Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:20]([CH:21]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=4[F:37])[OH:22])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CN(C)C=O>O1CCCC1>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:20]([C:21](=[O:22])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=4[F:37])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4ccc(C(=O)NCC)nc4)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(C(=O)NCC)nc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To 5-(3-{[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (73, 50 mg, 0.094 mmol) dissolved in 0.76 mL of tetrahydrofuran, Dess-Martin periodinane (48 mg, 0.113 mmol) was added, followed by 1 mL of dimethylformamide. The reaction was allowed to stir at room temperature for 1 hour, then quenched with water and the aqueous layer extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to provide the desired compound (P-2151, 30.6 mg). MS (ESI) [M+H+]+=528.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1O.[Br:12][CH2:13][CH2:14]Br.C([O-])([O-])=[O:17].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:17][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: BrCCBr
Reactant: COc1cccc(O)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCCBr)cc1OC
Yield: 46 %

Procedure:
To a solution of 2,3-dimethoxyphenol in acetone was added an equimolar amount of 1,2-dibromoethane and excess K2CO3 and heated under reflux overnight. The reaction mixture was filtered and the solvent was evaporated in vacuo. The pure product was obtained with flash chromatography in cyclohexane: EtOAc 5:1 in 46% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[O:27])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: OC1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(O)CC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and 4-hydroxypiperidine were coupled to give 118bp. 1H NMR (400 MHz, DMSO-d6), δ: 7.68 (m, 1H), 7.46 (m, 1H), 7.21-7.25 (m, 3H), 6.93 (m, 1H), 6.69 (m, 1H), 5.16 (s, 2H), 3.65 (m, 3H), 3.29 (s, 3H), 3.17 (m, 2H), 1.73 (m, 2H), 1.36 (m, 2H). LCMS (ESI) m/z: 485.1
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:28])([F:29])[F:15])[CH:18]=2)=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2cccc(C(F)(F)F)c2)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=402.06.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH:21]([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CN(C)C=O>[ClH:1].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:11]=[C:10]([N:12]3[CH:21]([CH3:22])[CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)[C:9]3[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cccc2c(N3Cc4ccccc4CC3C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3Cc4ccccc4CC3C)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 35 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.5 g of the compound (4.4 mM) prepared in Example 12 and 15 ml of dimethyl-formamide, 0.7 ml of 4-fluoroaniline(6.6 mM) was added, 0.7 g of the title compound was prepared.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[NH2:14])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[OH:26][C:27]([C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1C(C(F)(F)F)(O)C(F)(F)F)[NH2:39])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29]>>[F:4][C:3]([F:6])([F:5])[C:2]([C:7]([F:10])([F:9])[F:8])=[O:1].[OH:26][C:27]([C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[NH2:39])([C:28]([F:30])([F:29])[F:31])[C:32]([F:35])([F:34])[F:33].[O:18]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:17]1[CH:11]=[CH:12][C:13]([NH2:14])=[CH:15][CH:16]=1
Reactant: Nc1ccc(Oc2ccc(N)cc2C(O)(C(F)(F)F)C(F)(F)F)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: Nc1ccc(Oc2ccc(N)cc2C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: Nc1ccc(Oc2ccc(N)cc2)cc1
Product: O=C(C(F)(F)F)C(F)(F)F

Procedure:
The reaction liquid was found by gas chromatography (GC) analysis to contain 43.5% of the target compound, 3-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-4,4′-oxydianiline, 2.9% of 3,3′-bis(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)-4,4′-oxydianiline, and 46.6% of the total of various imines produced by the reaction of hexafluoroacetone with the amine moiety of 4,4′-oxydianiline.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Br:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:9]([O:26][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Br:18])=[CH:21][CH:22]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(COC(=O)c1ccc(CBr)cc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Triethylamine (16 ml, 115 mmol) and bromoacetophenone (22.9 g, 115 mmol) were dissolved in 450 ml of ethyl acetate. The solution was stirred at 50° C. and 4-(bromomethyl)benzoic acid (17.5 g, 155 mmol) was added in seven equal portions over a three hour period. Stirring was continued for an additional 8 hours at 50° C. Precipitated triethylaminehydrobromide was removed by filtration and the ethyl acetate solution was washed with (3×150 ml each) of 10% citric acid, brine saturated sodium bicarbonate and brine. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was recrystallized from dichloromethane-petroleum ether to give fine white crystals (10.2 g, 27% yield). 1H NMR (DMSO-d6) δ 7.99 (m, 4H), 7.69-7.54 (m, 5H), 5.74 (s, 2H), 4.77 (s, 2H); 13C NMR (DMSO-d6) δ 193.7, 165.9, 144.6, 134.9, 131.2, 131.0, 130.7, 130.6, 130.2, 129.9, 128.8, 128.6, 68.2, 34.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCCC>ClCCl>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccccc2)cn1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A solution of 5-amino-2-methoxypyridine (2.48 g, 20.0 mmol) and N-ethyldiisopropylamine (2.84 g, 22.0 mmol) in dichloromethane (20 ml) was cooled in an ice-bath. Benzoyl chloride (3.09 g, 22 mmol) was slowly added by means of a syringe. The cooling bath was removed and stirring was continued at room temperature for 18 hours. Dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo leaving a dark solid. Crystallisation from ethyl acetate:heptane yielded the title compound (3.44 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:16][C:13](=[O:15])[CH3:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([n+]([O-])c1)CCCC2
Product: CC(=O)OC1CCCc2cc(C)cnc21
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
7.02 Grams of 3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide was dissolved in acetic anhydride, and the solution was heated at 90° C. with stirring for 3.5 hours. Acetic anhydride was removed by evaporation under reduced pressure, then an aqueous solution of sodium carbonate was added to make the residue alkaline and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue thus obtained was purified by a silica gel column chromatography (eluent: dichloromethane) to obtain 7.18 g of 3-methyl-8-acetoxy-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].C1(C)C=CC=CC=1>C(O)C>[Br:1][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:12][CH:11]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(C(=O)CBr)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Bromine (1.25 ml; 25 mmol) is added dropwise to a solution of 4′-isobutylacetophenone (3.52 g; 20 mmol) in 60 ml of ethanol cooled down to approximately 5° C. After stirring the reaction mixture for 30 minutes at this temperature, stirring is continued for one hour at ambient temperature. The reaction medium, to which small portions of toluene are added, is concentrated to dryness. After purification on a silica column (eluent: ethyl-heptane acetate: 5-95), a colourless oil is obtained with a yield of 57%.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:15]=[C:16](SC)[NH:17][C:18](=[O:23])[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1C(OC(C)(C)C)=O.CN1C(=O)CCC1.[ClH:48]>C(OCC)(=O)C.C(O)C>[ClH:48].[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:15]=[C:16]([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]2)[NH:17][C:18](=[O:23])[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CSc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(N)=O)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NCC2CCCCN2)[nH]c(=O)c1C(N)=O
Temperature: 180 °C
Reaction time: 4 h

Procedure:
A mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 294) (200 mg), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (1.12 g) and NMP (1 mL) was heated at 180° C. for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to give a white amorphous. To a mixture of the white amorphous, ethyl acetate (10 mL) and ethanol (5 mL), 4M hydrogen chloride in ethyl acetate (5 mL) was added under ice cooling and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-[(piperidin-2-ylmethyl)amino]-1,6-dihydropyrimidine-5-carboxamide hydrochloride (126 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M62) (0.36 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (234 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:14]([CH3:21])[C@@H:15]([O:19][CH3:20])/[CH:16]=C/C)[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[O:22]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C@H:3]([C@@H:14]([CH3:21])[C@@H:15]([O:19][CH3:20])[CH:16]=[O:22])[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)[C@H](C=O)OC)[C@@H](C)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2,2-Dimethyl-propionic acid (E)-(2S,3S,4S,5S)-3,5-dimethoxy-2,4-dimethyl-oct-6-enyl ester (2.0 g, 6.94 mmol) in anhydrous dichloromethane (60 ml) at −78° C., ozone was bubbled through until a pale blue colour persisted. Nitrogen was then bubbled through until the solution turned colourless. Triphenylphosphine (2.7 g, 10.4 mmol) was added and the reaction was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo and the product purified by flash chromatography (SiO2, iHex/EtOAc, 20:1 then 4:1) to afford 1.62 g (81%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.51 (d, J=4.1 Hz, 1H), 4.14 (dd, J=10.8 Hz, 3.3 Hz, 1H), 4.00 (dd, J=10.8 Hz, 5.9 Hz, 1H), 3.36-3.29 (m, 2H), 3.33 (s, 3H), 3.32 (s, 3H), 1.93 (m, 2H), 1.20 (s, 9H), 0.84 (d, J=7.0 Hz, 3H), 0.78 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[C:5](=[O:7])=[O:6].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11].Cl>CS(C)=O.O>[CH3:1][S:2][C:10]([F:12])([F:11])[C:9]([F:13])([F:8])[C:5]([OH:7])=[O:6]
Reactant: CS
Reactant: FC(F)=C(F)F
Reactant: O=C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSC(F)(F)C(F)(F)C(=O)O
Reaction time: 8 h
Yield: 98.5 %

Procedure:
NaSCH3 was prepared by distilling 24 g (0.50 mol) of methyl mercaptan into a stirred suspension of 24 g (0.50 mol) of 50% NaH/mineral oil in 170 ml of dimethyl sulfoxide over a 2-hr period. The mixture was charged into a 400-ml tube with 27 g (0.6 mol) of CO2 and 50 g (0.50 mol) of tetrafluoroethylene and shaken at 50° for 8 hrs. The reaction mixture was poured into a cold solution of 300 ml of concentrated HCl in 1 liter of water, and the resulting mixture was extracted continuously with ether. Removal of volatiles from the extracts at 5 mm gave 94.6 g of 3-methylthiotetrafluoropropionic acid. This acid was stirred at 85° to 95° while a mixture of 125 ml (about 1.2 mol) of 30% H2O2 and 75 ml of acetic acid was added dropwise over 2 hrs. The mixture was stirred at 90° to 95° for 3 hrs more, then evacuated at full pump to remove volatiles.
Reaction SMILES: [Li+:1].CCC[CH2-].[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[N:26]=[C:25]([CH3:27])[N:24]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([C@@H:35]3[CH2:37][C@H:36]3[C:38]([O:40]CC)=O)[CH:29]=2)[N:23]=1.[Cl:43][CH2:44]I>C1COCC1.CCOC(C)=O>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:1].[Cl:43][CH2:44][C:38]([C@H:36]1[CH2:37][C@@H:35]1[C:30]1[CH:29]=[C:28]([N:24]2[C:25]([CH3:27])=[N:26][C:22]([CH3:21])=[N:23]2)[N:33]=[C:32]([CH3:34])[N:31]=1)=[O:40]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc([C@H]2C[C@@H]2C(=O)CCl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2 M solution of lithium diisopropylamide (LDA) was prepared by the addition of N-butyllithium (8.0 mL, 2.5 M, 20 mmol) to diisopropylamine (2.4 g, 24 mmol) in THF (2 mL) at 0° C. After stirring for 1 h, the LDA solution (6.6 mL, 13.2 mmol) was added to a flask containing 1-4 (1.0 g, 3.3 mmol) and chloroiodomethane (2.9 g, 17 mmol) in THF (33 mL) at −78° C. The mixture was stirred at −78° C. for 2 h then warmed to room temperature and diluted with EtOAc (30 mL). The solution was washed with saturated aqueous sodium bicarbonate (2×20 mL) and brine (1×20 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (20-40% EtOAc/hexanes) to afford 1-5 as a white solid.
Reaction SMILES: C(=[O:6])C(C)(C)C.[NH2:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1.CC(C)(C)C=NC1CCNC1.[Cl:24][C:25]1[C:26](F)=[C:27]([F:41])[CH:28]=[C:29]2[C:34]=1[N:33]([CH:35]1[CH2:37][CH2:36]1)[CH:32]=[C:31]([C:38]([OH:40])=[O:39])[CH2:30]2.N12CCN(CC1)CC2>C(#N)C.CN(C)C=O>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:26]2[C:25]([Cl:24])=[C:34]3[C:29]([C:30](=[O:6])[C:31]([C:38]([OH:40])=[O:39])=[CH:32][N:33]3[CH:35]3[CH2:37][CH2:36]3)=[CH:28][C:27]=2[F:41])[CH2:9]1
Reactant: O=C(O)C1=CN(C2CC2)c2c(cc(F)c(F)c2Cl)C1
Reactant: CC(C)(C)C=O
Reactant: NC1CCNC1
Agent: C1CN2CCN1CC2
Agent: CC(C)(C)C=NC1CCNC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1
Reaction time: 1 h

Procedure:
0.95 g (11 mmol) of pivalaldehyde are added dropwise to a solution of 0.86 g (10 mmol) of 3-aminopyrrolidine in 10 ml of acetonitrile at room temperature in the course of 5 minutes, during which the temperature rises from 22.5° C. to 27.5° C. The mixture is subseqently stirred for 1 hour and a virtually complete conversion into 3-(2,2-dimethylpropylideneamino)-pyrrolidine is found by checking the reaction by gas chromatography. The mixture is then diluted with 10 ml of acetonitrile and 10 ml of dimethylformamide, 3 g (10 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-3-quinolinecarboxylic acid and 2.2 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane are added and the mixture is heated under reflux for 1 hour. Work up gives the same result as described under Example 2a).
Reaction SMILES: S(Cl)(Cl)=[O:2].O[C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]([NH:12][CH2:13][C:14](O)=[O:15])[CH:9]=[CH:10][CH:11]=1.[CH3:20][OH:21]>>[CH3:20][O:21][C:14](=[O:15])[CH2:13][NH:12][C:8]1[CH:9]=[C:10]([OH:2])[CH:11]=[CH:6][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)CNc1cccc(O)c1[N+](=O)[O-]
Product: COC(=O)CNc1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
Thionyl chloride 30.84 g (260 mM) was added dropwise with ice cooling to N-(hydroxy-2-nitrophenyl)-amino acetic acid 45.78 g (0.216 mole) dissolved in methanol 500 ml for 30 mins.; then the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered, the filtered material was washed with methanol and dried to obtain the yellow solid product. The above filtrate was concentrated in vacuo and the precipitated material was washed with chloroform and dried. The solid materials thus obtained were combined to obtain the product 47.5 g (yield: 97%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:18][NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: N#Cc1c[nH]nc1N
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2C#N)cc1OC1CCCC1
Reaction time: 24 h

Procedure:
A solution of 3-amino-4-cyanopyrazole (5.0 g, 0.16 mol), 3-cyclopentyloxy-4-methoxybenzaldehyde (10.0 g, 0.045 mol) and sodium acetate (0.2 g, 2.4 mol) in methanol (70 mL) was placed in a stirred reaction flask equipped with a pH stat controlling a syringe pump and syringe filled with 3 N acetic acid in methanol. The pH stat was set to maintain pH 7. After 24 hours, more 3-cyclopentyloxy-4-methoxybenzaidehyde (7.0 g, 0.031 mol) was added and the reaction was continued. After 48 hours, more 3-cyclopentyloxy-4-methoxybenzaldehyde (4.0 g, 9.0 mmol) and sodium cyanoborohydride (0.5 g, 7.9 mmol) was added and the reaction was continued. After 72 hours, more sodium cyanoborohydride (0.5 g, 7.9 mmol) was added and after 96 hours, the reaction was stopped log and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (75mL) and water (50 mL). The ethyl acetate layer was washed with water (2×50 mL) and evaporated. The crude product was chromaotgraphed over 200 g of flash chromatography silica gel. Elution with 2% methanol/methylene chloride removed some impurities including 3-cyclopentyloxy-4-methoxybenzyl alcohol. Continued elution with methanol/methylene chloride mixtures of increasing methanol concentration afforded 8 g (56%) of nearly pure title compound. Pure 3-(3-cyclopentyloxy-4-methoxy-benzylamino)-4-cyanopyrazole, mp 159-160° was obtained by recrystallization from methanol.