Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:17])=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2C[C@@H]2CN2CCC[C@@H]2C)=[CH:21][CH:20]=1.[NH3:35]>>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:35])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: N
Product: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 1E substituting 1-[2-(4-bromo-phenyl)-(1S,2S)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine (the product from Example 2A) for 1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine (the product from 1D). 1H NMR (300 MHz, CD3OD): 0.92 (m, 1H), 0.99 (m, 1H), 1.13 (d, J=6 Hz, 2H), 1.24 (m, 1H), 1.43 (m, 1H), 1.77 (m, 3H), 1.98 (m, 2H), 2.13 (dd, J=12 Hz, J=6 Hz, 1H), 2.30 (q, J=9 Hz, 1H), 2.41 (m, 1H), 2.94 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H) MS (DCl—NH3) m/z 294 (M+H)+.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([C:8]1[C:9]([C:14](O)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)C>N>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=1[C:14]([NH:2][C:3]([NH2:5])=[O:4])=[O:15]
Reactant: NC(N)=O
Reactant: CCc1cccnc1C(=O)O
Agent: N
Agent: [Na]
Product: NC(=O)NC(=O)c1ccccn1

Procedure:
A mixture of sodium (0.23 g, 10 mmol), urea (0.8 g, 13.3 mmol) and liquid ammonia (40 ml) was stirred until the blue colour was discharged, then ethyl 2-pyridinecarboxylic acid (2.85 g, 18.8 mmol) was added all at once. After 1 h the ammonia was evaporated and the residue triturated with water to give the above compound, mp 183°-185° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C1(C)C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1>C(OCC)(=O)C>[F:33][CH2:32][CH2:31][O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCCF)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Sodium hydride (55% oiliness, 140 mg, 3.2 mmols) was added to DMF (5 mL) solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (501.2 mg, 2.7 mmols) and stirred at room temperature for 30 minutes, followed by addition of 2-fluoroethyl p-toluenesulfonate (1.17 g, 5.4 mmols) and further 24 hours' stirring at the same temperature. Ethyl acetate was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil Sil FLASH 25+M, ethyl acetate:hexane=1:10→2:8) to provide the title compound (253 mg, 41%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:34]1[C:38]([C:39]2([C:43](=[O:45])[CH3:44])[CH2:42][CH2:41][CH2:40]2)=[CH:37][C:36]2[CH:46]=[CH:47][CH:48]=[CH:49][C:35]1=2>O1CCCC1>[S:34]1[C:38]([C:39]2([C:43](=[O:45])[CH2:44][Br:1])[CH2:40][CH2:41][CH2:42]2)=[CH:37][C:36]2[CH:46]=[CH:47][CH:48]=[CH:49][C:35]1=2
Reactant: CC(=O)C1(c2cc3ccccc3s2)CCC1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)C1(c2cc3ccccc3s2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
Phenyltrimethylammonium tribromide (1.72 g) was added in portions at −20° C. to a stirred solution of 1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]ethanone (1.05 g) in tetrahydrofuran (50 ml). The mixture was stirred at ambient temperature for 3 hours, then it was filtered, and allowed to stand at ambient temperature for a further 18 hours. The mixture was filtered once more, and the solvent was removed in vacuo. The residue was purified via flash chromatography over silica using a 1:49 mixture of ether and petroleum ether (b.p. 40-60° C.) as eluant. Appropriate fractions were combined, and the solvents removed in vacuo to give 1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-2-bromoethanone as an oil (0.46 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[O:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=3)[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:18].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]5[O:30][C:31]([C:34]([F:37])([F:35])[F:36])=[N:32][N:33]=5)[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cl
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5ccccc5)c4)c3c2)o1

Procedure:
The title compound was prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δ[2H6]DMSO 11.96(1H, bs), 9.58(1H, s), 8.91(1H, s), 8.69(1H, dd), 8.22(1H, s), 8.14(1H, d), 8.10(1H, d), 8.85(1H, d), 8.67(1H, dd), 7.30(5H, m), 5.71(2H, s); m/z (M+1+) 488.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4F)c3O2)cc1
Yield: 81.2 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.422 g (81%) of (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 99-101° C.; Anal. calcd. for C22H19FO4S: C, 66.32; H, 4.81. Found: C, 65.16; H, 4.86.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:21])=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1O
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl

Procedure:
A mixture of 49.1 g of 1-ethyl-6-methyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.197 mole) and 250 ml of phosphorus oxychloride is refluxed for 4 hours. Then the excess phosphorus oxychloride is removed by vacuum distillation and the residue is treated with water. The 4-chloro compound (42 g) is filtered under suction and recrystallized from n-hexane, mp 54°-56° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH3:13].[CH2:19]=O>ClCCCl>[CH2:12]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:19])[CH3:13]
Reactant: CCOCCCN
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C=O
Solvent: ClCCCl
Product: CCOCCCN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,2-dichloroethane (50 ml) were dissolved p-nitro-benzaldehyde (5 g) and 3-ethoxypropylamine (3.75 g), and to the mixture was added, under ice-cooling, triacetoxy sodium boro hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and to the mixture were added, under ice-cooling, 37% formalin (3.5 ml) and triacetoxy sodium boro hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 8 hours, and the solvent was evaporated. The residue was neutralized with 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and subjected to back extraction with 1N hydrochloric acid. The mixture was washed with ethyl acetate, neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N-(3-ethoxypropyl)-N-methyl-4-nitrobenzylamine (6.6 g) as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][N:15]=1)=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][N:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[N:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1cnc(NC(=O)CCl)nc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cnc(NC(=O)Cn2cc([N+](=O)[O-])cn2)nc1OC
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (A) (317 mg, 2.8 mmol), 2-chloro-N-(4,5-dimethoxypyrimidin-2-yl)acetamide (2.26 mmol), Cs2CO3 (1.0 g, 3.09 mmol) and MeCN (9.0 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 1 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtercake was redisolved in DCM and water, the org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated to yield N-(4,5-dimethoxypyrimidin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a crude which was used in the next step without further purification. LC-MS conditions B: tR=0.46 min, [M+H]+=309.10.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[NH2:10][C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O.C(Cl)(Cl)Cl>[N:10]([C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:1]=[S:2]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N=C=S)sc(C)c1C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a mixture of thiophosgene (5.10 mL, 7.64 mmol) and calcium carbonate (1.05 g, 10.54 mmol) in CHCl3/H2O (½ by volume, 6 mL) was added dropwise a solution of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (1.05 g, 5.27 mmol) in CHCl3 (7 mL) at 0° C. over a period of 1 h. The reaction mixture was the stirred for 2.5 h at 0° C., washed with water (3×). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (1.21 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H, J=7.1 Hz), 2.19 (s, 3H), 2.30 (s, 3H), 4.28 (q, 2H, J=7.1 Hz).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:19])[C:10]=3[CH:20]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([OH:18])[CH:15]([CH3:16])[CH3:17])=[C:11]([CH3:19])[C:10]=3[CH:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OCC3CC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
1-[5-(Cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (19.91 g) synthesized above was dissolved in mixed solvent of methanol (40 mL)-tetrahydrofuran (200 mL), and sodium tetrahydroborate (90%, 5.53 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (22.74 g, 100%) as a colorless oil.
Reaction SMILES: [N:1]1[N:11]2[C:12]3[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=3[C:2]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O.[NH2:20][CH:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:18].[N:23]12[CH2:28][CH2:27][CH:26]([CH2:25][CH2:24]1)[CH:21]([NH:20][C:13]([C:2]1[C:3]3=[C:12]4[C:7](=[CH:6][CH:5]=[CH:4]3)[CH2:8][CH2:9][CH2:10][N:11]4[N:1]=1)=[O:15])[CH2:22]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1nn2c3c(cccc13)CCC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NC1CN2CCC1CC2)c1nn2c3c(cccc13)CCC2
Reaction time: 1 h

Procedure:
0.3 g (1.5 mmol) of 7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-carboxylic acid were dissolved in 10 ml of methylene chloride. 1 ml of thionyl chloride was added and the mixture was boiled for 1 hour. The mixture was then evaporated in vacuum. 10 ml of methylene chloride, 1.0 g (7.9 mmol) of 3-aminoquinuclidine and 1.0 g (10 mmol) of triethylamine were added after which the mixture was stirred for 30 minutes. The mixture was then extracted with water. The methylene chloride layer was separated, washed with water, dried and evaporated in vacuum. The residue was chromatographed over silicagel using methylene chloride/methanol/ammonia in the ratio 84:15:1 as an eluent; Yield; 0.15 g (33%); melting-point 146°-147.5° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[NH:25][C:26](=[O:29])[NH:27][NH2:28]>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[NH:25][C:26](=[O:29])[NH:27][N:28]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1ccc(OC)c(NC(=O)NN)c1
Agent: Cl
Product: COc1ccc(OC)c(NC(=O)NN=c2c(=O)c3ccccc3c2=O)c1

Procedure:
ninhydrin, 4-(2,5-dimethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:17](=[O:29])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C)C=O>[N:30]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:17](=[O:29])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
2-[(4-{5-Oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]ethyl methanesulfonate (1.2 g, 2.9 mmol) was dissolved in N,N-dimethylformamide (2.7 mL). After sodium azide (280 mg, 4.3 mmol) was added in one portion, the temperature was brought to 65° C. and the reaction stirred for 6 hours. After cooling back to room temperature, water (10 mL) was added to quench the reaction. The product was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo to give the desired product (1.05 g, 96%). LCMS calculated for C13H10F3N6O3 (M−N2+H)+: m/z=355.0. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.93 (m, 2H), 7.79 (t, J=8.2 Hz, 1H), 6.75 (t, J=5.8 Hz, 1H), 3.52 (t, J=5.7 Hz, 2H), 3.44 (q, J=5.5 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of N-methylpiperazine (3.0 g, 29.9 mmol), triethylamine (3.6 g, 35.9 mmol) and methanesulfonyl chloride (Compound 19, 4.11 g, 35.9 mmol) in tetrahydrofuran (20 ml) was stirred at 0° C. for 2 hours. The mixture was filtered and the filtrate was evaporated to dryness to give a solid. The solid was redissolved in ethyl acetate and washed with water. Evaporation of the dried (magnesium sulfate) organic phase gave the title sulfonamide. 1HNMR(CDCl3): 2.35 (s, 3H), 2.53 (t, 4H, J=5.0 Hz), 2.79 (s, 3H) and 3.27 (t, 4H, J=5.0 Hz).
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=O)=[CH:16][CH:15]=2)[N:9]=1)CCCCCC.[CH2:23](Cl)[CH2:24]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:16]([C:13]1[CH:12]=[N:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:20])=[CH:21][CH:22]=2)=[N:9][CH:8]=1)[CH2:15][CH2:14][CH2:22][CH2:21][CH2:23][CH3:24]
Reactant: ClCCCl
Reactant: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.9 g. of 4-(4-n-heptylpyrimid-2-yl)benzoic acid amide are left for 80 minutes under reflux in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 1.9 g. of 5-n-heptyl-2-(4-cyanophenyl)-pyrimidine result, which are distilled in a high vacuum, having a m.p. of 44.2°-44.7°; cl.p. 50.1°-50.4°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CCO>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Solvent: CCO
Product: N#Cc1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and Raney Nickel (500 mg) in EtOH (50 mL) was stirred at room temperature under H2(1 atm) for 1 h. Raney Nickel was removed via filtration and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica get to give 6-amino-1H-indole-2-carbonitrile (1.0 g, 49%). NMR (DMSO-d6) δ 12.75(br s, 1 H), 7.82(d, J=8 Hz, 1 H), 7.57(s, 1H), 7.42(s, 1 H), 7.15(d, J=8 Hz, 1 H); MS (ESI) m/e (M+H+) 158.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.22 g of dl-trans-2-benzyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 6) in 10 ml of dimethylformamide was added dropwise, with ice-cooling, to 10 ml of dimethylformamide containing suspended in it 0.480 g of a 55% w/w suspension of sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for 60 minutes, after which 5.49 g of hexadecyl bromide were added, and the resulting mixture was stirred for a further 4 hours. Finally, the mixture was stirred at 60° C. for 60 minutes and then cooled. It was then poured into 100 ml of water, and extracted twice with ethyl acetate. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue was subjected to column chromatography resulting through 100 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:10 by volume gave 3.82 g of the title compound as a solid having a low melting point, melting at 28.5°-29.5° C. (cold methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]#N)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][NH:15]2.[OH-:24].[Na+].Cl.[OH2:27]>CCO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:27])=[O:24])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][NH:15]2
Reactant: O
Reactant: COc1nc(C#N)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1nc(C(=O)O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Reaction time: 0.83 h

Procedure:
To 6-methoxy-5-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinonitrile (0.5 g, 1.571 mmol) in EtOH (20 mL) was added sodium hydroxide (3.93 mL, 7.86 mmol). The reaction mixture was stirred for 50 minutes at reflux and was subsequently diluted with water and acidified with concentrated HCl. The volatiles were evaporated and the residue was purified by preparative HPLC, eluting with 45% acetonitrile (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 4 minutes. The product-containing fractions were combined and the volatiles removed by rotary evaporation to give the title compound.
Reaction SMILES: O[C:2]([CH3:16])(C)[C:3]([C:5]1C=CC(S(C)(=O)=O)=CC=1)=[O:4].CC(C)[C:19]([C:21]1C=CC(SC)=CC=1)=[O:20].[OH2:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:5][CH:3]([O:4][CH2:21][C:19]([OH:30])=[O:20])[CH:2]=[CH2:16]
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CSc1ccc(C(=O)C(C)C)cc1
Reactant: O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C)OCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of the alcohol of Step 3 (2.87 g, 11.8 mmol) and the acid from step 1 (2.0 g, 15.4 mmol) in CH2Cl2 (30 mL) was added CMC (7.5 g, 17.7 mmol), along with 50 mg of DMAP. After stirring overnight, H2O (20 mL) was ad ded and the product was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and evaporated. Purification was effected by flash chromatography (1:5 EtOAc:hexane) to yield 2.97 g of an oil.