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[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH2:24]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:29]1([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]4[N:5]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 77.4 %

Procedure:
N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (100.0 mg, 0.2854 mmol), 4-(4-morpholino)aniline (102 mg, 0.571 mmol) and N,N-Diisopropylethylamine (0.149 mL, 0.856 mmol) were dissolved in 1-Methoxy-2-propanol (1.08 mL, 11.1 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes. The reaction was then reduced en vacuo and the resulting residue was isolated and purified by Gilson prep HPLC to afford 102.60 mg of N-{2-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a lyophilized powder. (M+H)=465.1. 1H NMR (400 MHz, DMSO, d6) δ 9.43 (s, 1H), 8.98 (s, 1H), 8.83 (s, 1H), 7.72 (d, 1H, J=7.80 Hz), 7.55 (m, 4H), 7.45 (m, 1H), 7.00 (m, 4H), 3.78 (m, 4H), 3.14 (m, 4H), 2.68 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C@H:11]2[CH2:16][CH2:15][C@H](C#N)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[OH-:19].[K+].Cl.C(O)CO[CH2:25][CH2:26][OH:27]>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C@H:11]2[CH2:16][CH2:15][C@H:25]([C:26]([OH:27])=[O:19])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: [OH-]
Reactant: OCCOCCO
Reactant: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Agent: Cl
Agent: [K+]
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Temperature: 180 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.04 g of trans-4-[trans-4-(3-butenyl)cyclohexyl]cyclohexanecarbonitrile in 10 ml of diethylene glycol was treated with a solution of 2 g of potassium hydroxide in 10 ml of diethylene glycol and then stirred at 180° C. (oil bath temperature) for 2.5 hours. Subsequently, the reaction mixture was poured on to ice/water, acidified with 8 ml of 25 percent hydrochloric acid and extracted with diethyl ether. The organic phase was dried over magnesium sulphate, filtered and evaporated. Crystallization of the resulting beige crude product (1.06 g) from 50 ml of hexane gave 588 mg of trans-4-[trans-4-(3-butenyl)cyclohexyl]cyclohexanecarboxylic acid as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[NH4+:13]>O1CCOCC1>[Br:1][C:2]1[C:6]2[C:7]([NH2:13])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1nccc2occ(Br)c12
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc2occ(Br)c12
Temperature: 150 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
A mixture of 3-bromo-4-chlorofuro[3,2-c]pyridine (7.0 g, 22 mmol), 38 wt % aqueous ammonium hydroxide (75 mL) and dioxane (75 mL) in a Parr mini-reactor was stirred at 150° C. for two days. The solvent was removed in vacuo and water (200 mL) was added to the residue. The mixture was adjusted to pH 12 with 2N NaOH (aq) extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (4.6 g, 71%). 1H NMR (DMSO-d6, 400 MHz) 8.13 (s, 1H), 7.85 (d, 1H), 6.92 (d, 1H), 6.17-6.27 (bs, 2H); RP-HPLC (Conditions d) Rt 8.02 min.; MS: MH+ 213, 215.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH2:16][CH2:15][NH:14][CH2:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[Cl:17][C:18]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:14]1[CH2:15][CH2:16][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH2:13]1)=[O:21]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1ccc(-c2ncnc3c2CCNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccccc2)C1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of Intermediate 1 (55 mg, 0.26 mmol) in DCM (3 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (60 mg, 0.26 mmol) followed by EDCI (75 mg, 0.39 mmol), HOBt (28 mg, 0.21 mmol) and TEA (0.72 mL, 0.52 mmol). The mixture was stirred overnight and then loaded directly on a column. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product as a colorless foam (80 mg, 73%). MS (ESI) mass calcd. C21H15ClF3N3O, 417.09. m/z found 418.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.16-9.03 (m, 1H), 7.82-7.77 (m, 1H), 7.65-7.46 (m, 7H), 5.16-5.02 (m, 1H), 4.61-4.42 (m, 1H), 4.09-3.97 (m, 1H), 3.52-3.38 (m, 1H), 3.11-2.83 (m, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:5][N:4]=1.[I-].[NH2:21][N+:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[K+].CO>C(Cl)Cl.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=23)[CH:6]=[CH:5][N:4]=1
Reactant: N[n+]1ccccc1
Reactant: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CSc1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. solution of 2-(methylthio)-4-[(3-nitrophenyl)ethynyl]pyrimidine (4.0 g, 14.7 mmol) and N-aminopyridinium iodide (6.53 g, 29.4 mmol) in DCM (150 mL) was added potassium hydroxide (2.06 g, 36.8 mmol) in water (50 mL). The reaction was allowed to warm to rt and stirred for 16 h. The mixture was diluted with DCM and water. The organic layer was separated and the aqueous layer is extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to give a dark solid. The residue was dissolved in DCM and MeOH was added until the product formed as a precipitate. The product was collected by filtration and dried to supply the title compound (2.02 g) as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.36 (s, 1H), 8.62 (d, 1H, J=9.2), 8.54 (d, 1H, J=5.6), 7.94 (s, 1H), 7.82 (d, 1H, J=8.8), 7.54 (t, 1H, J=8.0), 7.46 (d, 1H, J=9.2), 7.16 (d, 1H, J=5.2), 2.59 (s, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:32]1[CH2:36][C@@H:35]([O:37][CH2:38][CH2:39][CH3:40])[CH2:34][N:33]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:30])[NH2:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C)C=C(C(N2[CH2:82][CH2:81][CH2:80][C@@H:79]2[CH2:83][O:84][CH3:85])=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[C:103](OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=C(C)C=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.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.COC[C@H]1CCCN1>ClCCl.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[C:26]([CH3:103])[CH:25]=[C:24]([C:28]([N:29]3[CH2:82][CH2:81][CH2:80][C@@H:79]3[CH2:83][O:84][CH3:85])=[O:30])[CH:23]=2)[C@H:9]([OH:8])[C@H:32]2[CH2:36][C@@H:35]([O:37][CH2:38][CH2:39][CH3:40])[CH2:34][NH:33]2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)N3CCC[C@@H]3COC)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC[C@H]1CCCN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)N3CCC[C@@H]3COC)c2)C1
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Step 8 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 28 mg, 0.038 mmol) in dichloromethane (1 mL) was added Hunig's base (14 mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (65 mg, 0.057 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 30 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.01 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 0.88 (3H, t, J=5 Hz), 1.48-1.54 (11H, m), 1.73 (1H, m), 1.92-2.09 (5H, m), 2.18 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.96 (1H, m), 3.05 (1H, m), 3.26-3.39 (5H, m), 3.47 (1H, m), 3.58 (1H, m), 3.68 (1H, m), 3.76 (1H, dd, J=5, 15 Hz), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.11-4.14 (1H, m), 4.41 (1H, brd s), 4.56 (1H, m), 6.59 (1H, m), 6.76 (1H, s), 6.77 (1H, s), 7.43 (1H, s), 7.72 (1H, s), 7.74 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 788.61.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:3]1=[O:21].O.NN>CO.[Ni]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)[C:3](=[O:21])[CH:2]2[CH3:1]
Reactant: CC1C(=O)N(C2CCN(C)CC2)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC1C(=O)N(C2CCN(C)CC2)c2ccc(N)cc21
Yield: 95 %

Procedure:
A solution of compound 3-methyl-1-(1-methylpiperidin-4-yl)-5-nitroindolin-2-one (0.1 g, 0.345 mmol) in dry methanol (3 mL) was treated with Ra—Ni (0.05 g of wet slurry) followed by hydrazine hydrate (0.1 mL, 3.456 mmol) at room temperature. The resulting mixture was refluxed for 2 min. in a pre-heated oil bath and brought to room temperature. The reaction was filtered through celite bed and washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 5-amino-3-methyl-1-(1-methylpiperidin-4-yl)indolin-2-one (0.085 g, 96%) as a syrup. 1H NMR (DMSO-d6) δ: 1.24 (d, 3H, J=7.8 Hz), 1.42-1.54 (m, 2H), 1.96 (t, 2H, J=10.2 Hz), 2.18 (s, 3H), 2.26-2.34 (m, 2H), 2.85 (d, 2H, J=11.1 Hz), 3.25-3.30 (m, 1H), 3.91-4.02 (m, 1H), 4.75 (s, 2H), 6.43 (dd, 1H, J=2.1, 8.4 Hz), 6.56 (d, 1H, J=1.5 Hz), 6.79 (d, 1H, J=8.4 Hz); ESI-MS (m/z, %) 260 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[C:7]2[CH:12]3[C:13]([CH3:15])([CH3:14])[C:9](C)([CH2:10][CH2:11]3)[C:8]2=O)=[CH:4][CH:3]=1.[N:20]1[C:27]([Cl:28])=[N:26][C:24]([Cl:25])=[N:23][C:21]=1Cl.[C:29]1(C)C=CC=CC=1>>[C:12]12([CH3:29])[C:13]([CH3:14])([CH3:15])[CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]2=[C:6]=[C:5]1[CH:18]=[CH:19][C:2]([NH:1][C:21]2[N:23]=[C:24]([Cl:25])[N:26]=[C:27]([Cl:28])[N:20]=2)=[CH:3][CH2:4]1
Reactant: CC12CCC(C(=Cc3ccc(N)cc3)C1=O)C2(C)C
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccccc1
Product: CC12CCC(CC1=C=C1C=CC(Nc3nc(Cl)nc(Cl)n3)=CC1)C2(C)C
Temperature: 40 °C

Procedure:
0.1 mol of 4-aminobenzylidenecamphor, dissolved in toluene, is added dropwise to a solution of 0.1 mol of cyanuric chloride in toluene. The reaction mixture is heated to 40° C. Working-up leads to 36 g (88%) of a pale yellow solid. Melting point: 238° C.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][N:6]([CH:9](O)[CH3:10])[CH2:5][CH2:4]1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17](Cl)=[CH:18][CH:19]=2)[N:14]=1.C([O:27]C(C)C)(C)C>ClC1C=CC=CC=1.C(Cl)Cl.C(N(CCOCCOC)CCOCCOC)COCCOC>[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:27][CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)=[CH:18][CH:19]=2)[N:14]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CC(C)OC(C)C
Reactant: CC(O)N1CCOCC1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: Nc1ccc2ccc(OCCN3CCOCC3)nc2n1

Procedure:
Tris(3,6-dioxaheptyl)amine (1.47 g), pulverized potassium hydroxide (80% pure, 6.75 g) and morpholinoethanol (12 g) are added to a suspension of 2-amino-7-chloro-1,8-naphthyridine (16.2 g) in chlorobenzene (450 cc). The mixture is brought to 120° C. and maintained at this temperature for 3 hours. The suspension obtained after cooling is separated by filtration. The separated product is washed with chlorobenzene (3×50 cc) and water (3×50 cc). The solid obtained is redissolved in methylene chloride (400 cc). The insoluble material which remains is removed by filtration. The filtrate is dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The crude product obtained (23.5 g; m.p. 164° C.) is stirred in the presence of isopropyl ether (100 cc), filtered and dried at 30° C. under reduced pressure (0.07 kPa). 2-Amino-7-(2-morpholinoethoxy)-1,8-naphthyridine (13.9 g), m.p. 164° C., is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C:13](=[CH2:29])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Yield: 66 %

Procedure:
1.0 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione is reacted, using 2.0 g of p-toluenesulfonic acid, analogously to Example 42 and purified, thus obtaining 680 mg of 21-acetoxy-17α-hydroxy-6-methylene-4-pregnene-3,20-dione, mp 194°-196° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:10][CH:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:12][CH3:13])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH:11]([N+:10]#[C-:8])[CH2:12][CH3:13]
Reactant: CCC(NC=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(CC)c1cccs1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
231 g of triethylamine are added to a solution of 96.5 g of 2-(1-formylaminopropyl) thiophene in 500 ml of methylene chloride and the mixture is cooled at below -30° C. 105 g of phosphorus oxychloride are added dropwise to the mixture at below -30° to -20° C. and and the mixture is stirred at the same temperature for 1 hour. After the reaction, the mixture is poured into 1 litter of an aqueous 10% potassium carbonate solution. The aqueous mixture is stirred at room temperature for 1 hour and the methylene chloride layer is separated therefrom. Said methylene chloride layer is washed with water, dried and evaporated to remove solvent. The residue is distilled under reduced pressure to give 74.5 g of 1-(2-thienyl)propyl isocyanide as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]=3[O:20][C:7]=2[C:6]([O:21][CH3:22])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>O.CC(C)=O>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]2[C:8]3[C:7](=[C:6]([O:21][CH3:22])[CH:5]=[CH:4][C:3]=3[C:1]([OH:25])=[O:2])[O:20][C:10]=2[CH2:11]1)=[O:16])[CH3:19]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C=O)c23)C1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Yield: 41 %

Procedure:
Ethyl 5-formyl-8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (from step 6) (0.310 g, 1.02 mmol) was taken in acetone water mixture. To this was added sulphamic acid (0.148 g, 1.53 mmol) and sodium chlorite (0.157 g, 1.73 mmol) and stirred for half an hour. After removing acetone under diminished pressure and dilution with water, it yielded 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (41%) which was filtered out, washed with water and dried.
Reaction SMILES: FC(F)(F)S(OC1[C:12]([Cl:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[Cl:15])(=O)=O.CCO[C:21]([CH3:23])=O.C[N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]#[N:25])[CH:9]=[C:8]([Cl:15])[C:21]=1[CH3:23]
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: Cc1cc(Cl)c(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1c(Cl)cc(C#N)cc1Cl
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a degassed solution of the triflate from Step A (40.92 g, 132.8 mmol) in 250 mL of DMF was added Zn(CN)2 (15.6 g, 132.8 mmol) and Pd(PPh3)4 (7.67 g, 6.64 mmol). The reaction was stirred at 80° C. for three days. Another portion of Zn(CN)2 (10 g) and Pd(PPh3)4 (5 g) was added the reaction was stirred at 80° C. for 24 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by crystallization (10% EtOAc/hexane) provided the titled product as white needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: CCN(CC)CC
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 10.0 mmol) and triethylamine (2.8 ml, 19.9 mmol) in EtOH (40 ml) was added to a microwave vial containing commercially available Cl2Pd(dppf)2-DCM (0.41 g, 0.50 mmol) and potassium vinyltrifluoroborate (2.0 g, 15 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave (3R)-6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=O)[CH2:8]1>C1COCC1>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][CH2:8]1
Reactant: O=C1COc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of LiAlH4 (34 mL, 1M in THF) is added dropwise via addition funnel to a cold (0° C.) solution of (2H)1,4-benzoxazin-3(4H)-one (5.04 g) in freshly distilled THF (110 mL). The LiAlH4 is added at such a rate to keep the reaction temperature below 10° C. The mixture is stirred at room temperature for 2 h and then is quenched successively with water (5 mL), 15% NaOH (5 mL), and water (5 mL) again. The resulting precipitate is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2Cl2 and dried (Na2SO4), filtered, and concentrated to afford the product benzomorpholine as a yellow oil which was used without further purification in the next step.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]=2[CH2:18][CH2:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:18]([C:8]1[O:9][C:10](=[O:17])[C:11]2[C:16]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:19][CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1oc(=O)c2ccccc2c1-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 72.7 %

Procedure:
4-Phenyl-3-propyl-1H-isochromen-1-one (intermediate C20.3, 107 mg, 0.405 mmol), N-bromosuccinimide (86 mg, 0.486 mmol), benzoyl peroxide (25 mg, 0.1 mmol) were reacted in CCl4 (2 mL) at 100° C. for 2 hrs. The reaction mixture was then purified on Biotage 50 g silica gel cartridge with a gradient of hexane and EtOAc to give the title compound (101 mg, 72.7%) as a yellowish oil.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=2/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[CH:13][CH:12]=1.[OH2:37]>O1CCCC1>[CH3:9][S:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=2/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[CH:13][CH:12]=1)(=[O:2])=[O:37]
Reactant: CSc1ccc(-c2sc(NC(C)=O)nc2/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Reactant: O
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium peroxymonosulfate (408 mg) was suspended in water (1 ml) and tetrahydrofuran (1 ml), and then N-{5-[4-(methylthio)phenyl]-4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (182 mg) in tetrahydrofuran (3 ml) was added dropwise to the suspension at 0° C. The reaction mixture was stirred at room temperature for 2 hours, and then water was added to the suspension. The precipitate was filtered in vacuo. The solid was washed with water and ethyl acetate to give N-{5-[4-(methylsulfonyl)phenyl]-4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (83 mg) as a yellow solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][S:2][CH:3]=1)=[O:8])=[O:20]
Reactant: NCC(=O)c1ccsc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccccc1Cl)c1ccsc1
Yield: 95.7 %

Procedure:
7.5 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 10.0 g of sodium bicarbonate and 8.86 g of 2-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 11.3 g of N-(2-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.