Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][CH:7]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CO>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:36])([F:35])[F:37])[CH:27]=1)[C:23]([N:21]([CH:7]([CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:5]([OH:39])=[O:4])[CH3:22])=[O:38]
Reactant: COC(=O)CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
25 ml of 1N sodium hydroxide are added to a solution of 7.8 g (15 mmol) of 3-[N-(3,5-bis-trifluoromethyl-benzoyl)-N-methyl-amino]-4,4-diphenyl-butanoic acid methyl ester in 100 ml of tetrahydrofuran/methanol (2:1). After 5 hours the reaction mixture is concentrated by evaporation, diluted with water and rendered acidic with cold 2N hydrochloric acid. The white precipitate is filtered off, then washed with water and dried under a high vacuum at 50° C. The title compound is obtained in the form of a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.14; Rt (HPLC)=19.2 min; 1H-NMR (400 MHz, d6 -DMSO, 150° C.) d 7.96 (br, 1H), 7.42-7.19 (m, 12H), 5.42 (br, 1H), 4.45 (d, 1H), 2.79 (dd, 1H), 2.72 (s, 3H), 2.37 (dd, 1H); FAB-MS (M+H)+ =510.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1B(O)O.[CH3:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[N:17]1[CH:18]=[CH:19][C:15]([CH3:14])=[N:16]1
Reactant: COc1cc(C)c(B(O)O)cc1C
Reactant: Cc1cc[nH]n1
Product: COc1cc(C)c(-n2ccc(C)n2)cc1C

Procedure:
A similar reaction to Reference Preparation example 33 using 2,5-dimethyl-4-methoxy-phenylboronic acid instead of 4-methoxy-3-methyl-phenylboronic acid, and using 3-methyl-1H-pyrazole instead of 3,4,5-trimethyl-1H-pyrazole gave 1-(2,5-dimethyl-4-methoxy-phenyl)-3-methyl-1H-pyrazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.BrC1C=CC(F)=C(C(F)(F)F)C=1.C(OC(N1CCNCC1)=O)(C)(C)C.[ClH:50].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:50].[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][C:16]=1[C:21]([F:23])([F:22])[F:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(C(F)(F)F)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: Fc1ccc(Br)cc1C(F)(F)F
Solvent: CCOC(C)=O
Product: Fc1ccc(N2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
By a similar operation as in Starting Material Synthetic Example 16, 4-[4-fluoro-3-(trifluoromethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester was synthesized from 5-bromo-2-fluorobenzotrifluoride (Aldrich Co., 1.5 g) and 1-(tert-butoxycarbonyl)piperazine (1.38 g). These were dissolved in ethyl acetate, 4N hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 6 hr. The precipitated solid was collected by filtration and dried to give 1-[4-fluoro-3-(trifluoromethyl)phenyl]piperazine hydrochloride (1.31 g, yield 75%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:45]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:25]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:15]([C:13]([NH:12][C:5]5[C:4]([CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=5[CH2:10][CH3:11])=[O:14])=[N:16][N:17]([CH3:35])[C:18]=4[C:27]=3[N:26]=2)[CH2:34][CH2:33]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(Cc4ccccc4)CC3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL), DIPEA (0.2 mL, 1.1 mmol) and benzylbromide (0.011 mL, 0.090 mmol) were added. The mixture was stirred at room temperature for 2 h. Dichloromethane was added and the solution was washed water. The organic layer was then dried over Na2SO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 95/5) to 31 mg of the title compound. (75% yield)
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[CH2:4]1.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]=1[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[CH2:4]2)=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=S1(=O)CCCC(CBr)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CCCS(=O)(=O)C2)cc(C)c1Br
Temperature: 130 °C
Reaction time: 8 h

Procedure:
3-(Bromomethyl)tetrahydro-2H-thiopyrane 1,1-dioxide (1 g) is dissolved in 40 mL of N,N-dimethylformamide. 4-Bromo-3,5-dimethylphenol (885 mg) and cesium carbonate (2.85 g) are added and the reaction mixture is stirred at 130° C. overnight. The reaction mixture is concentrated under vacuum. Water is added and the mixture is extracted with ethyl acetate, The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 800 mg.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][C:27]([CH2:29]O)=[CH:26][C:25]=4[CH:31]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][C:27]([CH2:29][N:43]5[CH2:44][CH2:45][CH:40]([CH3:39])[CH2:41][CH2:42]5)=[CH:26][C:25]=4[CH:31]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CC1CCNCC1
Reactant: OCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2o1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1CCN(Cc2cc3cc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)ccc3o2)CC1
Reaction time: 1 h

Procedure:
32 μL (0.40 mmol) methanesulphonic acid chloride are added to a solution of 100 mg (0.28 mmol) {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-benzofuran-2-yl}-methanol and 69 μL (0.50 mmol) triethylamine in 5 mL DCM at 0° C. and the reaction is stirred for 1 h at this temperature. Another 70 μL (0.89 mmol) methanesulphonic acid chloride are added and the reaction is stirred overnight at RT. Then 0.24 ml (2.00 mmol) 4-methylpiperidine is added and the reaction is stirred for 2 hours at RT. The reaction solution is diluted with water and the aqueous phase extracted twice with DCM. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (DCM/methanol 9:1).
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.FC(F)(F)C(O)=O.[C:15]1([C:21]2[C:25]3[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:24]=3[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:31]>>[ClH:31].[CH3:7][N:5]([CH2:4][CH:27]1[C:26](=[O:30])[C:25]2[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:22][O:23][C:24]=2[CH2:29][CH2:28]1)[CH3:6]
Reactant: CN(C)CN(C)C
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Temperature: -10 °C
Reaction time: 48 h

Procedure:
Bis-dimethylaminomethane (0.51 g) was added to 2.5 ml of trifluoroacetic acid which had been previously chilled to -10° C. 6,7-Dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (1.0 g) was then added and the reaction was warmed for 1 hour at 100° C. and then allowed to stand an additional 2 days at room temperature. The reaction mixture was poured into 5% HCl and washed with ether, after which the aqueous phase was treated with solid sodium bicarbonate until basic. Extraction with ether followed by drying and concentration gave an oil. The hydrochloride was formed in ethereal HCl and was recrystallized from dichloromethane/ether to give 0.95 g of 6,7-dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazol-4(5H)-one hydrochloride, m.p. 178°-180° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28]>C(Cl)Cl>[CH2:25]1[C:26](=[O:27])[N:22]([O:4][C:3]([CH2:2][Br:1])=[O:5])[C:23](=[O:28])[CH2:24]1
Reactant: O=C(O)CBr
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CBr)ON1C(=O)CCC1=O

Procedure:
Bromoacetic acid (20 mmoles) was treated with dicyclohexyl-carbodiimide (22 mmoles, 1.1 equivalents) and N-hydroxysuccinimide (22 mmoles) in 30 ml CH2Cl2 at 4° C. according to the procedure of M. S. Bernatowicz and G. R. Matsueda (Anal. Biochem. 155:95, 1986) to give the N-succinimidyl bromoacetate as a white solid.
Reaction SMILES: NC1C(C=[N:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=NC(Cl)=C(Cl)N=1.ClC1C=CC(C(Cl)=O)=CC=1.NN>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][NH2:11])=[O:21])=[CH:15][CH:16]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=NNC(=O)c1ccc(Cl)cc1
Agent: NN
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: NNC(=O)c1ccc(Cl)cc1

Procedure:
p-Chlorobenzoic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide by the reaction of p-chlorobenzoyl chloride with hydrazine to form p-chlorobenzoylhydrazine, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:3]2[O:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=2[NH:1][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])=[CH:16][CH:15]=1
Reactant: CC(C)(C)c1cc(N)c(-c2ccncc2)o1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of 3-amino-2-(4-pyridinyl)-5-tert-butylfuran (Method A2; 0.10 g, 0.46 mmol) and 2,3-dichlorophenyl isocyanate (0.13 g, 0.69 mmol) in CH2Cl2 was stirred at room temp. for 2 h, then was treated with 2-(dimethalamino)ethylamine (0.081 g, 0.92 mmol) and stirred for an additional 30 min. The resulting mixture was diluted with EtOAc (50 mL), then was sequentially washed with a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using column chromatography (gradient from 10% EtOAc/90% hexane to 40% EtOAc/60% hexane) to give the desired compound as a white solid (0.12 g, 63%); mp 195-198° C.; TLC (60% EtOAc/40% hexane) Rf 0.47; 1H NMR (DMSO-d6) δ1.30 (s, 9H); 6.63 (s, 1H); 7.30-7.32 (m, 2H), 7.58 (dm, J=6.62 Hz, 2H), 8.16 (dd, J=2.57, 6.99 Hz, 1H), 8.60 (dm, J=6.25 Hz, 2H), 8.83 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO-d6) δ 28.5 (3C), 32.5, 103.7, 117.3 (2C), 119.8, 120.4, 123.7, 125.6, 128.1, 131.6, 135.7, 136.5, 137.9, 150.0 (2C), 152.2, 163.5; CI-MS m/z (rel abundance) 404 (M+H)+, 15%), 406 ((M+H+2)+, 8%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>C1C=CC=CC=1>[CH3:9][CH:10]1[C:2]2[C:1](=[C:6]([OH:7])[CH:5]=[CH:4][C:3]=2[CH3:8])[C:12](=[O:13])[CH2:11]1
Reactant: Cc1ccc(O)cc1
Reactant: O=C1CCCO1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(O)c2c1C(C)CC2=O

Procedure:
Likewise, a mixture of 21.6 g. (0.2 mol) of p-cresol and 17.2 g. (0.2 mol) of γ-butyrolactone is added into a mixture of 79.8 g. (0.6 mol) of anhydrous aluminium chloride and 15.0 g. (0.26 mol) of sodium chloride which mixture has been molten at 140°C, and the resultant mixture is heated at a temperature of 140°-200°C for about 3 minutes. After cooling, the reaction mixture is poured into a hydrochloric acid-ice and the resulting acidic solution is stirred with benzene. The benzene layer is taken up and dried with anhydrous sodium sulfate. The solvent is removed by distillation, and the residue is further subjected to vacuum distillation, whereby yellowish liquid is distilled out at 95°-105°C/2mmHg, which liquid is solidified on cooling. Upon recrystallization from n-hexane after decolorization with active carbon, 14.9 g. of whitish-purple crystals of 3,4-dimethyl-7-hydroxyindan-1-one having a melting point of 52°-53°C is obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(S([N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:38][O:39][Si](C(C)(C)C)(C)C)=[CH:34][CH:35]=3)[CH:30]=[C:29]2[C:53]#[N:54])(=O)=O)C=CC=CC=1>>[OH:39][CH2:38][CH:37]([C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[NH:28][C:29]([C:53]#[N:54])=[CH:30]2)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(c1)cc(C#N)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#Cc1cc2cc(C(CO)c3ccccc3)ccc2[nH]1
Yield: 78.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1.0 M in THF, 1.6 mL) was added to a solution of -benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole-2-carbonitrile (0.56 g, 1.055 mmol) and the resulting mixture was refluxed for several hours. The solvent was evaporated under reduced pressure and the residue was diluted with water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 35/65 to 50/50) to afford 218 mg (75% yield) of 5-(2-hydroxy-1-phenyl-ethyl)-1H-indole-2-carbonitrile CCLXX as a light yellow foam.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][OH:16].C(OCC)C>ClCCl>[Br:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: OCc1ccc(Cl)cc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(Cl)cc1Br
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Add pyridinium chlorochromate (432 mg, 2 mmol) to a solution of 2-bromo-4-chlorobenzyl alcohol (200 mg, 0.9 mmol) in dichloromethane (4 mL). Stir the resulting mixture for 2 h. Add diethyl ether (4 mL) and stir for 20-min. Decant the diethyl ether solution. Wash the remaining solids with diethyl ether twice. Combine the diethyl ether solutions and concentrate. Chromatograph on silica gel, eluting with 20:80 to 1:1 ethyl acetate:dichloromethane to give 2-bromo-4-chlorobenzaldehyde as a white solid (167 mg, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1

Procedure:
A solution of benzyl-(2S)-2-cyano-4,4-difluoropyrrolidine-1-carboxylate, hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) in ethanol was refluxed under nitrogen for 5 hours. Mixture was concentrated and residues taken up in ethyl acetate and washed with water and brine. Combined organics were dried over Na2SO4 and evaporated to give title compound as a foam.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[C:9]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[C:22](=O)[O:23][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)=[CH:13]2)[CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[OH-].[NH4+:39]>CN(C)C=O>[N:1]([CH2:4][C:5]1[N:10]=[C:9]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[C:22](=[O:23])[NH:39][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)=[CH:13]2)[CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [NH4+]
Reactant: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])n4)c4ccccc34)C(=O)OC2=O)c2ccccc21
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])n4)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
The product from step b) was heated with ammonium hydroxide (5 mL) and dimethylformamide (5 mL) at 75° C. for 5 h in a sealed flask. The flask was cooled and the content partitioned between ethyl acetate and water. The organic phase was washed with ammonium hydroxide. Evaporation afforded 188 mg of the sub-title product, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[OH2:11]>C(O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]([NH2:8])=[O:11])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: O
Solvent: CCO
Product: NC(=O)Cc1ccc(O)cc1
Yield: 98.4 %

Procedure:
(0.0032 g, 0.007 mmol) of the platinum complex, prepared as in Example 1, was stirred with 4-hydroxybenzyl cyanide (1.0 g, 7.5 mmol) and 5 ml (0.28 mol) of water and 5 ml ethanol and the mixture heated under reflux for 18 hours. After cooling the liquids were removed using a rotary evaporator to give 4-hydroxy phenylacetamide (1.116 g) corresponding to 98% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C@@H:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][C@@H:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: C[C@H](O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: C[C@H](O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (S)-1-Hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2H), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21 (dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].C(O)(=O)C.[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][C:17]([CH2:19][N:29]3[CH2:30][CH2:31][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)s1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
In a 250 ml round bottomed flask 5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate B37) (780 mg, 2.60 mmol) was dissolved in 30 ml of DCM then acetic acid (0.446 ml, 7.79 mmol) and benzyl piperazine-1-carboxylate (1.503 ml, 7.79 mmol) were added. After few minutes sodium triacetoxyhydroborate (2.75 g, 12.99 mmol) was added and the mixture was stirred at r.t. The mixture was poured into 100 ml of DCM and 100 NaHCO3 sat. sol. then phases were separated and the organic one was concentrated to dryness to leave a brown oil that was immediately purified by chromatography eluting with Hexane\EtOAc mixtures to leave the title compound (903 mg, 1.790 mmol, 68.9% yield) as a yellow oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C@H:13]([NH:15]S(C(C)(C)C)=O)[CH3:14])=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C@H:13]([NH2:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(F)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A 1,4-dioxane solution of 4N hydrochloric acid (5 mL) was added to N-[(1R)-1-(4-fluoronaphthalen-1-yl)ethyl]-2-methylpropane-2-sulfinamide (527 mg, 2.2 mmol), and the mixture was stirred for 30 minutes at room temperature. The precipitate generated was filtered, washed with ether, and was then dried under reduced pressure to give the title compound (358 mg, 70%).