Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OP(OCC)OCC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:14]([N:21]1[C:8]([CH3:9])=[C:5]2[C:4]([CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6]2)=[N:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCOP(OCC)OCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c2ccc(Cl)cc2nn1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
A solution of 1-(4-chloro-2-nitrophenyl)ethanone (12.5 g, 63 mmol) and benzylamine (13.7 g, 125 mmol) in 200 mL toluene was treated with titanium(IV) isopropoxide (53.5 g, 188 mmol) and heated at 60° C. for 16 h. The solvent was removed in vacuo and the residue taken up in triethylphosphite (31 g, 187 mmol) and the mixture heated cautiously to 150° C. for 2 h. The reaction was cooled to rt and diluted with 30 mL absolute ethanol. 3 mL of 4N aq NaOH was added dropwise with vigorous stirring. After 5 min, the solids were filtered off and the solution diluted with 60 mL absolute ethanol and 60 mL 1N aq NaOH. After stirring overnight, the ethanol was removed in vacuo and the residue diluted with water. Filtration gave the desired product as a dark brown solid (9.86 g, 62%) 1H-NMR (DMSO): δ 7.72 (dd, 1H, J=9, 1 Hz), 7.61 (dd, 1H, J=2, 1 Hz), 7.23 to 7.36 (m, 3H), 7.15 to 7.20 (m, 2H), 6.96 (dd, 1H, J=9, 2 Hz), 5.60 (s, 2H), 2.58 (s, 1H); MS: LC/MS (+esi): m/z=275.1 [MH]+; LC/MS rt=3.51 min.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33][OH:34]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][CH2:32][CH2:33][O:34][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1
Reactant: COCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and 2-methoxyethanol in dioxane and DMF. ES-MS m/e (%): 467 (M+Na+, 24), 445 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(Cl)c3)n2)CCN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 43A is reacted analogously to the synthesis of the compound of Example 1 with 18 mg (0.18 mmol) of 2-oxopiperazine. 76 mg (86% of theory) of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:28][CH:27]=1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 27.2 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-2-methylpropan-1-one (604 mg, 1.93 mmol) was reacted with 4-((dimethylamino)methyl)aniline (882 mg, 3.87 mmol) to afford the desired product (224 mg, 27%) as a yellow solid: ESI MS m/z 432, [C22H30BrN3O+H]+
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([NH2:19])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[N:10]=1)([CH3:5])([CH3:4])[CH3:3].Cl.[NH+]1C=CC=CC=1.O>CCOC(C)=O>[NH2:19][C:8]1[N:9]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[N:10]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: COc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Temperature: 195 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
In a 500 mL round bottom flask was added 5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride (8.42 g, 30 mmol) and pyridinium hydrochloride (13.8 g, 120 mmol). The reaction mixture was heated neat at 195° C. with stirring for 3 h. The mixture was cooled to room temperature, water (300 mL) and EtOAc (300 mL) were added, and then the organic phase was washed with saturated aq NaHCO3 and brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was purified by MPLC (80:20 hexane/EtOAc) to give the product 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (1.3 g, 19%). 1H-NMR (DMSO-d6) δ 7.20 (t, 1H), 7.00 (m, 2H), 6.50 (d, 1H), 5.30 (s, 1H), 5.10 (bs, 2H), 1.30 (s, 9H); MS LC-MS [M+H]+=232.2, RT=0.57 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH2:16][N:17]([CH:21]3[CH2:23][CH2:22]3)[CH:18]([CH3:20])[CH3:19])[CH:15]=1)[O:12][C:11]([CH3:25])([CH3:24])[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:21]1([N:17]([CH2:16][C:14]2[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:24])([CH3:25])[CH2:10][C:9]3([CH3:27])[CH3:26])[CH:18]([CH3:20])[CH3:19])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cc(CN(C(C)C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)N(Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 8-[(cyclopropyl-isopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 38, 0.09 g, 0.26 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with a 1M solution of sodium hydroxide (3 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (0.079 g, 96%). It was used as such for the next step.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cn1
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: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.012 g of product in 49% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:32]([Cl:31])[CH:33]=3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(Cl)c(Cl)c2)c1=O
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 3,4-dichlorobenzyl bromide (480 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (154 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.12 (br. s., 1 H), 7.58 (dd, J=5.05, 3.03 Hz, 2 H), 7.29 (dd, J=8.34, 2.02 Hz, 1 H), 4.97 (s, 2 H), 4.62 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.63 (s, 3 H), 1.27 (q, J=12.88 Hz, 2 H), 1.11 (q, 1 H)
Reaction SMILES: [OH-].[Na+:2].O.O.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Na+:2].[CH2:18]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:14])=[O:15])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous NaOH (40 mL of a 15% aqueous solution, 150 mmol) is added to 20 g (86.2 mmol) of 4-hydroxybenzenesulfonic acid sodium salt dihydrate at RT. An additional 20 mL of water is added, and the mixture is warmed slightly to dissolve the salt. Benzyl bromide (19.2 g, 112.1 mmol) in 8 mL of ethanol is then added in several portions. The mixture is heated to reflux. After 30 min, additional 20 mL of water is added, and heating is continued for 3.5 h, followed by continued stirring at RT overnight. After cooling in the refrigerator for 3 h, the solid product is collected by filtration and washed with water (20 mL), ethanol (40 mL), and ether (40 mL) and then dried overnight under vacuum to give 4-benzyloxybenzenesulfonic acid sodium salt.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:51][N:52]1[C:56]([SH:57])=[N:55][N:54]=[N:53]1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:57][C:56]5[N:52]([CH3:51])[N:53]=[N:54][N:55]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1nnnc1S
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCN3CC(C)C)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4nnnn4C)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
In THF (12 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(hydroxymethyl)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.60 g), and pyridine (3 droplets) and thionyl chloride (0.16 ml) were added to the mixture. The solution was stirred at room temperature for 1 hour, and added dropwise to a solution of 1-methyl-1,2,3,4-tetrazole-5-thiol (154 mg) and triethylamine (1.23 ml) in THF (12 ml) at 0° C. The mixture was stirred at room temperature for 2 hours, and stirred for 16 hours at 50° C. After allowing to be cooled to room temperature, the reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-1,2,3,4-tetrazol-5-yl)sulfanyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 245) (520 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:8]=[CH:7][CH:6]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]2[C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=[N:8]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-n2nccc2CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2nccc2CN)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (0.344 g, 1.24 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added water (0.5 mL) and triphenylphosphine resin (0.5 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-[2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-methylamine as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:9]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCBr
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCN1CCCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
Procedure 1a—The first N-substitution of azepane was carried out using butyl bromide as an N-alkylating agent to form 1-butylazepane. To a stirring solution of azepane (49.97 g, 503.8 mmol) in methanol (220 cm3) cooled in an ice-water bath was added dropwise 1-bromobutane (57 cm3, 530 mmol), and then potassium carbonate (72.5 g, 524 mmol). The mixture was vigorously stirred at room temperature for 24 h. The resulting suspension was filtered through a sintered glass fret and the solution concentrated under reduced pressure at 45° C. in a rotary evaporator. A yellowish suspension was thus obtained and distilled in vacuo (45-47° C., 5.5 mmHg) to give 1-butylazepane as a colourless liquid (50.30 g, 64.3%). δH (500.13 MHz, CDCl3) 2.62 (4H, t, 3J(H,H)=5.5 Hz), 2.45 (2H, m), 1.64 (4H, br m), 1.59 (4H, br m), 1.45 (2H, m), 1.30 (2H, sextet, 3J(H,H)=7.4 Hz), 0.90 (3H, t, 3J(H,H)=7.4 Hz); δC (125.76 MHz, CDCl3) 58.2, 55.7, 29.8, 28.0, 27.1, 20.9, 14.1. ESI-MS: m/z=156 [M+H]+ (100). Calcd. for C10H22N: 156.1752; found: 156.1755.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][NH:12][CH2:11]1>CN(C)C=O.COC(C)(C)C>[CH3:8][S:7][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH:14]([CH3:16])[CH2:15][CH:10]([CH3:9])[CH2:11]2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: CC1CNCC(C)C1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CSc1nsc(N2CC(C)CC(C)C2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
In 9 ml of N,N-dimethylformamide was dissolved 740 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, and 1.25 g of 3,5-dimethylpiperidine (a mixture of 8:2 geometrical isomers) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with tert-butyl methyl ether, and extracted with tert-butyl methyl ether after the addition of 10% hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 860 mg of 3-methylthio-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:23]#[N:24])[CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:23]#[N:24])[CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1-c1ccnc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of {5-[2-(1-cyano-cyclopropyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 18.2) (295 mg), DCM (4 mL) and TFA (1 mL) is stirred for 2 h at rt and then concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 182 mg of the title compound: ESI-MS: 257.1 [M+H]+; tR=2.54 min (System 1); TLC: Rf=0.30 ((DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:15](O)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(c1ccccc1)N1CCC2(CC1)Cc1ccccc1C2=O
Yield: 62.2 %

Procedure:
A solution of 6.14 g (19.0 mmoles) 1-benzoyl-4-(phenylmethyl)-4-piperidinecarboxylic acid in 61 ml concentrated sulfuric acid was stirred 18 hours at room temperature to give a deep red solution. The solution was carefully diluted with ice-bath cooling with 300 ml H2O and extracted with 3×300 ml ethyl acetate. The extract was washed with 25 ml water and brine, dried, and the solvent was removed in vacuo to give a white foam. The foam was stirred under ether and filtered off to give 3.61 g (62%) product, m.p. 149°-154° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][C:43]([CH3:51])=[C:44]([O:49][CH3:50])[CH:45]=2)[O:40][C:39]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][C:43]([CH3:51])=[C:44]([O:49][CH3:50])[CH:45]=4)[O:40][C:39]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(=O)c(I)c(-c3ccccc3)oc2cc1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C
Yield: 41 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-6-methoxy-7-methyl-2-phenyl-chromen-4-one (78 mg, 0.20 mmol) was reacted to give the title compound (40 mg, 41%). 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 7.41-7.17 (m, 10H), 5.04 (s, 1H), 3.94 (s, 3H), 2.60-2.46 (m, 4H), 2.39-2.35 (m, 3H), 2.13-2.00 (m, 1H), 1.90-1.76 (m, 1H), 1.48-1.10 (m, 9H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C:53]([OH:56])([CH3:55])[CH3:54])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.I[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C:53]([OH:56])([CH3:54])[CH3:55])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC(C)(C)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)I
Agent: [F-]
Solvent: CC#N
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC(C)(C)O)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-(2-hydroxy-2-methyl-propoxy)-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate in acetonitrile (0.02 M) at 0° C. was added iodotrimethylsilane (2 eq.) and stirred for 10 min at 0° C. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in THF (0.2 M) and added tetrabutylammonium fluoride (2 eq.), and the reaction was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 7% [2 M NH3 in MeOH] in DCM) to afford the title compound as a colorless oil. 1H NMR (acetone d-6): δ 7.30 (s, 2H), 7.20 (d, 2H), 6.85 (d, 2H), 6.65 (s, 1H), 6.55 (s, 1H), 6.38 (s, 1H), 4.30-4.45 (m, 6H), 3.50-3.80 (m, 4H), 3.00-3.48 (m, 8H), 2.70-2.90 (m, 2H), 2.55 (t, 2H), 2.30-2.40 (m, 4H), 1.70-1.85 (m, 4H), 1.30 (s, 6H), 0.4-0.9 (m, 4H). LRMS [M+H]=713.2
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])[CH:17]=1
Reactant: COc1cc(OC)c(-c2nc3ccccc3[nH]2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2nc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-70A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp>240° C. (dec.). 1H-NMR (DMSO-d6) δ 8.72 (s, 1H), 12.10 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.08–8.02 (m, 3H), 7.80 (d, J=15.4 Hz, 1H), 7.59 (s, 2H), 7.17–7.13 (m, 2H), 6.89 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H). MS m/z=429 ([M+H]+, 100%).