Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH2:11][CH2:10]1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:23][NH2:24])=[O:19])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CCN1CCN(c2ccccc2OC)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Yield: 86.1 %

Procedure:
A solution of ethyl 3-[4-(2-methoxyphenyl)piperazino]propanoate D1 (8.30 g, 28.38 mmol) and hydrazine monohydrate (8.52 g, 8.3 mL, 170.03 mmol) in ethanol (80 mL) was refluxed for 18 hrs. The solvent was evaporated under reduced pressure, the resulting solid was slurred in 50% acetone in hexane, filtered and dried to afford 6.80 g (87%) 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing 4-methylbenzoyl chloride (55 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 10.7 mg of the product: MS m/z 453 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21].[I-].[Na+]>CN(C=O)C>[Cl:14][C:10]1[N:9]=[C:8]2[N:7]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=3)[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]2=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.045 g, 0.19 mmol) in DMF (1.5 ml) under an inert atmosphere of Argon is added sodium hydride (0.008 g of a 60% dispersion in mineral oil, 0.21 mmol). After stirring at 0° C. for 30 minutes, the reaction mixture is stirred at room temperature for two hours and then re-cooled to 0° C. 4-Methylsulphonylbenzyl bromide (0.076 g, 0.3 mmol) in DMF (1.5 ml) is added followed by sodium iodide (0.076 g, 0.30 mmol) and the resulting solution is stirred at room temperature overnight. The reaction mixture is poured onto water (20 ml) and extracted with 1:1 ethyl acetate/diethyl ether. The organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the titled product. (MH+ 407)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.CC1C2[O:20]C=CC=2C=CC=1>>[CH3:11][C:10]1[C:4]2[O:3][C:2]([CH:1]=[O:20])=[CH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc2cccc(C)c2o1
Reactant: Cc1cccc2ccoc12
Product: Cc1cccc2cc(C=O)oc12

Procedure:
2,7-Dimethyl-benzofuran. 7-Methyl-benzofuran (cf. compound (2) g.) is subjected to a WILSMEYER reaction to form 7-methyl-benzofuran-2-aldehyde which is converted into 2,7-dimethyl-benzofuran by a WOLFF-KISHNER reaction by the method described in Bull.Soc.Chim.France 29, 1875 (1952). The product thus obtained has the following peaks in its MS: 146 (100%), 145 (92%) and 131 (32%).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[NH:13][N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1.[H-].[Na+].[CH2:26](Br)[CH3:27].Cl>CN(C=O)C.O>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[N:13]([CH2:26][CH3:27])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1
Reactant: CCBr
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)[nH]ncc3c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(CC)ncc3c12
Temperature: 5 °C
Yield: 46 %

Procedure:
To a solution of ethyl 6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 6 of example 4) (261 mg, 0.803 mmol) in n,n-dimethyl formamide, sodium hydride (33 mg, 0.803 mmol) was added at 20-30° C. under nitrogen. Ethyl bromide (95.4 mg, 0.88 mmol) was added to the reaction mixture. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10° C. Water (100 ml) was added dropwise to the reaction mixture at 0-10° C. and acidified with dilute hydrochloric acid. The precipitate obtained was filtered and dried in oven. It was purified by silica gel column chromatography using 10% ethyl acetate in chloroform. White colored solid (130 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21]O)=[CH:9][N:8]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][Cl:37])=[CH:9][N:8]=1
Reactant: COc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The above 1-(3-methoxybenzyl)-4-hydroxymethyl-6,7-dimethoxyisoquinoline (339 mg, 1.0 mmol) was dissolved in 5 ml of methylene chloride. Then at −30° C., triethylamine (160 ul, 1.10 eq) and methanesulfonyl chloride (85 ul, 1.10 eq) was added. The mixture was stirred at −30° C. for 30 minutes and then at room temperature overnight. The mixture was extracted with methylene chloride and water. After evaporation of solvents, a solid was obtained to give 1-(3-methoxybenzyl)-4-chloromethyl-6,7-dimethoxyisoquinoline (361 mg, 100%). ES-MS calculated for C20H20O3NCl (m/e) 357.39, observed 358.5 (M+1).
Reaction SMILES: [CH2:1]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:18]([O-])(=O)C(C(CC([O-])=O)C([O-])=O)O>>[C:8]([O:10][CH3:18])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)CCCCCCCCCCCCCO
Reactant: O=C([O-])CC(C(=O)[O-])C(O)C(=O)[O-]
Product: CCCCCCCCCCCCCC(=O)OC

Procedure:
We compared the production of ω-hydroxy myristic acid and α,ω-tetradecanoic acid by a Candida tropicalis strain lacking CYP52A13, CYP52A14, CYP52A17, CYP52A18, FAO1, FAO1B, FAO2A, FAO2B, CYP52A12, CYP52A12B, ADH-A4, ADH-A4B, ADH-B4, ADH-B4B, ADH-A10 and ADH-B11 and with CYP52A17 added back under control of the isocitrate lyase promoter (DP428).
Reaction SMILES: [CH:1]1[C:6]([C:7]#[N:8])=[CH:5][C:4]2[C:9]([CH2:12][CH2:13][CH2:14][CH2:15]N3CCN(C4C=CC5OC(C(N)=O)=CC=5C=4)CC3)=[CH:10][NH:11][C:3]=2[CH:2]=1.ClCCCC(C1C2C(=CC=C(C#N)C=2)NC=1)=[O:39].[BH4-].[Na+].Cl>C(O)(C)C>[OH:39][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[C:4]2[C:3](=[CH:2][CH:1]=[C:6]([C:7]#[N:8])[CH:5]=2)[NH:11][CH:10]=1
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Reactant: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#Cc1ccc2[nH]cc(CCCCO)c2c1

Procedure:
As per the process described in CN'932 publication, vilazodone is prepared by reacting 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile with sodium borohydride in isopropanol at reflux temperature, followed by treating the reaction mass with dilute hydrochloric acid and subsequent workup and then subjecting to column chromatography purifications to produce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile. The hydroxylbutyl intermediate obtained is then subjected to sulfonylation using a sulfonylating agent selected from p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride to produce corresponding sulfonylated intermediate, which is then condensed with 5-(1-piperazinyl)benzofuran-2-carboxamide in acetonitrile to produce vilazodone.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][C@@H:21]2[C@@H:28]([CH2:29][O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:27][C@H:24]([O:25][CH3:26])[C@H:23]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:22]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:39]([O:38][C@@H:23]1[C@@H:22]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:21]([O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:28]([CH2:29][O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:27][C@@H:24]1[O:25][CH3:26])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.543 g, 2.71 mmol) is dissolved in hot toluene (2 0 ml) and methanol (80 ml) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D -glucopyranoside as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:26])[NH:7][C:8](=[O:25])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1.[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:26])[N:7]([CH2:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[C:8](=[O:25])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: BrCc1cccs1
Reactant: COCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of 4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 53%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][N:13](C)C=O>C(OCC)(=O)C.[C-]#N.[C-]#N.[Zn+2]>[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:12]#[N:13])[C:3]=2[CH:4]=[CH:5][N:6]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc2cnccc12
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc2cnccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
5-Bromoisoquinoline (8 g, 38.65 mmol) and dimethyl formamide (100 mL) were mixed and stirred. The reaction solution was added with Zn(CN)2 (2.72 g, 23.19 mmol) and Ph(PPH)4 (1.78 g, 1.55 mmol), followed by stirring for about 4 hours at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (5.8 g, 97%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.[F:28]C1C=CC(NC(=O)OC(C)(C)C)=CC=1NC1C(C=O)=CN=C(SC)N=1>>[F:28][C:19]1[CH:18]=[CH:17][C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:15][C:14]=1[N:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: CSc1ncc(C=O)c(Nc2cc(NC(=O)OC(C)(C)C)ccc2F)n1
Product: CSc1ncc2ccc(=O)n(-c3cc(NC(=O)OC(C)(C)C)ccc3F)c2n1
Yield: 59 %

Procedure:
This compound (270 mg, 59% yield) as a light yellow crystalline solid was prepared according to the procedures described for Intermediate 51, using tert-butyl (4-fluoro-3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (58) (430 mg, 1.14 mmol) as the starting material. m/z (ESI, +ve ion) 403.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.64 (1H, s), 7.70 (1H, d, J=9.6 Hz), 7.55 (1H, br. s.), 7.28-7.35 (1H, m), 7.17 (1H, t, J=9.0 Hz), 6.72 (1H, d, J=9.6 Hz), 6.56 (1H, br. s.), 2.22 (3H, s), 1.49 (9H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-126.87 (1F, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:21]=[N:20][CH:19]=2)[CH2:11][C@H:10]([C:33]([O:35][CH3:36])=[O:34])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:36][O:35][C:33]([C@H:10]1[CH2:11][C@@H:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:21]=[N:20][CH:19]=2)[CH2:13][NH:8][CH2:9]1)=[O:34]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (1.14 g, 2.30 mmol) was dissolved in CH2Cl2 (12 mL). Trifluoroacetic acid (6 mL) was added and the solution was stirred at ambient temperature for 3 h. The solution was concentrated to dryness to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:28][C@H:27]2[C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[CH2:28][C@H:27]2[C:29]([OH:31])=[O:30])=[CH:24][CH:25]=1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1

Procedure:
Experimental procedure analogous to that describing the synthesis of I-2a-I except that 4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazole-5-carbaldehyde and racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) were used to give 1.05 g of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.78 Hz, 2H), 7.65 (d, J=8.78 Hz, 2H), 6.97 (d, J=8.60 Hz, 2H), 6.60 (d, J=8.60 Hz, 2H), 4.46 (s, 2H), 2.53 (m, 1H), 2.50 (s, 3H), 1.80 (m, 1H), 1.60 (m, 1H), 1.36 (m, 1H). ES-MS m/z 360 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15]([CH3:19])([CH3:18])[C:16]#[N:17].Cl[CH2:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].O>CN(C=O)C>[CH:24]1([C:22](=[O:23])[CH2:21][O:14][C:12]2[CH:11]=[CH:10][C:9]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:8]([F:7])[CH:13]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C#N)c1ccc(O)cc1F
Reactant: O=C(CCl)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(OCC(=O)C2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
Potassium carbonate (3.1 g, 22 mmol) was added to a solution of 2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile (1.0 g, 6.0 mmol) and 2-Chloro-1-cyclopentyl-ethanone (3.3 g, 22 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-15% EtOAc in hexanes) to give the product (1.2 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.57-1.93 (m, 14H), 3.10 (m, 1H), 4.64 (s, 2H), 6.65 (d, J=9.6 Hz, 2H), 7.37 (t, J=8.9 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
A solution of 4-nitro 1,2-phenylene diamine(1.53 g, 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride(1.76 g, 10.0 mmol) and triethyl amine(1.01 g) in DMF for 12 h at 23° C. The reaction mixture was partitioned between saturated NH4Cl and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized (EtOH) to afford desired (0.275 g, 9%). 1H NMR(DMSO) 9.5(s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74(d, 2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d,1H, J=2 Hz), 6.79 (d, 1H, J=8 Hz), 6.5(s, 2H, br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([N+:20]([O-])=O)[CH:5]=1>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([NH2:20])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(N)c1

Procedure:
25 g of 3,5-dinitro-4-phenoxy-benzoic acid methyl ester are dissolved in 250 ml of ethyl acetate, combined with 10 g of Raney nickel and hydrogenated. After absorption of the calculated amount of hydrogen, the catalyst is filtered off, the solvent is removed, whereupon the remaining oil crystallises. The raw product may be further reacted directly or recrystallized from methanol/water, whereby the diamino ester is obtained in form of colorless crystals melting at 140°-142° C in excellent yield. Alternatively, the hydrogenation may also be carried out in an autoclave at 50° C and 100 atmospheres gauge pressure. The reaction time is then 3 to 5 hours, depending on the reactivity of the Raney nickel.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([NH2:15])[C:9](=[CH:13][CH:14]=1)[C:10]([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:14]=[CH:13][C:9]2[C:10](=[O:12])[O:11][C:1]([CH3:2])=[N:15][C:8]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cc(F)ccc2c(=O)o1
Reaction time: 1 h

Procedure:
A mixture of acetyl chloride (4.6 ml) and 4-fluoroanthranilic acid (5 g) in acetic anhydride (100 ml) was heated under reflux for 48 hours, cooled and filtered. The filtrate was added to ice/water, stirred for 1 hour and extracted with ethyl acetate. The extract was dried and the solvent removed under reduced pressure to give 7-fluoro-2-methyl-3,1-benzoxazin-4-one, m.p. 159°-160°. (Compound 2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:12])[CH3:11]
Reactant: Cc1cccc(C)c1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)cccc1C
Yield: 102.5 %

Procedure:
100 g (0.82 mole) of 2,6-dimethylphenol and 167.4 g (1.64 mole) of acetic anhydride were refluxed for 4 h. The reaction mixture was poured onto ice and extracted with methylene chloride. The organic phase was washed with dilute sodium hydroxide solution, dried and concentrated under reduced pressure. 138 g of 2,6-dimethylphenyl acetate were obtained. To this product were added 120.2 g (0.9 mole) of anhydrous aluminum chloride in portions, during which the temperature rose to 85° C. The mixture was then heated at 110° C. for 30 min and left to cool. The viscous paste was poured onto ice/hydrochloric acid, and the precipitated product was filtered off. Recrystallization from 1/1 methanol/water resulted in 103.6 g of 3,5-dimethyl-4-hydroxyacetophenone.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:7]([N:8]=[C:15]=[S:16])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(N2CCOCC2)c1N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(N2CCOCC2)c1N=C=S

Procedure:
Reaction of 6-methyl-2-morpholinoaniline (9.6 g) in dioxan (25 ml) and water (100 ml) with thiophosgene (5.7 ml) at 0° C. for 30 minutes and at room temperature for 3 hours gave 6-methyl-2-morpholinophenyl isothiocyanate as an oil.