Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.O=P(Cl)(Cl)Cl.[I:11][C:12]1[N:13]=[C:14]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)[N:15]2[C:20]=1C(=O)NC=N2>N1C=CC=CC=1>[NH2:1][C:5]1[C:20]2=[C:12]([I:11])[N:13]=[C:14]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)[N:15]2[N:2]=[CH:3][N:4]=1
Reactant: c1nc[nH]n1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)ncnn32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1H-1,2,4-triazole (0.881 g, 0.0128 mol) in pyridine (3.00 mL) was charged with POCl3 (0.396 mL, 0.00425 mol) and stirred at rt for 15 min. To this mixture was drop wise added methyl trans-4-(5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.570 g, 0.00142 mol) in pyridine (6.00 mL) and stirred at rt for an additional 2.45 h. The reaction was quenched with excess 2 M of NH3 in i-PrOH (40.00 mL) at 0° C. and allowed to stir at rt for an additional 3 h. The reaction was concentrated in vacuo and partitioned between EtOAc and sat. NaHCO3 and, separated. The aqueous was washed with EtOAc (3×) and the combined organic fractions were washed with brine (1×). The aqueous was re-extracted with CHCl3 (3×) and the organic was added to the EtOAc fractions. The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude brown/red solid was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 438 mg, (76% yield) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.54 (m, 2H), 1.55-1.71 (m, 2H), 1.92-2.07 (m, 4H), 2.35-2.46 (m, 1H), 3.06-3.19 (m, 1H), 3.61 (s, 3H), 6.77 (br. s., 1H) 7.86 (s, 1H) and 8.44 (br. s., 1H); MS (ES+): m/z 401.85 [MH+].
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:38][C:39](=[O:41])[CH3:40])([CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([O:25]CC4C=CC=CC=4)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.CO.[C].[Pd]>[C:35]([O:34][CH2:33][C:6]([NH:38][C:39](=[O:41])[CH3:40])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)NC(CCc1ccc(-c2cccc3c(OCc4ccccc4)cccc23)cc1)(COC(C)=O)COC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)NC(CCc1ccc(-c2cccc3c(O)cccc23)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
The compound (1.45 g) of Example (1-1) was dissolved in ethyl acetate (30 mL) and methanol (10 mL), 10% palladium carbon (500 mg) was added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. After celite filtration, the filtrate was concentrated, and the residue was washed with diethyl ether to give the object product (0.99 g) as white crystals.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:14][CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]([O:17][CH2:16][CH2:15][O:14][C:13]1[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]([OH:21])=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(OCCO)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(3,5-ditert.butyl-4-hydroxyphenoxy)ethyl methacrylate was prepared by adding dropwise a solution of 3.1 grams of methacryloyl chloride in 15 milliliters of tetrahydrofuran to a solution of 7 grams of 2-(3,5-ditert.butyl-4-hydroxyphenoxy)ethanol and 11 grams of triethylamine in 50 milliliters of tetrahydrofuran. The addition was completed in 5 minutes and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then poured into a solution of 20 milliliters of concentrated hydorchloric acid in 400 milliliters of water and the oil which precipitated was separated by extraction with petroleum ether. The extract was allowed to evaporate and the solid residue was recrystallized from petroleum ether to yield 4 grams of product which melted at 68° C. to 70° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[OH:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].COCCOCCOC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[O:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27]
Reactant: COc1ccc(I)c(OC)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c(OC)c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
In a sealed tube purged with nitrogen, 1-iodo-2,4-dimethoxybenzene (40) (3.02 g, 11.4 mmol), (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (2.50 g, 10.4 mmol), Cs2CO3 (5.10 g, 15.6 mmol), 3,4,7,8-tetramethyl-[1,10]-phenylthroline (0.50 g, 2.1 mmol), CuI (0.16 g, 1.0 mmol), diglyme (10 mL) and toluene (30 mL) were placed. The reaction mixture was stirred at 130° C. for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (600 mL) and washed with water (200 mL). The solid material was removed by filtration. The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1S,2R,4aS,8aS)-1-(2,4-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (41) (2.50 g, 64%) as an off white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1.C(OCC)(=O)C>[C:31]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (1.3 g) in THF (13 ml) were added triethylamine (0.752 ml) and acetyl chloride (0.385 mL) at 0° C., and the mixture was gradually warmed from 0° C. to room temperature, and stirred overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (0.965 g).
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1[O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]3[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=3[CH:39]=2)=[O:28])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1[O:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]3[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=3[CH:39]=2)=[O:28])[CH2:24][CH2:25]1)[CH3:2]
Reactant: CCI
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OCCN2CCC(NC(=O)c3ccc4c(c3)NC(=O)CS4)CC2)cnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl iodide (13 μL, 0.16 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide (90 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by potassium carbonate (22 mg, 0.16 mmol, 1.0 eq). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(4-ethoxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide as a white lyophilizated powder (29 mg, 32% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:7]2)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=3)[CH2:9]2)=[O:22])=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2

Procedure:
400 mg (1.35 mmol) N-(5-acetyl-indan-2-yl)-4-fluoro-benzamide were dissolved in 10 ml of methanol, then 100 mg (2.7 mmol) sodium borohydride were added. The mixture was worked up by dropping onto ice/HCl, the resulting solid was filtered off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][CH:4]=1.II.[I:24](O)(=O)(=O)=O>C(O)C.O>[I:24][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][CH:9]([C:13]([F:14])([F:15])[F:16])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCOC(=O)C1=Cc2ccc(OC)cc2OC1C(F)(F)F
Agent: II
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Temperature: 70 °C
Yield: 86.4 %

Procedure:
To a solution of 8 g (26.5 mmol) of ethyl 7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 60 mL of ethanol was added 2.8 g (11.2 mmol) of iodine, followed by addition of a solution of 9.0 g (39.5 mmol) of periodic acid in 25 mL of water. The resulting solution was heated to 70° C. for five hrs. After cooling to room temperature, the volatiles were removed, the residue was dissolved in ethyl acetate, and the organic phase washed with saturated aqueous sodium sulfite and satr' brine. The resultant solution was dried over anhydrous magnesium sulfate and the volatiles were removed. The residue was purified by silica gel chromatography with hexane/ethyl acetate mixture to afford 9.8 g (70%) of a light yellow solid: 1H NMR (CDCl3/300 MHz) 7.62(s, 1H), 7.60(s, 1H), 6.49(s, 1H), 5.69(q, J=6.9 Hz, 1H), 4.30(m, 2H), 3.89(s, 3H), 1.34(t, J=7.2 Hz, 3H). MS (ESI+) 428.9(M+1, 100). HRMS (EI) m/z calcd for (C14H12F3O4) 427.9732, found 427.9741.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:18])([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)(C)(C)C.Cl>CO>[I:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([NH2:7])([CH3:17])[CH3:18])=[CH:15][CH:14]=1
Reactant: CC(C)(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(N)Cc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1.10 g (2.93 mmol) 2-(4-iodophenyl)-1,1-dimethyl-ethyl-carbamic acid tert-butyl ester (I52.9) in 10 mL MeOH are added 7.04 mL (8.80 mmol) HCl (1.25M in MeOH). The mixture is stirred at 50° C. for 3 h. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1>[CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)O
Reactant: CNc1ccc(C(=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CNc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
4-(Methylamino)benzoate (2.00 g, 13.2 mmol) was dissolved in tert-butanol (66 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg, 0.464 mmol) and 4-dimethylaminopyridine (81 mg, 0.660 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1, v/v) to give the title compound (2.14 g; yield, 78%) as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].CC(O)=O.[CH:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:31]#[N:32])[CH:28]=2)[CH2:23]1)=O.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH:22]([CH2:20][NH:10][CH2:9][CH2:8][NH:7][C:6](=[O:11])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:30]2)#[N:32]
Reactant: N#Cc1ccc2c(c1)CC(C=O)C2
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCC1Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2-amino-ethyl)-carbamic acid tert-butyl ester (400 mg, 2.5 mmol), NaBH3CN (315 mg, 5.0 mmol) and HOAc (300 mg, 5.0 mmol) in 30 mL MeOH was added 2-formyl-2,3-dihydro-1H-indene-5-carbonitrile (430 mg, 2.5 mmol). The mixture was stirred at RT overnight, and then sat. Na2CO3 (50 mL) was added and stirred for 30 min. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-TLC to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([OH:34])=O)[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:34])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (340 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (267 mg) was added thereto at 0° C., the temperature was returned to room temperature, and the mixture was stirred for 1 hour under nitrogen atmosphere. The solvent and excess thionyl chloride were evaporated under reduced pressure, and the resulting residue was suspended in tetrahydrofuran (30 ml), which was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (197 mg) and triethylamine (906 mg) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred at room temperature for 1 hour under nitrogen atmosphere, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (337 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([S-:4])[CH2:2][CH3:3].[Na+].[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9](F)[CH:8]=1.O>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]([S:4][CH2:1][CH2:2][CH3:3])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cc(F)cc(Br)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Dissolve sodium propanethiolate (7.5 g) in DMF (250 mL) at ambient temperature, then chill to −30° C. and add 1-bromo-3,5-difluorobenzene (8.35 mL). After 1 hour, warm to −15° C., and stir for an additional 3 hours. Pour into water (2 L) and extract into hexanes (3×500 mL). Wash the resulting organic solution with saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate), filter and concentrate. Filter through a plug of silica gel, wash with 10:90 ethyl acetate:hexanes and concentrate to give 1-bromo-3-fluoro-5-propylsulfanylbenzene (16.2 g, 90%). The title compound is prepared essentially as described in Preparation 343.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH3:12])[N:7]=1)=[O:5])[CH3:2].[C:13](=[O:16])([O-])[O-].[K+].[K+].C=O.Cl[CH:22]([F:24])[F:23]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:13][OH:16])=[C:9]([O:11][CH:22]([F:24])[F:23])[N:8]([CH3:12])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: FC(F)Cl
Reactant: CCOC(=O)c1cc(O)n(C)n1
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C)c(OC(F)F)c1CO
Temperature: 25 °C
Yield: 82 %

Procedure:
In 50 ml of DMF were suspended 8.5 g (0.05 mole) of the 3-ethoxycarbonyl-5-hydroxy-1-methylpyrazole synthesized in Reference Example 3 and 10.5 g (0.08 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 2.3 g (0.08 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 20.9 g (0.15 mole) of potassium carbonate was added. Therein was blown 8.6 g (0.10 mole) of chlorodifluoromethane. The reaction mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate three times. The organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 24.3 g (purity: 42.2%, yield: 82.0%) of a crude solution of title compound. The crude solution was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain a title compound as white crystals.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([CH3:14])[S:13][C:7]=2[S:6]1(=[O:16])=[O:15])(C)(C)C.ClC1C=CC=CC=1Cl.C(=O)(O)[O-].[Na+]>CCOCC>[CH3:14][C:12]1[S:13][C:7]2[S:6](=[O:16])(=[O:15])[NH:5][C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: Cc1cc2c(s1)S(=O)(=O)N(C(C)(C)C)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: Cc1cc2c(s1)S(=O)(=O)NC2=O
Yield: 83.1 %

Procedure:
A mixture of 0.2 gm (0.77 millimols) of N-tert. butyl-5-methyl-thieno[3,2-d]isothiazole-3(2H)-one-1,1-dioxide and o-dichloro-benzene was refluxed for 8 hours. After cooling, the reaction mixture was distributed between a mixture of ether and aqueous sodium bicarbonate solution. The separated aqueous solution was acidified and extracted with methylene chloride. After evaporation and recrystallization from methanol, 0.13 gm (83% of theory) of 5-methyl-thieno[3,2-d]isothiazole-3(2H)-one-1,1-dioxide was obtained.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH2:8])C.C(N(CC)CC)C.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=O>C1COCC1>[Br:19][C:20]([CH3:25])([CH3:24])[CH2:21][NH-:8].[CH:4](=[O:3])[CH2:5][CH2:6][CH3:7]
Reactant: CCOC(CCCN)OCC
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C[NH-]
Product: CCCC=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 ml of dry THF, 8.1 g (0.05 mol) 4-aminobutyraldehyde diethyl acetal and 8.4 ml (0.06 mol) triethylamine were added. The reaction flask was kept in ice-water bath, and 2-bromoisobutyryl bromide (7.5 ml, 0.06 mol) was added dropwise by a syringe over 30 min. The reaction was then stirred for 2 hours at room temperature. The white amine halide salt precipitate was filtered off by Buchner funnel. After evaporating half of the THF under reduced pressure, the filtered THF solution was treated with 25 ml of 20% trifluoroacetic acid aqueous solution overnight to cleave the diethyl acetal protection group. The mixture was neutralised by addition of 5% of NaHCO3 water solution to pH 8, and the product aldehyde was extracted three times by 50 ml DCM each time. After evaporation of DCM, a red-yellow liquid was obtained. Further purification was carried out by silicon column using DCM as eluent. The final product is colorless liquid, and stored at −20° C. freezer.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH:23]([CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([CH:26]1[CH2:31][CH2:30][CH:29]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:18][C:7]1[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc2c(cc1Br)OCC2
Temperature: 65 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a mixture of tert-butyl (2,3-dihydro-1-benzofuran-5-yl)carbamate (410 mg) and acetonitrile (9.00 mL) was added N-bromosuccinimide (341 mg), followed by stirring at 65° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 92:8) to obtain tert-butyl (6-bromo-2,3-dihydro-1-benzofuran-5-yl)carbamate (178 mg) as a colorless solid.