Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=4)[O:25][C:26]=3[CH3:27])[CH2:15]2)[C:3]=1[C:4]([O:6]C)=[O:5].Cl>C(O)(C)(C)C.[OH-].[K+]>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=4)[O:25][C:26]=3[CH3:27])[CH2:15]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCc2nc(-c3ccc4ccccc4c3)oc2C)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1cccc(CO[C@@H]2CCC[C@H](OCc3nc(-c4ccc5ccccc5c4)oc3C)C2)c1C(=O)O
Reaction time: 48 h

Procedure:
94 mg of methyl 2-methyl-6-[(1R,3S)3-(5-methyl-2-naphthalen-2-yloxazol-4-yl-methoxy]cyclohexyloxymethyl]benzoate are stirred at 90° C. in a mixture of 10 ml of tert-butanol and 1 ml of 10 N potassium hydroxide solution. After two days, the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 72 mg of 2-methyl-6-[(1R,3S)3-(5-methyl-2-naphthalen-2-yloxazol-4-yl-methoxy)cyclohexyloxymethyl]benzoic acid as an amorphous solid. C30H31NO5 (485.59), MS(ESI): 486 (M+H+).
Reaction SMILES: FC1C=CC=C(F)C=1C([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=O.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([OH:28])=O>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:28]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Product: COc1ccc(Cl)cc1C(=O)Nc1c[nH]nc1C(=O)O

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 5-chloro-2-methoxy-benzoic acid as the starting acid to give 4-(5-chloro-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (12 g) as a colourless solid. (LC/MS: Rt 2.48, [M−H+]− 294)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[C:22]1([C:28]2[NH:29][C:30](=[O:33])[NH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:19][C:11]1([CH3:20])[O:10][C:9](=[O:21])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH:32]=[C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:29][C:30]3=[O:33])=[CH:3][CH:4]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]cc(-c2ccccc2)[nH]1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Product: CC1(C)OC(=O)N(c2ccc(-n3cc(-c4ccccc4)[nH]c3=O)cc2)[C@H]1c1ccccc1
Yield: 9 %

Procedure:
The title compound was prepared as described in General Scheme B using intermediate C in place of intermediate B and 4-phenyl-1H-imidazol-2(3H)-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.). Purification was performed using preparative LC/MS with 0.1% NH4OH in ACN and water as the mobile phase. The pure fractions were dried under reduced pressure to afford (4S)-5,5-dimethyl-3-(4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-4-phenyl-1,3-oxazolidin-2-one as a white solid (15 mg, 0.055 mmol, 9% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.01 (br. s., 1H), 7.71-7.65 (m, 2H), 7.62-7.50 (m, 4H), 7.41-7.34 (m, 4H), 7.34-7.20 (m, 4H), 5.49 (s, 1H), 1.65 (s, 3H), 0.92 (s, 3H). m/z (ESI) 426.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C=O)c3)nn3ccnc23)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN4CCCCC4)c3)nn3ccnc23)n1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzaldehyde (28 mg, 0.070 mmol) and piperidine (7 mg, 0.077 mmol) were dissolved in 1,2-dichloroethane (8 mL), stirred for 1 h, then sodium triacetoxyborohydride (44 mg, 0.21 mmol) was added followed by AcOH (0.1 mL). After 15 h, the solvent was removed and the residue was purified by chromatography (silica gel, dichloromethane/methanol 40/1) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(piperidin-1-ylmethyl)phenyl)imidazo[1,2-b]pyridazin-8-amine (17 mg, 21%) as an orange solid. 1H NMR (300 MHz, CD3OD): δ 8.80 (s, 1H), 8.00 (s, 1H), 7.91-7.84 (m, 2H), 7.59 (s, 1H), 7.48-7.41 (m, 3H), 6.30 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.4 Hz), 4.30-4.26 (m, 1H), 3.60-3.43 (m, 4 h), 2.51-2.47 (m, 4 h), 2.15-2.05 (m, 3H), 1.78 (brs, 1H), 1.63-1.60 (m, 4 h), 1.51-1.46 (m, 2H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 468, tR=1.397 min, HPLC: 99.52% at 214 nm, 98.65% at 254 nm, tR=5.76 min.
Reaction SMILES: [Cl:1][C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH2:19]CO)=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH2:19][CH2:5][O:4][C:2]([Cl:1])=[O:3])=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=1
Reactant: COc1cc(CCO)c([N+](=O)[O-])cc1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(CCOC(=O)Cl)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Trichloromethyl chloroformate (0.26 ml, 2.2 mmol) in THF (5 ml, dist. over CaH2) was cooled by means of an ice bath to 0° C. A solution of 2-(4,5-dimethoxy-2-nitrophenyl)ethanol (500 mg, 2.2 mmol) and Et3 N (218 mg, 0.3 ml, 2.2 mmol, dist. over CaH2) in THF (15 ml, dist. over CaH2) was added dropwise thereto for 10 min. The ice bath was then removed and the solution was stirred further at room temperature. After being stirred for 30 min, a spatula tip of activated carbon was added to the reaction mixture, which after being stirred for another 2.5 h was filtered by suction at room temperature over Celite. The solvent and the excess reagent were removed from the filtrate by distillation in a high vacuum and 2-(4,5-dimethoxy-2-nitrophenyl)ethoxycarbonyl chloride (624 mg, 98%) was obtained as a yellow brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([CH3:16])[C:22](=[O:23])[C:21]1[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=1
Reactant: CNc1cnccc1-c1ccncc1OC
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cnccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 55, from (3′-methoxy-[4,4′]bipyridinyl-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (24%). MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([NH:15][NH2:16])=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:18]([O-])=O.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([N:15]=[N+:16]=[N-:18])=[O:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cc(-c2cccc(F)c2)on1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(-c2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a suspension of 5-(3-fluorophenyl)isoxazole-3-carbohydrazide (22.5 g, 101 mmol) in H2O (2000 mL) and HCl (2 N, 101 mL, 2.0 equiv.) at 0° C. was added a solution of sodium nitrite (13.9 g, 202 mmol, 2.0 equiv.) in H2O (100 mL). The suspension was stirred at RT for 16 h. The precipitate was filtered and washed with H2O. The solid was dried under high vacuum to give 5-(3-fluorophenyl)isoxazole-3-carbonyl azide as a yellow solid (20 g, 85%). LRMS (M+H+) m/z 179.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH:21]([CH2:26][C:27](=O)[CH2:28][CH3:29])[CH2:22][C:23]([OH:25])=[O:24]>C(O)(C)C>[CH3:20][CH:21]([CH2:26][C:27]1[N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[C:12]2[C:17]([C:28]=1[CH3:29])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCC(=O)CC(C)CC(=O)O
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)CC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and 3-methyl-5-oxoheptanoic acid as the starting materials and isopropanol as the solvent, the title compound was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:18]=2[N:17]=1.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][O:31][C:33](=[O:35])[CH3:34])[C:18]=2[N:17]=1
Reactant: CC(=O)Cl
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)CO)c2cc1OC
Solvent: c1ccncc1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)COC(C)=O)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 68, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-2-methyl-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione (63 mg, 0.144 mmol) and acetyl chloride (18 ml, 0.25 mmol) in pyridine (1 ml) is heated at 50° C. for 18 hours. After evaporation, flash chromatography (19:1 dichloromethane-methanol elution) affords acetic acid 3-[8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-2,6dioxo-1,2,6,7-tetrahydro-purin-3-yl]-2-methyl-propyl ester, [MH]+ 482.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c(F)c1

Procedure:
Basic displacement reaction of 4-hydroxy benzaldehyde and 3,4 difluorobenzonitrile using potassium carbonate in anhydrous DMF at reflux temperatures affords the above compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26](C#N)=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(C#N)ccc1OCCOCc1ccccc1
Reactant: CNC(=O)c1ccccc1C
Product: COc1cc(-c2cc3ccccc3c(=O)[nH]2)ccc1OCCOCc1ccccc1
Yield: 23.6 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-(2-benzyloxyethoxy)-3-methoxybenzonitrile (9.57 g) were reacted, to give 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]isoquinolin-1-one (3.20 g)
Reaction SMILES: [OH:1][C:2]1([CH3:15])[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7]C(=O)OC(C)(C)C.[ClH:16].O1CCOCC1>ClCCl>[ClH:16].[NH2:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:15])[OH:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC1(C)O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(O)CCC[C@@H]1N

Procedure:
A solution of tert-butyl N-[(1S)-2-hydroxy-2-methyl-cyclopentyl]carbamate (mixture of cis and trans diastereomers) (6.66 g, 30.9 mmol), 4 M HCl in dioxane (46.4 mL, 185.6 mmol), and dichloromethane (62 mL) is stirred at room temperature for 1 h. The reaction is concentrated in vacuo, and then redissolved in MeOH and reconcentrated to give the title compound as a brown oil (5.09 g). LC-ES/MS m/z 116 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[CH:27]=[C:26]([CH3:33])[N:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:11][CH:12]3[CH2:13][N:14]([C:24]4[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[CH:27]=[C:26]([CH3:33])[N:25]=4)[CH2:15][CH:16]3[CH2:17]2)=[O:9])[CH:7]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Product: Cc1cc(N(C)C)nc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 21 and (2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine. MS (ESI): mass calculated for C22H25FN8O, 435.49; m/z found 437.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.99-7.93 (m, 1H), 7.73 (s, 2H), 7.23-7.18 (m, 1H), 7.15-7.12 (m, 1H), 5.69 (s, 1H), 3.88-3.80 (m, 2H), 3.71-3.62 (m, 2H), 3.59-3.52 (m, 1H), 3.49-3.32 (m, 2H), 3.15-2.83 (m, 9H), 2.24 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][OH:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[C:1]1([S:7]([C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][O:13][S:24]([CH3:23])(=[O:26])=[O:25])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)S(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)S(=O)(=O)c1ccccc1
Yield: 103.1 %

Procedure:
A solution of 3-benzenesulfonyl-3-methyl-butan-1-ol (2.17 g, 9.5 mmol), triethylamine (2.0 ml, 14.25 mmol), methanesulphonyl chloride (0.9 ml, 11.78 mmol) and 4-N,N-dimethylaminopyridine (12 mg, 0.01 mmol) was stirred at 0° C. for 45 min. After quenching with satd. NaHCO3, the mixture was extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to give the title product (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1.[Se](=O)=[O:18]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][C:13]([CH:16]=[O:18])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([CH:8]=[CH2:9])[CH:7]=1
Reactant: O=[Se]=O
Reactant: C=Cc1cnc(-c2ccc(C)nc2)c(Cl)c1
Solvent: C1COCCO1
Product: C=Cc1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
4.0 g of 3-chloro-6′-methyl-5-vinyl-2,3′-bipyridine (14) (17.3 mmol) prepared in Example 10 was dissolved in 50 mL of 1,4-dioxane, and 5.8 g of selenium dioxide (52 mmol) was added thereto. The mixture was refluxed under heating and stirring for 18 hours, and cooled to room temperature. Then, the mixture was concentrated under reduced pressure, and dissolved in ethyl acetate to be washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent:ethyl acetate/hexane=1/4) to obtain 3.2 g of 3-chloro-5-vinyl-2,3′-bipyridine-6′-carbaldehyde (yield 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:21]([CH3:22])[CH3:20])=[O:17])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[4-(benzyloxy)-2-methylphenyl]acetic acid (1.1 g, 4.29 mmol) was dissolved in DMF (5 ml) and dimethylamine (6.44 ml, 12.88 mmol), DIEA (2.25 ml, 12.88 mmol), and HATU (3.26 g, 5.58 mmol) added. The mixture was stirred at RT for overnight. The residue was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. to afford the title compound. LC/MS (m/z): 284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].Br[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(C(C)c3ccccc3)c3cc(Cl)ccc23)c1
Reaction time: 1 h

Procedure:
3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.100 g, 0.30 mmol) was dissolved in DMF (3 mL) then sodium hydride (60% dispersion in mineral oil, 0.015 g, 0.36 mmol) was added followed by (1-bromoethyl)benzene (0.045 mL, 0.33 mmol). After 1 hour, the reaction was quenched with HCl (1N), followed by standard workup. Silica gel chromatography yielded the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[NH2:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:17])[CH3:16]
Reactant: NCC1(Nc2ccccc2)CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
620 mg (2.45 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide are added to 500 mg (2.45 mmol) of (1-aminomethylcyclohexyl)phenylamine in 10 ml of dimethylformamide. The reaction medium is stirred at 100° C. under microwave irradiation for 30 min. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20, v/v). 580 mg of N-(2,6-diisopropylphenyl)-2-[(1-phenylaminocyclohexyl-methyl)amino]acetamide are obtained in the form of a beige solid. Yield=56%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[C:14]([CH3:32])[N:13]=1>C1COCC1.CCOC(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[O:30][CH3:31])=[C:14]([CH3:32])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminium hydride (1M in hexanes, 5.44 mL) was added over 10 min to a suspension of the product from example 21 step (iii) (0.5 g) in THF (10 mL) at 0° C. The mixture was allowed to warm to rt and stirred for 1 h. EtOAc (10 mL) was added cautiously and then the reaction mixture was added to ice/water (100 mL). The mixture was stirred for 30 min and then diluted with EtOAc (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to afford the subtitle compound, 0.39 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[CH3:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1B(O)O>COCCOC.C(OCC)(=O)C>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]4[C@H:6]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]34)[CH:10]=2)=[C:27]([CH3:26])[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: COc1ccc(B(O)O)c(C)c1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A (80 mg, 0.18 mmol) in 25 mL of DME (10 mL) was added 2-methyl-4-methoxyphenyl boronic acid (45 mg, 0.27 mmol) and TEA (0.26 mL, 1.8 mmol). The mixture was degassed with a stream of nitrogen for 20 min and then there was added Pd(dppf)2 (15 mg, 0.1 mmol) and the mixture was stirred at 85° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with sat'd aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with hexanes/ethyl acetate) to afford (35 mg, 45% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 7.13 (d, 1H, J=8.1 Hz), 6.97 (s, 1H), 6.75 (m, 3H), 3.83 (s, 3H), 3.79 (m, 1H), 3.65 (m, 2H), 3.52 (m, 3H), 3.21 (m, 2H), 3.01 (m, 2H), 2.24 (s, 3H), 1.97 (m, 2H), 1.60 (m, 2H), 1.21 (s, 9H). LRMS (ES+): 467 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[O:5][C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C@@H:3]1[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].I([O-])(=O)(=O)=O.[Na+]>CO>[CH:6]([O:5][C@H:4]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)[C@@H:3]([CH:2]=[O:1])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])=[O:7]
Reactant: COc1ccc(-c2ccc(CC[C@H]3O[C@@H](O)[C@@H](O)[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@@H](C=O)CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Reaction time: 2 h

Procedure:
To a solution of the compound obtained from step g above (0.56 g) in methanol (4 mL) at 0° C., a solution of sodium metaperiodate (0.736 g in 1 mL of water) was added. The reaction mixture was stirred for 2 hours at the same temperature. After stirring the reaction mixture for an additional 1 hour at room temperature, the reaction mixture was evaporated on a rotary evaporator. The residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain the title compound (0.54 g).