Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:6])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of Hydrocortisone (3.65 g, 10 mmol) in acetonitrile (450 ml), succinic anhydride (1.65 g, 15 mmol) and DIEA (1.7 ml, 10 mmol) were added and the reaction mixture stirred at room temperature for 36 h. HPLC analysis of the reaction mixture showed 93% of the title compound. The solvent was evaporated and the residue redissolved in ethyl acetate and washed with water. The ethyl acetate phase was evaporated under reduced pressure and the residue triturated in diethyl ether to obtain 4.4 g of white powder in 95% yield. RtI 5.94'.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CC(N(C)C)=O>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC(=O)N(C)C
Solvent: CCCCO
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 61.1 %

Procedure:
(R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DMA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH2:18]O)[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:27]>C(Cl)Cl>[Br:27][CH2:18][C:16]1[N:17]=[C:13]([C:12]2[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][N:9]=[N:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:14][CH:15]=1
Reactant: BrP(Br)Br
Reactant: OCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Solvent: ClCCl
Product: BrCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 193.1 %

Procedure:
To a solution of (2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)methanol (220 mg, 0.66 mmol) in DCM (8 mL), PBr3 (91 mg, 0.33 mmol) was added at 0° C. and the reaction mixture was warmed to rt and stirred for 12 h. After completion of starting material, reaction was quenched with saturated NaHCO3 solution, extracted with ethyl acetate (2×25 mL), washed with brine (1×10 mL). Solvent was removed under reduced pressure to obtain the crude product 4-(bromomethyl)-2-(3,5-diphenylpyridazin-4-yl)oxazole (250 mg) which was carried to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: NCc1ccc2ccccc2n1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3n2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and 2-(aminomethyl)quinoline in DME. ES-MS m/e (%): 342 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:8]([CH2:9][CH3:10])[C:13]([NH:12][CH3:11])=[O:14])=[CH:6][CH:7]=1
Reactant: CCNc1ccc(Cl)nc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CCN(C(=O)NC)c1ccc(Cl)nc1
Yield: 93.6 %

Procedure:
In 30 ml of toluene was dissolved 2.4 g (0.015 mole) of 2-chloro-5-ethylaminopyridine, followed by addition of 3.4 g of methyl isocyanate. The mixture was refluxed for 15 hours. After cooling, the resulting crystals were collected by filtration, washed with a small amount of Et2O and dried. The procedure gave 3.0 g of N-(6-chloro-3-pyridyl)-N-ethyl-N'-methylurea as pale yellow crystals.
Reaction SMILES: ClC(OCC)=O.[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[N:25][C:24]=3[CH3:32])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10].C[N:34]1CCOCC1.N>C(Cl)Cl.CO>[NH2:34][C:29]([C:27]1[N:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C@H:14]3[CH2:13][CH2:12][C@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[C:24]([CH3:32])=[N:25][CH:26]=1)=[O:30]
Reactant: CN1CCOCC1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(=O)O)cnc3C)cc2)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(N)=O)cnc3C)cc2)CC1

Procedure:
Ethyl chloroformate (245 μl, 2.54 mmol) was added dropwise to a stirred solution of 6-{4-[trans-4-(methoxycarbonyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carboxylic acid (Intermediate 65-1, 751 mg, 2.12 mmol) and N-methylmorpholine (350 μl, 3.18 mmol) in DCM (20 mL) at 0° C. Ammonia (5 mL of a 7M solution in MeOH) was added. The reaction mixture was allowed to warm up over 1 h then was concentrated and the residue was purified by chromatography eluting with 0-10% MeOH/DCM to give the title compound (226 mg, 30%) as a solid; 1H NMR δ 9.00 (1H, s), 8.08 (1H, s), 7.74 (1H, s), 7.70 (2H, d), 7.40 (2H, d), 3.63 (3H, s), 2.70-2.55 (1H, m), 2.67 (3H, s), 2.50-2.35 (1H, m), 2.10-1.98 (2H, m), 1.96-1.83 (2H, m), 1.65-1.43 (4H, m); MS 354.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.[F-].[Cs+]>O1CCOCC1.O>[Cl:18][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[N:25][CH:26]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:22]=2)[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=1
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Reactant: Fc1ccc(CNc2cc(Cl)nc(Cl)n2)c(F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(CNc2cc(Cl)nc(-c3cncc(C(F)(F)F)c3)n2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of (2,6-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-benzyl)-amine (1 g, 0.0034 mol) and 5-trifluoromethylpyridine-3-boronic acid (0.726 g, 0.0038 mol) were taken in dioxane:water (20:5) ml and to this CsF (2.1 g, 0.0138 mol) was added and degassed. Then bis-triphenylphosphine-palladium(II) chloride (0.24 g, 0.00034 mol) was added and degassed. The mixture was stirred at 60° C. for 12 hrs. The reaction was cooled to room temperature diluted with water (50 ml) and ethyl acetate (100 ml). After standard work-up, the residue was purified by column chromatography to get compound as white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]([NH:23][CH3:24])=[O:22])=[CH:16][N:17]2[CH3:20])=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[CH3:24][NH:23][C:21]([C:15]1[C:14]2[C:18](=[CH:19][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:17]([CH3:20])[C:16]=1[Cl:1])=[O:22]
Reactant: CNC(=O)c1cn(C)c2cc(OC)ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)c1c(Cl)n(C)c2cc(OC)ccc12
Temperature: 60 °C
Yield: 86.6 %

Procedure:
N-Chlorosuccinimide (0.150 g, 1.12 mmole) was added to a solution of 6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75a (0.243 g, 1.11 mmole) in CCl4 (10 ml) and DMF (3 ml). The reaction mixture was heated to 60° C. for 3 h and concentrated. The residue was purified by reverse phase chromatography eluting with 0–1% CH3OH in 1:1 EtOAc and CH2Cl2 to give a brown colored oil (0.243 g, 87% yield); 1H NMR (300 MHz, CDCl3) δ 7.61 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 6.19 (1H, s), 3.35 (3H, s), 2.96 (3H, s), 2.52 (3H, s); ESIMS (MH+): 253.05.
Reaction SMILES: [CH3:1][C:2]12[C:9]([C:11]#[CH:12])([OH:10])[C:6]([CH3:13])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[H][H]>[Ni]>[CH3:13][C:6]12[C:9]([CH2:11][CH3:12])([OH:10])[C:2]([CH3:1])([CH2:8][CH2:7]1)[CH2:3][CH2:4][CH2:5]2
Reactant: [H][H]
Reactant: C#CC1(O)C2(C)CCCC1(C)CC2
Agent: [Ni]
Product: CCC1(O)C2(C)CCCC1(C)CC2
Yield: 85 %

Procedure:
A solution of 178 g (1 mole) 5 in 1000 ml destilled methanole was mixed with 1 g Raney nickel and hydrogenated in an autoclave (20 bar/20° to 30° C.). After about 4 h the uptake of hydrogen was finished (2 equivalents H2). The reaction mixture was taken from the autoclave, filtered, evaporated and distilled. This resulted in 155 g (85%) of 7 in form of a colorless oil having a boiling point (1 mm) of 68° C. IR: 3500/3600 cm-1 (O--H).--NMR (CCl4): δ=0.88, s (1-, 5-CH2), 0.97, t, J=7 Hz (--CH2 --CH3), 1.45 ppm, br.s (6-, 7-CH2).--MS: m/e (%)=153 (100, M+ -29), 135 (56), 125 (20), 123 (20), 107 (71), 99 (20), 95 (45), 69 (46).C12H22O (M=182.30).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]([NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CCCCCCCC(N)=O
Product: CCCCCCCC(=O)NC(NC(=O)CCCCCCC)c1ccc(N(CC)CC)cc1
Yield: 68 %

Procedure:
Compound 54 was prepared from octanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 68%. 1H NMR (400 MHz, DMSO) δ 8.21 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 6.42 (t, J=8.0 Hz, 1H), 3.29-3.31 (m, 4H), 2.06-2.14 (m, 4H), 1.47-1.50 (m, 4H), 1.08-1.24 (m, 16H), 1.06 (t, J=7.2 Hz, 6H), 0.94 (t, J=7.2 Hz, 6H). LC-MS (ESI): m/z 446.3 (M+H)+. HRMS (ESI) for C27H48N3O2 (MH+): calcd, 446.3741. found 446.3734.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1])([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(C)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Temperature: 0 °C
Yield: 44 %

Procedure:
To a solution of methyl 5-methylthiophene-2-carboxylate (109 g, 700 mmol) in conc. sulfuric acid (850 ml) was added dropwise a solution of fuming nitric acid (31 ml, 738 mmol) in conc. sulfuric acid (150 ml) under ice-cooling in such a manner that an inside temperature did not exceed 5° C. After the completion of the dropwise addition, the mixture was stirred under ice-cooling for 30 min, and slowly poured into ice (2 kg). The precipitated solid was collected by filtration, washed with water (500 ml×6) and dried under reduced pressure to give methyl 4-nitro-5-methylthiophene-2-carboxylate (62 g, yield 44%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][Cl:27])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 82.4 %

Procedure:
To a solution of 4-butoxy-7-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (2.35g, 7 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was added thionyl chloride (1.0 ml, 14 mmol) and the obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (2.04 g, 82.6%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[C:10]([CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)#[N:11]
Reactant: N#CCCc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCC#N)cc1)c1ccccc1

Procedure:
The title product was prepared from 3-(4-hydroxyphenyl)proprionitrile and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (11%, colourless oil). HPLC-MS: m/z=281.2 (M+1); Rt: 3.75 min, purity 80%.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:16]=[CH:15]C(C(O)=O)=[C:10]([Cl:17])[CH:9]=1>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[CH:16]=[CH:15][C:1]([C:2]([Cl:4])=[O:3])=[C:10]([Cl:17])[CH:9]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Oxalylchloride (0.86 ml, 10.2 mmol) was added dropwise to a suspension of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.5 mmol) in DCM (20 ml) at rt. After the addition of 5 drops of DMF, the reaction mixture was refluxed for 4 h, then cooled to rt and concentrated in vacuo to give 4-bromo-2-chloro-benzoyl chloride (2.15 g, 100%) which was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.98 (d, J=8.5 Hz, 1H), 7.70 (d, J=2 Hz, 1H), 7.57 (dd, J=2 and 8 Hz 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.OCl.C(Cl)(=O)C([Cl:28])=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([Cl:28])=[O:17])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: OCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCc1cccs1)CC(=O)Cl

Procedure:
2-(N-(Ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetic acid (14 g, 54.41 mmol) was dissolved in dry dichloromethane (DCM) (300 mL). To this suspension was added 0.1 mL of DMF, followed by the careful addition of oxyl chloride (10.4 g, 81.93 mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time 0.5 mL of additional oxalyl chloride was added. The solvent was evaporated under vacuum to give 2-(N-(ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetyl chloride. This acid chloride was re-dissolved in dry DCM (300 mL) and AlCl3 (18.1 g, 135.74 mmol) was added at room temperature. The reaction was kept at room temperature for 1 hour then quenched by the slow addition of ethanol (about 10 mL). The mixture was then poured into ice and stirred for 1 hr. The aqueous mixture was extracted with DCM (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to give a residue, which was purified by silica gel chromatography to produce ethyl 4,5,7,8-tetrahydro-4-oxothieno[3,2-d]azepine-6-carboxylate (7.4 g, 30.92 mmol).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#N>C(#N)C1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:20]=1
Reactant: C#CCCCCCC
Reactant: COc1cccc(C#N)c1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1cccc(OC)c1
Reaction time: 23 h
Yield: 80 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-methoxybenzonitrile (0.245 ml; 0.266 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 23 h at 65° C. showed the presence of 1.60 mmol (80% yield) of 1-methoxy-3-(1-octynyl)benzene and no remaining 3-methoxybenzonitrile in the reaction mixture.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O)([CH3:9])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6].[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:21]([NH:20][CH2:15][C:14]2[CH:17]=[C:10]([C:2]([CH3:9])([CH3:1])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])[CH:11]=[CH:12][C:13]=2[O:18][CH3:19])[C@@H:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)C#CC(C)(C)c1ccc(OC)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COC(=O)C#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 59 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[N:34]1([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC4)c3)n2)n1
Yield: 52.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.200 g, 0.409 mmol) by treatment with commercially available azetidine [CAS-no. 503-29-7] (0.14 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 53%) as a white solid. MS (ISP) 510.2 [(M+H)+]; mp 158° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:41]2[CH2:46][CH2:45][N:44]([C:13](=[O:15])[C@H:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 4-azetidin-1-yl-piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:22])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CI
Reactant: CCCCCc1c(-c2ccccc2)[nH]c2ccc(Br)cc12
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-3-pentyl-2-phenyl-1H-indole (1.711 g, 5.000 mmol) was reacted with k-t-butoxide (0.589 g, 5.250 mmol) and methyl iodide (0.745 g, 5.250 mmol) in DMF (15 ml) to give the product (1.113 g, 3.124 mmol, 62%) as a colorless oil. 1H DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.13-1.18 (m, 4H), 1.44-1.50 (m, 2H), 2.58 (t, J=7.6 Hz, 2H), 3.53 (s, 3H), 7.27 (dd, J=2.0, 8.7 Hz, 1H), 7.41-7.44 (m, 3H), 7.48 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.0 Hz, 2H), 7.71 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 356/358 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C(#N)C>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc(CO)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cnc(CCl)c(C)c1[N+](=O)[O-]
Temperature: 12.5 °C

Procedure:
8.0 ml (0.11 mole) of thionyl chloride in 20.0 ml of methylenechloride was added to a solution of 20.0 gms 2-hydroxymethyl-3,5dimethyl-4-nitropyridine, of formula-II obtained in step-(a), at temperature of 10-15° C. over a period of 1 hr. The reaction is maintained at 10-15° C. for further 30 min. Aqueous 10% solution of sodium carbonate was slowly added to the reaction mixture at 10-15° C. and pH adjusted to 8.0 to 8.5. The organic base (compound) is over anhydrous sodium sulfate and solvent was removed under vacuum to obtain crude product. (purity 85%) Pure compound is isolated by re-crystallization from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1NC2=O
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-8-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-8-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.