-(R)-hydroxy-2-(S)-nitropropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (18.37 g, 41.9 mmol) in dry methanol (900 mL). Cool in an ice bath and portionwise sodium borohydride (6.34 g, 167.6 mmol) over 8 minutes. Stir for 10 minutes. And concentrate. Partition the residue between ethyl acetate (200 mL) and water (200 mL), filter through Celite® and wash with ethyl acetate. Wash the organic layer with saturated aqueous sodium chloride, combine aqueous washes and extract with ethyl acetate. Combine the organic layers, dry (magnesium sulfate), filter and concentrate to give the desired compound as a crude foam. Suspend the Celite® cake in ethyl acetate, filter, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to obtain more desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:21][CH2:22][CH2:23][OH:24])[CH2:19][OH:20]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:8][N:21]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:19][OH:20])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCNCCO
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(CN(CCO)CCO)cc(C(C)(C)C)c1O
Temperature: 77.5 °C
Reaction time: 6 h

Procedure:
In a round bottom flask taken 2.24 gm of 3,5-ditertbutyl-4-hydroxy benzyl bromide and 0.6 ml of N, N-diethanol amine and dissolved in 100 mL of benzene. The reaction mixture was refluxed with constant stirring at 75-80° C. for 6 hrs. The product was crystallized out in the form of colorless needles. The solvent was decanted, crystals were filtered off and washed with pure benzene. The yield of the product is 1.43 gm (64%). Product was identified by 1H-NMR and FT-IR spectroscopic techniques.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][CH3:35])=[NH:33].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=[N:30][NH:31][C:32](=[NH:33])[NH:34][CH3:35])[CH2:9]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: CNC(=N)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: CNC(=N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(C)c21
Temperature: 25 °C
Reaction time: 60 h
Yield: 145.6 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (78 mg), 1-amino-3-methylguanidine p-toluenesulfonate (86 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (1 ml) was stirred at room temperature for 60 hours, and crystals precipitated during the reaction were filtered and washed with ethanol. To the crystals were added ethyl acetate (60 ml) and 2 N sodium hydroxide (5 ml) to dissolve the crystals. The separated ethyl acetate layer was washed with water (10 ml, thrice), to which was added 2 N hydrochloric acid (0.3 ml). The mixture was concentrated under reduced pressure, and the residue was washed with a mixture of ether/ethanol=4/1 and dried to give 6-(2-chlorophenyl)-3-methyl-4-(1-methylguanidin-3-yl)imino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 92) (80 mg) as colorless solid.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2)C(C)=O.Cl>CO>[NH2:1][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: Cl
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Yield: 92.3 %

Procedure:
14.6 g of 5-acetamino-6-nitro-indane were boiled under reflux overnight in 1.5 l of methanol with 300 ml of hydrochloric acid in methanol and then evaporated. 11.8 g of crude product were recrystallized from acetonitrile. There were obtained 10.9 g (92.3% of theory) of 5-amino-6-nitro-indane of melting point 131°-132° C.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[SH:19][C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][S:19][C:20]2[NH:21][C:22]3[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(S)[nH]c2c1
Reactant: CCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Product: CCCc1c(OCC(O)CSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O

Procedure:
Ethyl 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio]benzimidazole-5-carboxylate was prepared in a similar manner to Example 2 with 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-1,2-epoxypropane (1.91 g) and ethyl 2-mercaptobenzimidazole-5-carboxylate (1.70 g). 2.10 g (58.1%) of the esters was obtained as a yellow oil. This ester (2.10 g) was converted to the title compound (870 mg. 44.1%) as pale brown crystals in the same manner as Example 2, mp 133-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:31])([F:30])[O:29][C:25]=5[CH:24]=4)[CH2:22][CH2:21]3)=[O:19])[N:11]=2)[CH:5]=[N:6][C:7]=1[O:8]C.Cl>O1CCOCC1>[NH2:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:10]2[N:11]=[C:12]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:30])([F:31])[O:29][C:25]=5[CH:24]=4)[CH2:21][CH2:22]3)=[O:19])[CH:13]=[CH:14][C:15]=2[CH3:16])[CH:3]=1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1c[nH]c(=O)c(N)c1
Temperature: 90 °C
Yield: 50.6 %

Procedure:
To N-(5′-amino-6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (53 mg, 0.1166 mmol) in 1,4-dioxane (2 mL) was added 4M aq hydrochloric acid (0.5 mL, 2.0 mmol) and the reaction mixture was heated to 90° C. After one hour the reaction was quenched with triethlyamine (0.5 mL). The reaction mixture was evaporated to dryness and the residue was dissolved in N,N-dimethylformamide (2 mL) and purified by reverse phase HPLC. The fractions from the HPLC purification were neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (3×10 mL). The organics were dried over sodium sulfate and evaporated to yield the product (26 mg, 48%). ESI-MS m/z calc. 440.4. found 441.3 (M+1)+. Retention time 1.39 minutes.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[O:30]=[C:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:19](=[O:31])[O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCC(O)Cc1ccccc1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Cc1ccccc1
Yield: 85.8 %

Procedure:
Dry DMSO (3.0 ml, 43.54 mmol) in CH2Cl2 (6.9 ml) was added dropwise to a solution of oxalyl chloride (1.73 ml, 19.91 mmol) in CH2Cl2 (35 ml) at −60° C. under a nitrogen atmosphere. After stirring for 2 mins at −60° C. a solution of (RS)-benzyl-N-(2-hydroxy-3-phenylpropyl)carbamate (preparation 1) (5.18 g, 18.15 mmol) in CH2Cl2 (17 ml) was added dropwise over 10 mins followed by triethylamine (17.63 ml, 90.74 mmol). The resultant mixture was allowed to warm to room temperature, whereupon water (100 ml) was added. The aqueous mixture was extracted with CH2Cl2 (3×100 ml) and the combined organic extracts washed with sat aq brine (2×250 ml) and dried over MgSO4. Filtration away from the drying agent followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO2; eluting with 40:60 hexane:ethyl acetate) to give the desired product (yellow crystalline solid, 4.41 g, 86%). 1H NMR (CDCl3) δ:3.72 (s, 2H), 4.11 (d, 2H), 5.09 (s, 2H), 5.45 (s, br, 1H), 7.20-7.37 (m, 10H). LRMS m/z=301.0 (M+18)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([Cl:35])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:14]1[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]=[C:17]2[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:12])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 16 h at ambient temperature to give the title compound as off-white solid. MS: m/e=489.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH:36]CC4C=CC(OC)=CC=4)[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH2:36])[CH2:33][CH2:34][CH2:35]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(CNC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(C)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)CCC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)-N-(4-methoxybenzyl)cyclobutanamine (500 mg, 0.758 mmol) (Example 112D) in anhydrous dichloromethane (20 mL) and water (1.0 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (224 mg, 0.986 mmol) and stirred for 20 minutes at ambient temperature. Additional 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (50 mg, 0.220 mmol) was added to the mixture, and the reaction stirred one hour at ambient temperature. The reaction was quenched with saturated sodium bicarbonate, and layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 100% ethyl acetate to 5% methanol in ethyl acetate, to provide the title compound. MS ESI(+) m/z 539.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[C:12]([Cl:18])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]=2[C:8]([O:26][CH3:27])=[CH:7][CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]1[C:8]([O:26][CH3:27])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:17]2=1
Reactant: COC(=O)c1ccc(OC)c2c1c1cccc(Cl)c1n2CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c2c3cccc(Cl)c3n(CC3CCCCC3)c12
Yield: 98.2 %

Procedure:
To a solution of methyl-8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazole carboxylate (95 mg 0.2464 mmoles) in 5 mL methanol, 2 mL of 10% sodium hydroxide solution was added and refluxed for 3 hrs. Methanol from the reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate (50 mL) and washed with 10% sodium hydroxide solution (2×20 mL), this aqueous layer was acidified with 1N HCl and extracted with ethyl acetate (2×25 mL), dried over sodium sulfate and concentrated to give 90 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(F)c1
Reactant: BrCc1ccc2ccccc2c1
Product: Fc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating (3RS,4RS)-1-benzyl-4-(3-fluorophenyl)-piperidin-3-ol with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless oil; MS: 426 (M+H)+. By cleavage of the benzyl protecting group with 2,2,2-trichloroethyl chloroformate in an analogous manner to that described in Example 12(c) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-(3-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 510 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][CH2:3][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1
Reactant: CNC(=O)c1cc2ccccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2s1
Temperature: 0 °C
Yield: 98.8 %

Procedure:
To a stirred suspension of N-methyl benzothiophene-2-carboxamide (10.0 g, 52 mmole) in dry THF (75 mL) under argon was added a solution of 1.0 M LiAlH4 in THF (135 mL, 135 mmole) over 15 minutes. The reaction quickly became clear and was heated at reflux for 2 days. After cooling to 0° C. the reaction was carefully quenched with the sequential addition of H2O (5.1 mL), 15% NaOH in H2O (5.1 mL), and H2O (15.3 mL). The mixture was filtered through a pad of Celite® and the filter pad was rinsed with Et2O (50 mL). The filtrate was concentrated to afford the title compound (9.11 g, 99%) as a pale yellow oil which solidified in the freezer 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.3 Hz, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.33 (m, 2H), 7.17 (s, 1H), 4.06 (s, 2H), 2.53 (s, 3H), 1.56 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][C@@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](NCC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccccc1
Reaction time: 15 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (91 mg, 0.250 mmol) was dissolved in THF (4 mL) and (R)-α-methylbenzylamine (0.048 mL, 0.375 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (47 mg, 0.749 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 15 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 52 mg, 0.111 mmol, 44%) 1H NMR (400 MHz, CDCl3) 7.62, 7.39-7.22, 7.14, 7.07-6.99, 6.89-6.80, 6.57, 5.41, 4.56, 4.02, 3.76, 2.73, 2.36-2.18, 1.60, 1.39, 0.97, 0.52