Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[O:38])[CH:34]=[CH:35][CH:36]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[O:38])[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(C(=O)c2cccc(N)c2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(=O)N4CCN(C)CC4)c3)nn12
Yield: 21.1 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (3-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (0.191 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 40.55 mg of {3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone as a lyophilized powder. (M+H)=443.9. 1H NMR (400 MHz, DMSO, d6) δ 9.63 (s, 1H), 8.99 (s, 1H), 7.76 (m, 3H), 7.45 (t, 1H, J=7.12 Hz), 7.30 (t, 1H, 7.84 Hz), 7.18 (d, 1H, J=8.25 Hz), 7.08 (t, 1H, J=7.45 Hz), 6.96 (m, 3H), 4.05 (m, 2H), 3.81 (s, 3H), 3.44 (m, 2H), 3.19 (m, 2H), 2.99 (m, 2H), 2.82 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([CH3:20])=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33]Cl)[C:25]([OH:27])=[O:26].O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([CH3:20])=[CH:10][CH:9]=2)[C:4]([S:7][CH2:33][C:32]([NH:31][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[Cl:21])=[O:35])=[N:5][N:6]=1
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3S)c2c1
Reactant: O=C(CCl)Nc1ccc(C(=O)O)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
Compound 8 (200 mg, 0.7 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (9) (174 mg, 0.7 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added and the mixture extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 304 mg of 4-[2-(5-amino-4-[7-methoxy-4-methylnaphthalen-1-yl]-4H-1,2,4-triazol-3-ylthio)acetamido]-3-chlorobenzoic acid (10) which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[C:5]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:4]1=2.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:25]([NH:2][CH:3]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[C:5]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:4]1=2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: NC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)NC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Under N2 was added 5,6-dihydro-4-amino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxidehydrochloride (3.2 g, 0.01 mol), triethylamine (2.2 g, 0.022 mol) and THF (100 ml). The mixture was stirred at room temperature while a solution of isobutyryl chloride (1.12 g, 0.0105 mol) in THF (10 ml) was added dropwise. After 18 hours, the mixture was poured onto saturated NaHCO3 and the suspension was extracted with ethyl acetate (3X). The combined organic extracts were dried, filtered and concentrated to dryness to yield 3.2 g (91%) of product.
Reaction SMILES: C([O:5][C:6](=[O:12])[C@@H:7]([CH3:11])[C@@H:8]([NH2:10])[CH3:9])(C)(C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=O.C(N(CC)CC)C>CCO>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:10][C@@H:8]([CH3:9])[C@H:7]([CH3:11])[C:6]([OH:5])=[O:12])=[O:14])[N:18]=1)#[N:36]
Reactant: C[C@H](N)[C@H](C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@H](C)C(=O)O
Temperature: 140 °C
Yield: 35.1 %

Procedure:
A mixture of (2S,3S)-3-amino-2-methyl-butyric acid tert-butyl ester (20 mg, 0.12 mmol), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.078 mmol), and triethylamine (0.050 mL) in EtOH (2 mL) was heated in a microwave reactor at 140° C. for 6 h. The resulting mixture was concentrated to dryness, and the residue was re-dissolved in CH2Cl2 and passed through a plug of silica gel. After evaporating the solvent, the residue was dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (2 mL) for 2 h. The mixture was concentrated in vacuo, and the resulting residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 11.1 mg of the title compound as a white solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][C:5]1([C:18](=[O:32])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH:21]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:30][N:28]([CH3:29])[C:27](=[O:31])[O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:18]([C:5]2([CH2:4][CH2:3][N:2]([CH3:33])[CH3:1])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[O:32])[CH:21]=1
Reactant: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1

Procedure:
Crude tert-butyl 4-(2-(dimethylamino)ethyl)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)piperidine-1-carboxylate from step C was treated with 1:1 TFA:CH2Cl2 (1.5 mL) for 45 min. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (30×100 mm C18 column, 0-50% MeOH:H2O (0.1% TFA), 12 min., 45 mL/min.) and lyophized to give impure title compound (173 mg) as the TFA salt. MS (ES+) [M+H]+=363.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:10]=[CH:9]/[C:8]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cccnc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
3-Bromopyridine (4 g, 25 mmol), methyl acrylate (2.6 g, 31 mmol), palladium(II) acetate (0.26 g, 1.2 mmol), tri-o-tolylphosphine (0.74 g, 2.4 mmol) and triethylamine (10 ml) were placed in a thick walled glass tube. The tube was sealed under argon and the mixture heated at 80° C. After 12 h the reaction mixture was allowed to cool to room temperature and chloroform (100 ml) was added. The mixture was washed with water (2×100 ml), the organics dried over anhydrous magnesium sulphate, and the solvent removed under reduced pressure. Column chromatography (flash silica gel; 1:1 ethyl acetate/hexane) yielded methyl E-3-(3-pyridyl)acrylate as a colourless oil (0.5 g, 12%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>O>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCNC1
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 10 ml of water, and 1.8 g of 3-pyrrolidinol are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.36 g of yellow powder are obtained, Yd=87.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[OH:17])=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1.C([O-])(O)=O.[Na+].[N:32]1[C:39]([Cl:40])=[N:38][C:36](Cl)=[N:35][C:33]=1[Cl:34]>C1COCC1>[CH2:20]([O:19][C:4]1[CH:3]=[C:2]([NH:1][C:36]2[N:38]=[C:39]([Cl:40])[N:32]=[C:33]([Cl:34])[N:35]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[OH:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1OCc1ccccc1)c1ccc(F)cc1O
Temperature: 25 °C

Procedure:
N-(4-Amino-2-benzyloxy-phenyl)-4-fluoro-2-hydroxy-benzamide (76) (0.060 g, 0.170 mmol) was dissolved in THF (3.4 mL), NaHCO3 (0.086 g, 1.02 mmol) was added and the mixture was chilled on a dry-ice/acetone bath. Cyanuric chloride (5) (0.032 g, 0.184 mmol) was dissolved in THF (2 mL) and added directly to the chilled solution while stirring. The ice bath was removed and the mixture continued to stir while warming to room temperature for 1 h. TLC (Rf: 0.8 compared to Rf: 0.35 for compound 76 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The reaction mixture was used immediately in the next step without purification or characterization.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:2][CH2:3][O:5][CH2:41][CH2:36]5)[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN5CCOCC5)c4)cc23)CC1
Yield: 50.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (22 mg, 0.42 mmol) for methanamine to afford 22.9 mg of the title compound (50.9%).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5](=O)[NH:4][CH:3]=1.C(Br)(=O)C([Br:23])=O>CN(C=O)C.ClCCCl>[Br:23][C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=C(Br)C(=O)Br
Reactant: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Br)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (0.52 g, 1.92 mmol) and 1,2-dichloroethane (10 ml) were placed in a vial (20 ml). To the resulting suspension was added carefully oxalyl bromide (0.53 ml, 1.24 g, 5.75 mmol). A foam was formed during the addition, and as the foam was settling down the stirring was started. DMF (3 drops) was added and the vial was sealed and the mixture was stirred overnight. Another portion of oxalyl bromide (0.2 ml, 0.46 g, 2.23 mmol) and DMF (3 drops) was added and the reaction was run for another 24 h. The mixture was partitioned between is DCM (20 ml) and water (20 ml) and the organic phase was dried. Filtration and evaporation gave a crude product, which was purified on silica, affording 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one (0.59 g, 93%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[S:5])[NH2:4].[P].[S].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=O>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]1[S:5][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:4]=1
Reactant: O=C(CBr)c1ccccc1O
Reactant: NC(=S)C(F)(F)F
Agent: [P]
Agent: [S]
Solvent: CCO
Product: Oc1ccccc1-c1csc(C(F)(F)F)n1

Procedure:
2,2,2-Trifluoroethanethioamide (which may be prepared by the method of J. H. Hillhouse et al., Phosphorus, Sulfur Relat. Elem. 1986, 26, 169-84) (157 mg, 1.22 mmol) in ethanol (1.3 mL) was added drop-wise to a solution of 2-bromo-1-(2-hydroxyphenyl)ethanone (119 mg, 0.55 mmol) in ethanol (1.3 mL) and the reaction was refluxed overnight. The reaction was concentrated in vacuo and purified via silica gel chromatography (Gradient: 5% to 20% ethyl acetate in heptane) to afford the title compound. Yield: 67 mg, 0.27 mmol, 49%. LCMS m/z 246.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 6.95 (ddd, J=8, 7, 1 Hz, 1H), 7.07 (dd, J=8.2, 1.2 Hz, 1H), 7.33 (ddd, J=8, 7, 2 Hz, 1H), 7.64 (dd, J=7.8, 1.6 Hz, 1H), 7.81 (s, 1H), 10.47 (s, 1H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[OH:13])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:21]1([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([OH:13])[CH:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9][OH:8])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: Oc1ccc(C(O)(c2ccccc2)C(CCOCc2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(O)cc1

Procedure:
The evaporation residue obtained in step (c) is dissolved in 300 ml of 94% ethanol. Then 2 g of 5% palladium-on-charcoal are added. The reaction mixture is stirred at room temperature under a hydrogen atmosphere until one equivalent of hydrogen is consumed. The catalyst is filtered off. The solvent is evaporated, and the residue is crystallized from toluene. The yield is 12.7 g (38% from desoxybenzoin) of a product having m.p. 192°-4° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](F)[CH:10]=2)=[N:7][CH:8]=1.Br.[CH:21]1([CH2:24][S:25]C(=N)N)[CH2:23][CH2:22]1.[OH-].[Na+]>CN(C)C=O>[CH:21]1([CH2:24][S:25][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=3)[CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:23][CH2:22]1
Reactant: N=C(N)SCC1CC1
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1SCC1CC1
Yield: 96.8 %

Procedure:
1.8 g (6.8 mmol) of 4-(5-trifluoromethylpyridin-2-yl)-2-fluorobenzonitrile, 1.6 g (7.6 mmol) of S-cyclopropylmethylisothiourea hydrobromide salt and 50 ml of N,N-dimethylformamide were put into a round-bottomed flask and stirred together with 1.6 g (8 mmol) of 20% aqueous sodium hydroxide overnight. The solvent was distilled off under reduced pressure, and the reaction mixture was separated with 50 ml of water and 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.2 g of 2-cyclopropylmethylthio-4-(5-trifluoromethylpyridin-2-yl)benzonitrile (yield 96%) as pale yellow feathery crystals (m.p. 135-136° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:40])[C:26]=1[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:29]>>[Cl:40][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:20])[C:26]=1/[CH:27]=[C:28](\[O:29][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)/[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OC

Procedure:
The compound was obtained starting from 3-benzyloxy-4-methoxy-benzoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O>CCCCCC.CS(C)=O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][C@@H:23]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:24]2)=[CH:35][CH:34]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
60% sodium hydride (240 mg, 6.0 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (20 ml). After stirring at room temperature for 50 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (1.20 g, 6.0 mmol) was added to the obtained suspension. They were stirred at room temperature for 60 minutes and then at 50° C. for 60 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-methoxyphenethyl)pyrrolidine (734 mg, 2.45 mmol) in dimethyl sulfoxide (10 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was poured into ice/water. After the extraction with a solvent mixture of hexane and ethyl acetate (1:1), the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with a mixture of the same solvents (3:1) and finally with a mixture of them (2:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl) pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (0.36 g, 36%).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(c2ccc(/C=C/C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
In a mixed solvent of THF (250 ml) and water (125 ml), (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (9.80 g) was dissolved, and the resulting mixture was cooled to 0° C. Barium hydroxide octahydrate (3.14 g) was added thereto and the resulting mixture was stirred at 0° C. for 8 hours. The reaction solution was concentrated to remove THF, and water (150 ml) was added thereto, followed by washing the resulting mixture with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:chloroform/methanol=10/1). The obtained crudely purified product was further purified by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=ethyl acetate) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (6.15 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C@@H:9]([CH2:12][OH:13])[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1C(=NO)C.P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+].C[N:29](C)[C:30](=O)[CH3:31].C(#N)C>>[CH3:31][C:30]1[O:1][C:2]2[C:11]3[O:10][CH:9]([CH2:12][OH:13])[CH2:8][O:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:29]=1
Reactant: CC(=NO)c1ccc2c(c1O)O[C@@H](CO)CO2
Reactant: CC(=O)N(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc3c(c2o1)OC(CO)CO3
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3.03 g (12.6 mmole) of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone oxime was dissolved in- a mixture of 1:3 N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled in an ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35 mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. The reaction mixture was stirred under nitrogen over a period of 48 hours. It was then added to an ice cold, saturated solution of sodium acetate, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated in vacuum. The resulting crude oil was column chromatographed on silica gel with 60% hexane/ethyl acetate to remove impurities and the product eluted with 40% hexane/ethyl acetate. After evaporation of the solvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the title compound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13]C(C#N)=[CH:15][C:3]1=2.S(=O)(=O)(O)O.[C:23]([OH:26])(=[O:25])[CH3:24].[OH-].[Na+]>O>[O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:24]([C:23]([OH:26])=[O:25])=[CH:15][C:3]1=2
Reactant: CC(=O)O
Reactant: N#Cc1ccc2oc3ncccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 3 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbonitrile, 30 ml of sulfuric acid, 30 ml of acetic acid and 30 ml of water is heated under reflux for 3 hours. The reaction mixture is poured on ice, and adjusted to pH 3 by addition of 10% sodium hydroxide. The crystalline precipitate is filtered off and recrystallized from a mixture of dioxane and dimethylformamide to give 1.5 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid melting at 293°-294°C.