Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Br[CH2:3][CH2:4][N:5]=[C:6]([OH:25])[C:7]1[C:8](=[CH:12][C:13](=[C:17]([CH:24]=1)[C:18](=[N:20][CH2:21][CH2:22]Br)[OH:19])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10].C[N:27](C)C=O>>[NH2:1][CH2:3][CH2:4][N:5]=[C:6]([OH:25])[C:7]1[C:8](=[CH:12][C:13](=[C:17]([CH:24]=1)[C:18](=[N:20][CH2:21][CH2:22][NH2:27])[OH:19])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(C(=O)O)c(C(O)=NCCBr)cc1C(O)=NCCBr
Reactant: N
Product: NCCN=C(O)c1cc(C(O)=NCCN)c(C(=O)O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of liquid ammonia, 22 ml. (1.0 mole), in 200 ml. of dimethylformamide is added portionwise 4.3 g. (10 mmole) of N,N'-bis(2-bromoethyl) pyromellitic diimide. The mixture is stirred at room temperature for 48 hours. Excess ammonia is removed by concentration under reduced pressure without heating. The concentrate is diluted with several volumes of dilute aqueous sodium bicarbonate and cooled. The insolubles are collected, rinsed with water, cold methanol and ethyl ether furnishing N,N'-bis(2-aminoethyl)pyromellitic diimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH2:37][CH:38]([OH:42])[CH2:39][CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:42][CH:38]([CH2:39][CH2:40][CH3:41])[CH2:37][CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(O)CCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 64.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-heptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 60%).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH:23]1[CH2:28][CH2:27]CCO1.BrCCCO>>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:28][CH2:27][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: C1CCC(OC2CCCCO2)OC1
Agent: OCCCBr
Product: O=C(c1ccccc1)C(CCCOC1CCCCO1)c1ccccc1

Procedure:
The compound is prepared from 19.6 g of desoxybenzoin and 22.3 g of tetrahydropyran-2-yl ether-protected 3-bromopropanol according to the procedure described in Example 1(a).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>O>[N:41]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([O:21][C:22]4[C:23]([CH3:32])=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:33][CH3:34])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCn1ccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (52 mg), potassium carbonate (53 mg), and imidazole (26 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 81%).
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[O:26])([CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:36])=O.Cl.[CH3:38][NH:39][CH3:40].C([BH3-])#N.[Na+]>CO>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([NH:27][C:25](=[O:26])[NH:24][C:6]2([CH2:13][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH2:3][CH2:1][N:39]([CH3:40])[CH3:38])[C:5]2=[O:36])[CH:33]=[CH:32][CH:31]=1
Reactant: CNC
Reactant: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CCN(C)C)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.2 %

Procedure:
To a solution of 0.386 g of (RS)-1-(formylmethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one in 50 ml of methanol was added 0.8 g of dimethylamine hydrochloride at room temperature, and 1.0 g of sodium cyanoborohydride was then added thereto. The mixture was stirred at room temperature for 1 day, followed by concentration. The concentrate was diluted with dichloromethane and washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was washed with dichloromethane to afford 0.107 g (26%) of the title compound.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCCCCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCCCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 12-morpholinyldodecylphthalimide (320 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[C:14]2([CH2:17][CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[C:8]([CH3:20])[C:9]([OH:19])=[C:10]([CH3:18])[CH:11]=2)[CH:6]=1.Cl>C1COCC1.O1CCOCC1>[CH3:1][O:2][NH:3][CH2:4][C:5]1[C:14]2([CH2:15][CH2:16][CH2:17]2)[O:13][C:12]2[C:7](=[C:8]([CH3:20])[C:9]([OH:19])=[C:10]([CH3:18])[CH:11]=2)[CH:6]=1
Reactant: CON=CC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CONCC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde O-methyloxime (150 mg) in 10 mL of THF at 0° C. was added BH3/pyridine complex (2.27 mL). Subsequently, 9 mL of HCl in dioxane (4.0 M solution) was added over a period of 1 hour. The reaction mixture was allowed to stir overnight. The mixture was extracted with ethyl acetate, washed with saturated NaHCO3, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 30% ethyl acetate in hexane to give 142 mg of 3-[(methoxyamino)methyl]-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-6-ol as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=6.59 (s, 1H, =CH), 6.45 (s, 1H), 5.50 (b, 1H), 4.75 (b, 1H), 3.81 (s, 2H), 3.62 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.40-1.75 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=146.3, 146.0, 134.0, 123.9, 120.3, 119.4, 119.1, 114.6, 81.1, 62.0, 54.7, 33.1, 16.5, 14.3, 11.2 ppm. MS: (m/z)=229.1 (M−NH2OMe+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[O:18]=[C:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:28][C:29]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[O:30])[CH:25]=2)[NH:20]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([NH:28][C:24]4[CH:25]=[C:26]5[C:21](=[CH:22][CH:23]=4)[NH:20][C:19](=[O:18])[CH2:27]5)=[O:30])=[CH:38][CH:37]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3c(c2)CC(=O)N3)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(c4)CC(=O)N5)cc3)[nH]c2c1

Procedure:
Compound 666 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-((2-oxoindolin-5-yl)aminocarbonyl)benzaldehyde. [M+H]+ calcd for C25H22N4O4: 443.16; found: 443.05.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].N/[C:20](/[CH3:24])=[CH:21]\[C:22]#[N:23]>C(O)CCC>[C:22]([CH2:21][C:20](=[N:13][NH:12][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12)[CH3:24])#[N:23]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: C/C(N)=C/C#N
Solvent: CCCCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NN=C(C)CC#N
Reaction time: 24 h

Procedure:
249 g of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester (1 mol) and 82 g of 3-aminocrotononitrile (1 mol) are heated together in 1.5 liters of butyl alcohol with stirring for 24 hours. The solvent is removed in vacuo and the residual 4-[2-(2-cyano-1-methylethylidene)hydrazino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester is recrystallized from alcohol, yield 309 g (80%); m.p. 190°-191°.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28]CC)=[O:27].[I-].[Na+]>CN(C)C=O.O>[CH:20]([O:19][P:14]([O:15][CH:16]([CH3:18])[CH3:17])([CH:3]([P:4]([O:9][CH:10]([CH3:11])[CH3:12])([O:5][CH:6]([CH3:8])[CH3:7])=[O:13])[CH2:32][CH2:31][CH2:25][C:26]([OH:28])=[O:27])=[O:23])([CH3:22])[CH3:21]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CCOC(=O)C(Br)CC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OP(=O)(OC(C)C)C(CCCC(=O)O)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.17 h
Yield: 8.7 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (2.56 g) was suspended in dry N,N-dimethylformamide (20 ml), and tetraisopropyl methylenebisphosphonate (20.0 g) was added dropwise thereto at room temperature. After stirring for 10 minutes, ethyl bromobutyrate (8.4 ml) was added dropwise thereto and the resulting mixture was stirred at 100° C. for 1 hour. Then, sodium iodide (0.85 g) was added thereto and stirred for 4 hours. Water was added thereto, followed by extraction (twice) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (50 ml), followed by adding thereto a 2N aqueous sodium hydroxide solution (10 ml), and the resulting mixture was stirred with heating under reflux for 3 hours. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and then the residue was purified by a silica gel column chromatography to obtain 5,5-bis(diisopropoxyphosphinoyl)valeric acid (1.88 g, yield 8.7%). 1H-NMR (CDCl3) δ: ppm; 1.34 (12H, d, J=6.3 Hz), 1.34 (12H, d, J=5.9 Hz), 1.8-2.4 (7H, m), 4.7-4.9 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][NH:12][CH:13]=1.C(N(CC)CC)C.[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([S:23](=[O:25])(=[O:24])[N:22]([CH3:27])[CH3:21])[CH:13]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Clc1ccc(-c2c[nH]cn2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cnc(-c2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-1H-imidazole (12.14 g), triethylamine (13 ml) and dimethylsulphamoyl chloride (7.5 ml) in tetrahydrofuran (50 ml) was stirred for 18 hours at room temperature and then heated under reflux until almost no starting material remained. The organic phase was diluted with ethyl acetate (300 ml), washed with dilute hydrochloric acid, water and aqueous sodium bicarbonate, dried and the solvent evaporated to give an oily solid which was treated to flash column chromatography and the product recrystallised to give 4-(2,4-dichlorophenyl)-1-(dimethylsulphamoyl)imidazole, m.p. 169°-171°.
Reaction SMILES: [F:1][C:2]([F:12])([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([CH3:11])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)C(C)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70588.2 %

Procedure:
Ethyl 4,4-difluoro-3-oxo-pentanoate (12.4 g, 0.068 mmol) was dissolved in toluene (100 ml) and cooled to 0° C. Sodium borohydride (3.12 g, 0.083 g) was added portionwise, and the mixture was allowed to reach room temperature overnight with stirring. The mixture was then cooled to 0° C. and acidified with 1 m HCl. The phases were separated, the aqueous phase was extracted two times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of methanol, the resulting solution was evaporated to dryness under reduced pressure to yield 8.76 g of a residue (0.048 mol, 70%) that were used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(CCl)c2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (95 mg, 0.3 mmol) in anhydrous dichloromethane (3 mL) was added triethylamine (0.063 mL, 0.45 mmol) followed by 3-(chloromethyl)benzoyl chloride (0.051 mL, 0.36 mmol). The mixture was shaken overnight at room temperature, concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC, MS (APCI) m/e 472 (M+H)+.
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]=[CH:30][C:29]=4[F:37])[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].[CH:3]1([CH2:36][NH:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]([F:37])=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]3)[CH:33]=2)[CH2:2][CH2:41]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC5CC5)ccc4F)cc23)CC1
Yield: 62.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-butanamine (38 μL, 0.524 mmol) for methanamine to afford 16.2 mg of the title compound (62.7%).
Reaction SMILES: [F:1][C:2]([P:8]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=[O:13])[O:9][CH2:10][C:11]#[CH:12])([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:21]([N:29]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[F:7][C:2]([P:8]([C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])(=[O:9])[O-:13])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:38]([N+:29]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:12][C:11]#[CH:10])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: C#CCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Product: C#CC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 91 %

Procedure:
Propargyl bis(pentafluoroethyl)phosphinate (4.131 g; 12.1 mmol) is slowly added dropwise to cooled (0° C.) trioctylamine (4.333 g; 12.3 mmol) in a 100 ml glass flask. An orange, more highly viscous solution forms spontaneously, which is warmed to room temperature. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature to 120° C. Trioctylpropargylammonium bis(pentafluoroethyl)phosphinate, [(C8H17)3—NCH2C≡CH][(C2F5)2P(O)O], (7.646 g; 11.0 mmol) is isolated as pale-orange liquid in a yield of 91% and a purity of 97%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ncc(Br)cn2)CCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
5-Bromo-2-iodopyrimidine (12.5 g, 43.88 mmol) was suspended in dry toluene (250 mL), then cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 20 mL) was added dropwise, and the reaction mixture was aged for 20 minutes prior to dropwise addition of a solution of cyclobutanone (3.75 g, 53.5 mmol) in dry toluene (10 mL). The reaction mixture was stirred at −78° C. for 45 minutes, then allowed to warm to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were dried over MgSO4 and the solvent removed under reduced pressure. The resulting brown oil was purified by chromatography on silica (Biotage, 340 g cartridge), eluting with a gradient of 0-100% ethyl acetate in heptanes, to afford the title compound (4.76 g) as a bright yellow solid. δH (500 MHz, CD3OD) 8.80 (s, 2H), 2.57 (dddd, J 11.2, 5.2, 4.4, 2.5 Hz, 2H), 2.32-2.23 (m, 2H), 1.93-1.76 (m, 2H). Method C HPLC-MS: MH+ m/z 230, RT 1.06 minutes.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][C:9](=[O:14])[C:8]=2[CH:7]=[CH:6][C:5]=1OS(C(F)(F)F)(=O)=O)[CH2:2][CH3:3].[CH3:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[CH:40].C(N(CC)CC)C.CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:14])[CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1c(OS(=O)(=O)C(F)(F)F)ccc2c1OCCC2=O
Reactant: C#CCCCCOc1ccccc1CCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1c(C#CCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A mixture of 1.14 g (3.37 mmol) of 2,3-dihydro-8-propyl-7-[[(trifluoromethyl)sulfonyl]oxy]-4H-1-benzopyran-4-one, 0.94 g (3.62 mmol) of 2-[(5-hexynyl)oxy]benzenepropanoic acid methyl ester, 4.9 mL of dry triethylamine, 0.197 g (0.28 mmol) of dichlorobis(triphenylphosphine)palladium (II), and 21 mL of dry dimethylformamide was stirred and heated at 100° C. for 3 hr. The mixture was cooled, poured into ice-water, and worked-up with ether in the usual manner. The orange-red, oily residue was flash chromatographed on silica gel. Elution with 1:1 hexane-ether gave 1.25 g (83%) of 2-[6-(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)-5-hexynyloxy]benzenepropanoic acid methyl ester as a yellow oil.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:32])[CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[Cl-].[NH4+]>[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:32])[C@H:27]([CH2:28][CH:29]1[CH2:30][CH2:31]1)[CH2:3][CH:1]=[CH2:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(CCC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC[C@@H](CC1CC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of N,N-diisopropylamine (5.46 mL, 39 mmol) in anhydrous tetrahydrofuran (90 mL) was cooled to −10° C. before adding a solution of n-butyllithium (2.5 M in hexanes, 15 mL, 37.5 mmol) dropwise over 10 minutes maintaining the temperature below 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before cooling to −78° C. A solution of (S)-4-benzyl-3-(3-cyclopropyl-propionyl)-oxazolidin-2-one (8.88 g, 32.5 mmol) in tetrahydrofuran (35 mL) was added dropwise over 10 minutes keeping the temperature below −70° C. The reaction mixture was stirred at −78° C. for 1 h then warmed to −15° C. for 2 h. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×60 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow gum. The gum was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title compound (5.3 g, 52%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.01-0.15 (m, 2H), 0.35-0.50 (m, 2H), 0.65-0.82 (m, 1H), 1.50-1.60 (m, 2H), 2.32-2.45 (m, 1H), 2.47-2.60 (m, 1H), 2.66-2.77 (m, 1H), 3.27-3.37 (m, 1H), 4.05-4.25 (m, 3H), 4.65-4.76 (m, 1H), 5.03-5.16 (m, 2H), 5.78-5.93 (m, 1H), 7.20-7.36 (m, 5H). LCMS (m/z) 314.1 [M+H], Tr=2.83 min.