Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl

Procedure:
A mixture of 30 g. of 7-chloro-4-hydroxyquinoline-3-carboxylic acid, ethyl ester, m.p. 299°-301°, (0.12 mol.) and 250 ml. of phosphorus oxychloride is refluxed for 4.5 hours. After removing the excess phosphorus oxychloride, the residue is triturated with water and dissolved in ether. The ethereal solution is washed with aqueous sodium carbonate (5%) and water, dried with sodium sulfate and the solvent is removed. The residual 4,7-dichloroquinoline-3-carboxylic acid, ethyl ester is triturated with petroleum ether (40°-60°), filtered off and dried; yield: 22 g. (68%); m.p. 81°-82°.
Reaction SMILES: C(O[CH:4]([O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH:12]=[CH2:13])=[CH:7][CH:6]=1)C.[C:18]([OH:22])(=[O:21])[CH2:19]C>>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][CH2:13][CH2:19][C:18]([OH:22])=[O:21])=[CH:9][CH:10]=1)=[O:15]
Reactant: CCC(=O)O
Reactant: C=CC(O)c1ccc(C(OCC)OCC)cc1
Product: O=Cc1ccc(C=CCCC(=O)O)cc1
Temperature: 140 °C

Procedure:
1-(4-Diethoxymethylphenyl)prop-2-en-1-ol (9.90 g, 42 mmol) was dissolved in triethyl ortho formiate (50 ml), and propionic acid (1.0 ml) was added. The solution was heated to 140° C. for 48 hours. Solvent was removed by rotary evaporation, and the orange oil was re-suspended in aqueous HCl (200 ml, 2 N). The mixture was heated to reflux for 4 hours, then cooled on an ice-bath for 30 min. Precipitated material was collected and washed twice with water and dried in a vacuum oven. Yield: 3.02 g (35%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:14][NH:15]C(N(C)C)=O)=[C:9]([CH:13]=1)[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:13]=[C:9]2[C:8]([CH2:14][NH:15][C:10]2=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)NCc1ccc(C(C)(C)C)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc2c(c1)C(=O)NC2
Yield: 29.3 %

Procedure:
A 500-mL, round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 107b (3.97 g, 14.2 mmol) and 12.1 N hydrochloric acid (100 mL) and heated to reflux. Trifluoroacetic acid (40 mL) was added and the reaction was refluxed overnight. After this time, the mixture was carefully neutralized to pH 7.5 with potassium carbonate (approximately 67 g) and then extracted with methyl t-butyl ether ((100 mL) and ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to afford a 29% yield (788 mg) of 107c as a white solid: mp 142-144° C.; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=1.5 Hz, 1H), 7.64 (dd, J=8.5, 2.0 Hz, 1H), 7.42 (dd, J=8.0, 0.5 Hz, 1H), 6.58 (s, 1H), 4.42 (s, 2H), 1.37 (s, 9H); MS (ESI+) m/z 190.1 (M+H).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)[C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl>CC(N(C)C)=O.C(OCC)(=O)C>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:16]([CH2:32][CH:31]=[CH:30][CH2:29][Cl:28])[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:15]
Reactant: ClC/C=C\CCl
Reactant: CCCCN(Cc1nc2ccccc2[nH]1)C(=O)c1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCN(C(=O)c1cccc(F)c1F)C(CC=CCCl)c1nc2ccccc2[nH]1
Reaction time: 0.08 h

Procedure:
N-butyl-N-(1H-benzoimidazol-2-ylmethyl)-2,3-difluorobenzamide (226 mg, 0.66 mmol) was dissolved in 3 mL dimethylacetamide at room temperature. Sodium hydride (29 mg, 0.72 mmol, 60% oil dispersion) was added and the reaction mixture stirred 5 minutes. Cis-1,4-Dichloro-2-butene was added and the reaction mixture stirred 90 minutes. The reaction mixture was diluted with 10 mL ethyl acetate, placed in a separatory funnel and washed 1×10 mL H2O then 1×10 mL brine. The organic phase was dried over MgSO4, filtered, concentrated, then purified by flash chromatography eluting with 1/1 ethyl acetate/hexane to afford 206 mg 2,3-difluoro-N-butyl-N-[(4-chlorobut-2-enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:29][C:27](=[O:28])[C@@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=2)[NH:25][C:23](=[O:24])[CH2:22][CH2:21][S:20][S:19][CH2:18][C@@H:17]([C:40]([N:42]2[C@H:46]([C:47]([NH:49][C@H:50]([C:55]([NH:57][CH2:58][C:59]([NH2:61])=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][NH2:54])=[O:48])[CH2:45][CH2:44][CH2:43]2)=[O:41])[NH:16][C:14](=[O:15])[C@H:13]([CH2:62][C:63]([NH2:65])=[O:64])[NH:12][C:10](=[O:11])[C@H:9]([C@H:66]([OH:68])[CH3:67])[NH:8][C:6]1=[O:7])[CH3:4].O.N.OO>C(#N)C>[CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:29][C:27](=[O:28])[C@@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=2)[NH:25][C:23](=[O:24])[CH2:22][CH2:21][S:20][S:19][CH2:18][C@@H:17]([C:40]([N:42]2[C@H:46]([C:47]([NH:49][C@H:50]([C:55]([NH:57][CH2:58][C:59]([NH2:61])=[O:60])=[O:56])[CH2:51][CH2:52][CH2:53][NH2:54])=[O:48])[CH2:45][CH2:44][CH2:43]2)=[O:41])[NH:16][C:14](=[O:15])[C@H:13]([CH2:62][C:63]([NH2:65])=[O:64])[NH:12][C:10](=[O:11])[CH:9]([C@H:66]([OH:68])[CH3:67])[NH:8][C:6]1=[O:7])[CH3:4]
Reactant: CCOc1ccc(C[C@H]2NC(=O)CCSSC[C@@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC2=O)cc1
Agent: N
Agent: OO
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C[C@H]2NC(=O)CCSSC[C@@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)C([C@@H](C)O)NC(=O)[C@H]([C@@H](C)CC)NC2=O)cc1

Procedure:
dissolving the linear atosiban in an acetonitrile aqueous solution, adjusting the pH value with ammonia water, adding H2O2 for oxidizing, filtering, purifying, and transferring to acetate salt and obtain the atosiban acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:21])=O>>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([Cl:21])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Reactant: O=S(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21

Procedure:
6.6 g (26.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid and 20 ml of thionyl chloride are heated to reflux until gaseous evolution has ceased. The mixture is evaporated to dryness and 7.1 g (100%) of the crude acid chloride are obtained, which product is used for the next step of the synthesis without further treatment.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)C(Br)c1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Yield: 54.4 %

Procedure:
In a manner similar to Example 16, 7.43 g of methyl α-bromo-α-[p-(p-chlorophenylthio)phenyl]acetate was reacted with 3.75 g of p-tert-butylphenol. Filtration of the crude reaction mixture yielded 5.4 g of white platelets, which yielded 4.8 g of white crystals, mp 106.5°-108.5° C on recrystallization from 100 ml of 80:20 hexane:chloroform.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][C:7]2=[O:14])([O-])=O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][C:7]2=[O:14]
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Under an inert atmosphere, a mixture of 6-nitro-2,3-dihydro-4H-chromen-4-one (5.4 g, 28 mmol), ethanol (250 mL), Raney nickel (1.5 g) and anhydrous hydrazine (8.8 mL, 0.28 mol) is stirred at ambient temperature overnight and filtered. The clear filtrate is concentrated to near dryness in vacuo. The resultant residue is treated with 6N hydrochloric acid and heated at reflux temperature for 1 hour, cooled in an ice bath, rendered basic with sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow crystalline solid, 3.4 g (75% yield), mp 136-137° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:43])[C:28]([C@@H:30]4[CH2:35][CH2:34][CH2:33][CH2:32][N:31]4C(OC(C)(C)C)=O)=[O:29])[CH2:23][CH2:22]3)=[C:17]([CH3:44])[C:16]=2[CH3:45])=[CH:11][CH:10]=1>C(Cl)Cl>[ClH:1].[ClH:1].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]([CH3:43])[C:28]([C@@H:30]4[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]4)=[O:29])[CH2:25][CH2:26]3)=[C:17]([CH3:44])[C:16]=2[CH3:45])=[CH:11][CH:10]=1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)[C@@H]3CCCCN3)CC2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add 4 M HCl in 1,4-dioxane (1.00 mL, 4.00 mmol) to a solution of (S)-tert-butyl 2-((1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)piperidin-4-yl)(methyl)carbamoyl)piperidine-1-carboxylate (80 mg, 0.152 mmol) in CH2Cl2 (2 mL). Stir the resulting mixture for 4 h at ambient temperature. Concentrate under reduced pressure and dry the residue in a vacuum oven at 45° C. to provide the title compound as pale yellow foam (79 mg, quantitative). ES/MS m/z 426.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[C:14]1([C:4]2[N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Product: FC(F)(F)Oc1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 4-chloro-2,6-diphenyl-pyrimidine (0.25 g, 0.93 mmol) and 4-trifluoromethoxy aniline (0.16 g, 0.93 mmol) according to the procedure as described above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([NH2:22])([NH2:21])=[N:17][C:18]([NH2:20])=[S:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:20]=[C:18]([NH:17][C:16]([NH2:22])=[NH:21])[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=S)N=C(N)N
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=N)N)sc2C1

Procedure:
Analogously to the preparation of Example C-01, 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester is reacted with 2-imino-4-thiobiuret to form the title compound. tR 2.55 min (LC-1); ESI-MS (+): m/z 298.25 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][C@H:9]([CH3:13])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][C@H:9]1[CH3:13])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3 g, 14.4 mmol) in dichloromethane (40 mL) was added triethylamine (2.0 mL, 14.4 mmol). The reaction was cooled to 0° C. and chloroacetyl chloride was added (1.1 mL, 14.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane and washed with 10% citric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (3.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:14][CH:13]=2.[OH-].[Na+:27]>O1CCCC1>[Na+:27].[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23])[CH:15]=[CH:14][CH:13]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21

Procedure:
(Z)-5-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid (100 mg, 3 mmol) (from Example 10 above) was dissolved in tetrahydrofuran (1 mL), and 1N sodium hydroxide (3 mL) was added. The resulting product, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid sodium salt, was purified via reverse-phase HPLC (acetonitrile-water over 15 minutes).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C:8]=2[NH:7][CH:6]=1)[CH3:4].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH2:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C:8]=2[N:7]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:6]=1)[CH3:4]
Reactant: CCc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a suspension of 60% sodium hydride (0.13 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.64 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.34 g) in dimethylformamide (1 ml), and the mixture was stirred at the same temperature for 24 hours and then at 40° C. for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropylether and hexane to give colorless crystals of 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3([CH2:20][CH2:19]3)[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[CH2:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:11]=2)[C:6]2([CH2:20][CH2:19]2)[CH2:7][NH:8]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C2(CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)CNCC21CC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7′-amino-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-carboxylate (0.350 g, 1.276 mmol) in CH2Cl2 (8 ml) was added trifluoroacetic acid (0.983 ml, 12.76 mmol). The reaction was stirred overnight and concentrated to provide the title compound as a trifluoroacetic acid salt.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:11])[C@@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:10][C:6]1([CH3:9])[O:5][C@H:4]([C:3]([Cl:11])=[N:2][O:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:8][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](C(Cl)=NO)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A solution of (S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (9.88 g, 55.01 mmol) in THF (200 mL) at 0° C. was added methanesulfonyl chloride (4.703 ml, 60.51 mmol), followed by N,N-diisopropylethylamine (10.54 ml, 60.51 mmol) and the reaction was stirred for 1 hour at ambient temperature, filtered and concentrated in vacuo. The residue was purified over silica gel (25 to 100% ethyl acetate in hexanes) to afford (S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (12.28 g, 47.65 mmol, 86.63% yield) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:7][C:6]=2[CH:28]=1.[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][C@@H:37]([CH3:41])[CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:14]([NH:16][CH2:17][C:18]([N:38]3[CH2:39][CH2:40][N:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36][C@@H:37]3[CH3:41])=[O:20])=[O:15])=[O:11])=[CH:7][C:6]=2[CH:28]=1
Reactant: C[C@H]1CN(c2ccccc2)CCN1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)c1cc2cc(Cl)ccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccccc2)CCN1C(=O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [[(2S)-2-[[(5-chloro-1-benzofuran-2-yl)carbonyl]amino]-3-(2-pyridyl)propanoyl]amino]acetic acid (150 mg), (S)-1-phenyl-3-methylpiperazine (79 mg), 1-hydroxy-benzotriazole (55 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (79 mg) in N,N-dimethylformamide (3 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (15 ml), and washed successively with saturated aqueous sodium hydrogencarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol 10:1) to give the title compound as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)=[C:7]2[CH3:27].C([Si]([O:43][C:44]([O:46][CH3:47])=[CH2:45])(C)C)(C)(C)C.C([O-])(=O)C.[Li+]>O1CCCC1>[CH3:47][O:46][C:44](=[O:43])[CH2:45][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)[C:9]([CH:12]([CH3:13])[CH3:14])=[N:10]2
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 96 h

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yl ester (0.075 g), tert-butyl-(1-methoxyvinyloxy)dimethylsilane (0.063 mL), lithium acetate (0.029 g) and tetrahydrofuran (2.0 mL) was purged with argon for 30 minutes, and then treated with tetrakis(triphenylphosphine)palladium (0) (0.017 g). The mixture was stirred at 70° C. for four days, cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (10:0 to 2:8 by volume) to give title compound as pale yellow oil (0.042 g).
Reaction SMILES: [O:1]1[CH2:3][C:2]21[CH2:8][CH2:7][CH2:6][N:5]1[CH:9]=[N:10][CH:11]=[C:4]21.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH2:3][C:2]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]2[CH:9]=[N:10][CH:11]=[C:4]12)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: c1ncn2c1C1(CCC2)CO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1(O)CCCn2cncc21
Temperature: 60 °C

Procedure:
A solution of 5 mmol of 6,7-dihydro-5H-spiro[imidazo[1,5-a]pyridine-8,2′-oxirane] in 15 ml of N,N-dimethylformamide is admixed with 10 mmol of sodium azide and the reaction mixture is heated at 60° C. for 4 hours. The mixture is poured into water and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)CO>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)c1cccnc1)n2Cc1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1cccnc1)n2Cc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
1-(4-fluorobenzyl)-5-methanesulfonyl-2-nicotinoylindole (0.14 g), hydrazine monohydrate (0.17 g), potassium hydroxide (0.05 g) and ethylene glycol (3 ml) were added under nitrogen atmosphere and the mixture was stirred at 110° C. for 8 hours. To the reaction solution was added water; and the mixture was extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to siilica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 13 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:23](=[O:25])=[O:24]>O1CCCC1>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: O=C=O
Reactant: Brc1ccc(OC2CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
To a −78° C. solution of 1-bromo-4-(cyclopropoxy)benzene (33 g, 154.9 mmol) in tetrahydrofuran (500 mL) add 1.6 M butyl lithium in hexane (96.8 mL, 154.9 mmol) while maintaining a temperature below −70° C. Stir the mixture at −78° C. for 20 minutes after the addition. Add dry ice (464.6 mmol) in 3 portions 5 minutes apart. Stir the mixture at −78° C. for 30 minutes. Remove the cooling bath and quench the mixture with 10% sodium hydrogen sulfate (NaHSO4) (200 mL). Warm the mixture to ambient temperature and extract 3× with EtOAc (300 mL). Combine the organics and wash once with brine, dry over sodium sulfate, filter, and concentrate under reduced pressure. Suspend the residue in diethyl ether and filter. Dry the solid in a vacuum oven to give the title compound (12.9 g, 47%): MS (m/z): 179 (M+1).