Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31](O)=[O:32]>>[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:32]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(O)c1nc2ccccc2[nH]1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3nc4ccccc4[nH]3)CC1)O2

Procedure:
Compound 74 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1H-benzimidazole-2-carboxylic acid and conditions outlined in procedure O. M.p.=266-268° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.17 (s, 1H), 7.92 (m, 2H), 7.76 (m, 2H), 7.56 (m, 2H), 7.24-7.35 (m, 2H), 5.46 (d, 1H), 4.48 (d, 1H), 3.82 (t, 0H), 3.33 (m, 1H), 3.18 (d, 2H), 2.17 (m, 2H), 1.85-2.04 (m, 2H); LCMS=446 [M+H].
Reaction SMILES: C(OC([CH2:8][NH:9][CH:10]([CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:11]([OH:13])=O)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:42][C:43]([Cl:59])([Cl:58])[CH2:44][O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][C@H:52]([NH2:56])[C:53](=[O:55])[NH2:54]>C(Cl)Cl>[Cl:42][C:43]([Cl:58])([Cl:59])[CH2:44][O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][C@@H:52]([C:53](=[O:55])[NH2:54])[NH:56][C:11](=[O:13])[C@H:10]([NH:9][CH3:8])[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CNC(Cc1cccs1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN[C@H](Cc1cccs1)C(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(N)=O
Reaction time: 8 h
Yield: 64.4 %

Procedure:
2-(tert-Butoxycarbonylmethylamino)-3-(2-thienyl)propionic acid (10.07 g; 35 mmole), HOBt (5.72 g; 42 mmole) and EDAC (7.09 g; 37 mmole) were added to methylene chloride (200 ml) and stirred for 15 min. ((5S)-5-amino-5-carbamoylpentyl)carbamic acid 2,2,2-trichloroethyl ester hydrochloride (12.61 g; 35 mmole) was added and the mixture was stirred overnight. Methylene chloride (200 ml) was added and the organic phase was washed with water (200 ml), an aqueous solution of sodium hydrogensulphate (200 ml), an aqueous solution of sodium hydrogencarbonate (200 ml) and water (200 ml). The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was dissolved in a solution of hydrogen chloride in ethyl acetate (3 M; 100 ml) and stirred for 30 min. Diethyl ether and water (500 ml) was added, the phases were separated and the acidic aqueous phase was treated with a solution of sodium carbonate to pH 10. The aqueous phase was extracted with methylene chloride (4×700 ml) and the phases were separated. The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo to afford 11.0 g of [(5S)-5-carbamoyl-5-((2R)-2-methylamino-3-(2-thienyl)-propionylamino)-pentyl]-carbamic acid 2,2,2-trichloroethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:29][CH:28]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:23][N:37]=[C:26]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([NH2:34])(=[O:35])=[O:36])=[CH:31][CH:32]=4)[N:25]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (146 mg, 58%). MS (ISP) 500.3 [(M+H)+]; mp 290° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]=O>O1CCCC1>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of trimethyl phosphonoacetate (3.0 ml, 18.6 mmol) in tetrahydrofuran (40 ml) under argon atmosphere at 0° C., 60% sodium hydride in oil (0.73 g, 18.3 mmol) was added at once and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, a solution of quinolin-2-carbaldehyde (1) (1.0 g, 6.2 mmol) in tetrahydrofuran (40 ml) was added. After stirring for 1 hour at room temperature, the reaction mixture was partitioned between ethyl acetate (150 ml) and 2N HCl (150 ml). The organic layer was separated, washed with water (100 ml), brine (50 ml), and dried (Na2SO4). The solvent was removed in vacuum and the residue was chromatographed on silica gel with chloroform-ethyl acetate (9:1) as eluent to give the title compound (1.07 g, 81%) as oil. 1H NMR (DMSO-d6, HMDSO), δ: 3.78 (3H, s); 7.11 (1H, d, J=16.0 Hz); 7.48-8.16 (5H, m); 7.81 (1H, d, J=16.0 Hz); 8.43 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCO
Product: CCCCCCCCCOC(=O)Cl

Procedure:
396 Parts of nonyl alcohol are reacted with phosgene to give 558 parts of nonyl chloroformate as a colourless liquid b.p. 70°-72° C/1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>CCCCCC.CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:28]([C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[Cl:20])(=[O:30])=[O:29])=[CH:11][C:10]=2[C:16]([F:17])([F:19])[F:18])[CH:7]=1
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1)c1ccc(Cl)cc1Cl
Yield: 21.5 %

Procedure:
Using the method of Example 17.4, 2-(3-chloro-5-pyridyloxy)-5-aminobenzotrifluoride (0.394 g) and 2,4-dichlorobenzenesulfonyl chloride (0.34 g) were combined to provide, after flash chromatography and trituration with hexane/ether the title compound as a crystalline solid (0.146 g). mp 129-130° C.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:9]1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].CCCCCC.O1CCCC1.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:50]([O:49][C:47](=[O:48])[CH2:46][C@@:10]1([C:14]([OH:16])=[O:15])[C@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)([CH3:53])([CH3:52])[CH3:51]
Reactant: COc1ccc(COC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]2C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Tetrahydrofuran (200 ml) was added to (4-methoxyphenyl)methyl (3S*,4S*)-1-benzyl-4-methylpyrrolidine-3-carboxylate obtained in Reference Example 2b (29.50 g, 87 mmol), followed by azeotropic dehydration. Tetrahydrofuran (200 ml) was further added, followed by azeotropic dehydration. Tetrahydrofuran (400 ml) was added to this product, which was cooled in a dry ice-ethanol bath, and a lithium diisopropylamide/n-hexane-tetrahydrofuran solution (129 ml, 1.11M, 144 mmol) was added over 27 minutes. After 30 minutes, a solution of tert-butyl bromoacetate (21.20 g, 144 mmol) in tetrahydrofuran (30 ml) was added over seven minutes. After 39 minutes, a 20% aqueous ammonium chloride solution (440 ml) was added, and ethyl acetate (440 ml) was further added to perform extraction. The resulting organic layer was washed with water twice (60 ml, 60 ml) and concentrated under reduced pressure at 30° C. Methanol (150 ml) and palladium hydroxide (885 mg) were added to the resulting concentrate, followed by stirring under hydrogen pressure (0.35 MPa) for seven hours and 20 minutes. Water (200 ml) and tetrahydrofuran (100 ml) were added to the reaction liquid, followed by filtration, and the catalyst was sequentially washed with methanol (50 ml) and water (50 ml×2). The filter washings were concentrated under reduced pressure at 50° C., the resulting aqueous layer was washed with tert-butyl methyl ether (100 ml), and the aqueous layer after washing was concentrated under reduced pressure at 50° C. Methanol (150 ml) was added to the resulting residue, and the mixture was ultrasonically treated and then filtered. The resulting solid was dried under reduced pressure at 50° C. to give the title compound (8.16 g, yield: 38.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([C:33]2[C:38]([NH2:39])=[CH:37][C:36]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:35][N:34]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:39][C:38]1[C:33]([C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:34][CH:35]=[C:36]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[CH:37]=1)=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: COc1ccc(-c2ncc(N3CCOCC3)cc2N)cn1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccc3S(C)(=O)=O)nc3cc(F)cc(F)c23)cn1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.140 mmol) and 6′-methoxy-5-morpholino-2,3′-bipyridin-3-amine in toluene to give 5,7-difluoro-N-(6′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(2-(methylsulfonyl)-phenyl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.64 (1H, d, J=1.8 Hz), 8.20 (1H, d, J=7.2 Hz), 8.00 (1H, dd, J=8.5, 2.4 Hz), 7.94 (1H, br. s.), 7.80 (1H, td, J=7.5, 1.4 Hz), 7.70 (1H, td, J=7.7, 1.4 Hz), 7.47 (1H, ddd, J=9.4, 2.4, 1.3 Hz), 7.42 (1H, d, J=7.2 Hz), 6.92-7.04 (2H, m), 6.88 (1H, dd, J=8.6, 0.8 Hz), 6.53 (1H, br. s.), 4.00 (3H, s), 3.78 (4H, t, J=4.7 Hz), 3.02-3.27 (7H, m), 1.97 (3H, s). Mass Spectrum (ESI) m/e=618.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([O:16][CH:17]([O:21][CH2:22]C)[CH2:18][C:19]#[N:20])C.C[O-].[Na+]>CO>[CH3:14][O:16][CH:17]([O:21][CH3:22])/[C:18](=[CH:4]/[C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:2]=1[CH3:1])/[C:19]#[N:20]
Reactant: CCOC(CC#N)OCC
Reactant: Cc1c(C=O)cccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)/C(C#N)=C/c1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (3.0 g, 16 mmol) and 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) in methanol (10 mL) was added a 25% sodium methoxide in methanol over 20 minutes. The mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). Two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and solvent was evaporated in vacuo. The residue was then purified to give product. (3.66 g, 64%); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 2.94 (m, J=11.37 Hz, 1H) 3.08 (m, J=4.80 Hz, 1H) 3.20 (s, 1H) 3.43 (d, J=10.36 Hz, 1H) 3.42 (d, J=11.12 Hz, 6H) 3.45-3.52 (m, 1H) 4.60 (d, J=4.80 Hz, 1H) 7.39 (t, J=7.71 Hz, 1H) 7.59 (dd, J=17.18, 7.83 Hz, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:25][CH3:26])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 84.2 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.338 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.46 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)palmitamide (0.336 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), δ 3.41 (s, 4H), δ 2.17 (t, J=7.5 Hz, 2H), δ 1.60 (m, 2H), δ 1.23 (m, 2H), δ 0.85 (t, 6.3 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.9, 51.1, 39.1, 36.9, 32.1, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.3 ppm; HRMS (ESI) calcd for C18H36N4O (M+) 324.2889. found 324.2879.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C([N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C)C.N1CCCC1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:28][CH2:30][CH2:33][CH2:31]3)=[CH:19][CH:18]=2)=[N:11][CH:12]=1
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.24 mL (3.04 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 800 mg (2.53 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol in 17 mL DCM and then a solution of 0.52 mL ethyldiisopropylamine in 3 mL DCM is added dropwise. The mixture is stirred for a further 30 min at 0° C., 0.51 mL (6.08 mmol) pyrrolidine is added, the reaction mixture is heated to RT and kept at this temperature for 5 h. To complete the reaction another 0.26 mL (3 mmol) pyrrolidine are added and stirred for 1 h at RT. The mixture is evaporated down i.vac., combined with 10 mL water and 20 ml EtOAc, acidified with 1 M HCl and the organic phase is separated off. The aqueous phase is made alkaline with 2 M Na2CO3 solution, extracted with 20 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[SH:34]>ClCCl>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[S:34][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1
Reactant: Cn1ccnc1S
Reactant: OCC1(CO)CCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1ccnc1SCC1(CO)CCC1
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 1.0 g (8.6 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 20 mL of dichloromethane was added 2.48 g (9.48 mmol) of triphenylphosphine and 2.18 g (9.48 mmol) of di-tertbutylazodicarboxylate. After 5 min of stirring, 1.03 g (9.05 mmol) of 1-methyl-2-mercaptoimidazole was added as a solid. After stirring for 2 h, the reaction was concentrated under vacuum and the residue was purified using silica gel chromatography eluting with ethyl acetate:hexane (3:7) to afford 1.3 g (71%) of (1-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}cyclobutyl)methanol as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.95 (s, 1H), 6.87 (s, 1H), 6.54 (br s, 1H), 3.62 (s, 2H), 3.56 (s, 3H), 3.43 (s, 2H), 1.98-1.75 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[N:15]1([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CCN(CC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of the product of Example 3 (2.4 g) in dioxane (30 mL) was added 4 N HCl in dioxane (30 mL). The resulting mixture was stirred at room temperature overnight, concentrated, and treated with 10% NaOH (50 mL). The resulting mixture was extracted with DCM (2×100 mL). The combined extracts were washed with water (30 mL) and brine (30 mL), and concentrated under reduced pressure to give the title compound as a brown-yellow oil (0.81 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15](=O)[O:16]C(C)(C)C)([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:16])[NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-4-methyl-phenol (6.15 gm; 50 mmol) in dioxane (100 mL) was added carbonic acid di-tert-butyl ester (9.8 gm; 45 mmol) followed by sodium bicarbonate (12.6 gm; 150 mmol in 75 mL of H2O). After stirring for 8 hours, the reaction was diluted with 100 mL of ethyl acetate and washed with 1N aqueous hydrochloric acid (2×100 mL), saturated aqueous sodium bicarbonate (1×100 mL), and brine (100 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to provide the desired (2-Hydroxy-5-methyl-phenyl)-carbamic acid tert-butyl ester as a brown solid (95% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].[C:21]1([CH:27]([N:34]=[C:35]=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:27]([NH:34][C:35]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]1=[O:20])=[O:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Solvent: ClCCl
Product: O=C(NC1CCN(C(c2ccccc2)c2ccccc2)C1=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol) in dry CH2Cl2 (15 ml) was added diphenylmethyl isocyanate (0.17 mg, 0.82 mmol) dropwise under nitrogen. The resulting mixture was stirred at room temperature for two days followed by refluxing for 5 hours. Removal of solvent under reduced pressure followed by column chromatography using hexane: ethyl acetate (2:1) gave the desired product in 65% yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([NH2:18])=O)=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]>CN(C)C=O>[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]#[N:18])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]
Reactant: Cc1cc2oc(C(N)=O)cc(=O)c2c(C)c1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2oc(C#N)cc(=O)c2c(C)c1Cl
Temperature: 0 °C

Procedure:
To 400 parts of N,N-dimethylformamide was slowly added 21 parts of phosphorus oxychloride with stirring and ice cooling. Then in small quantities 33.9 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxamide was added to the solution. After the addition was completed the reaction mixture was stirred at room temperature for 18 hours. The dark solution which resulted was poured into 1500 parts of ice/water. The precipitated solid was filtered off and crystallised from ethanol to give 30.5 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carbonitrile, melting point 142°-143° C.
Reaction SMILES: [CH2:1]([N:3]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])C.[CH3:16]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:3]([C:11]([CH2:15][CH3:16])([CH3:14])[CH:12]=[O:13])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)CO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)(C=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl ethyl(1-hydroxy-2-methylpropan-2-yl)carbamate (2.18 g, 10 mmol, 1.0 equiv) in DCM (150 mL) was added Dess-martin periodinane (4.24 g, 10 mmol, 1.0 equiv) portionwise at 0° C. The resulting mixture was stirred for 4 h at room temperature. Saturated solutions of aqueous sodium hydrogencarbonate and sodium thiosulfate were added. The resulting mixture was stirred for 0.5 h. The organic phase was separated, washed with saturated sodium hydrogencarbonate, brine, dried over sodium sulfate and concentrated to give 1.5 g (71%) of tert-butyl methyl(2-ethyl-1-oxopropan-2-yl)carbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)=[CH:25][CH:26]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
A mixture of ethyl 3-[3-(4-fluorophenyl)-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (950 mg), 2-chloromethylquinoline hydrochloride (600 mg), potassium carbonate (700 mg) and N,N-dimethylformamide (15 ml) was stirred at 60° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-(4-fluorophenyl)-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1210 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH2:1]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[BH4-].[Na+].[Cl-].[NH4+].Cl.N>CO>[C:4]1([CH:2]([OH:3])[CH2:1][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cn1cncn1)c1ccccc1
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Product: OC(Cn1cncn1)c1ccccc1

Procedure:
30 parts by weight of 1-phenacyl-1,2,4-triazole is dissolved in 300 parts by weight of methanol; at 5° to 10° C., 5 parts by weight of sodium borohydride is added in portions. After the mixture has been brought to room temperature, about 20 parts by weight of ammonium chloride is added, and the mixture is acidified with dilute hydrochloric acid, heated to boiling, made alkaline with ammonia, and evaporated. The solid residue is slurried with water. Filtration gives 27.5 parts by weight of 1-[2-phenyl-2-hydroxyethyl]-1,2,4-triazole.