Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.C=O.O.[C:42]([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:42])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
Benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (3.2 g, 6.12 mmol) was dissolved in methanol (32 ml), Formaldehyde in water (37%) (0.92 ml, 12.3 mmol) was added and stirred for 45 min before adding sodium cyanoborohydride (0.54 g, 8.57 mmol) portionwise. The reaction was stirred for 2 h at r.t. before adding water (1 ml) and evaporating off the solvent at r.t. The residue was purified by chromatography with 7M ammonia in methanol/DCM to give the desired compound as a yellow oil (mix of diastereomers) (2.05 g, 62%, 82% pure): MS (ESI+) for C28H36N6O5 m/z 537.6 [M+H]+; LC purity 82% (ret. time, 1.60 min); 1H NMR (500 MHz, CDCl3) δH 8.32-8.38 (m, 1H), 7.91-7.97 (m, 1H), 7.32-7.39 (m, 5H), 6.05-6.10 (m, 1H), 5.61 (br. s., 2H), 5.53 (ddd, J=16.5, 6.4, 1.8 Hz, 1H), 5.11 (m, 2H), 4.93-5.00 (m, 1H), 4.32-4.40 (m, 1H), 2.50-2.88 (m, 1H), 2.37-2.49 (m, 2H), 2.21-2.30 (m, 2H), 2.10 (m, 3H), 1.91-2.04 (m, 1H), 1.73-1.79 (m, 2H), 1.64-1.72 (m, 2H), 1.56-1.63 (m, 4H), 1.41 (s, 3H), 1.15 (q, J=9.7 Hz, 1H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.C(Cl)(=O)C>[CH3:22][C:21]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (6) (100 g; 0.365 mole) in acetic anhydride (200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed with little portions of absolute ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate was obtained as a white powder (121.4 g, yield 93%) mp. 176°-177° C. The structure was confirmed by spectroscopic means.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].N1C=CC=CC=1>C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[CH:15]=2)=[O:12])=[CH:2]1
Reactant: Cc1cccc(O)c1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1cccc(OC(=O)C(=O)c2c[nH]c3ccccc23)c1
Reaction time: 0.5 h

Procedure:
3-Indolylglyoxylyl chloride (104 g. ) was stirred in diethyl ether (500 ml.) and treated with m-cresol (108 g.) followed by pyridine (79 g.). After stirring for 30 minutes the solid product was collected by filtration, washed with water then with acetonitrile and dried to give m-cresyl 3-indolylglyoxylate as a yellow powder, m.p. 194°-197°. Yield 119 g. (85.5%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[CH:25](O)[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:25]([C:24]2[S:23][C:22]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)=[N:21][C:20]=2[CH3:19])[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([S:10]([CH2:12][C:13]([OH:15])=[O:14])=[O:11])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[CH:24]1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1>[CH3:24][O:14][C:13](=[O:15])[CH2:12][S:10]([CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([F:1])[CH:7]=1)[CH3:9])=[O:11]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)S(=O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 1.53 gm (5 millimols) of [1-(2-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 161°-163° C, in 15 ml of benzene was admixed with 0.24 gm (7.5 millimols) of methanol, and then a solution of 1.25 gm (6 millimols) of dicyclohexyl-carbodiimide in 5 ml of benzene was added. After stirring for one hour, the precipitated dicyclohexylurea was suction-filtered off, the filtrate was evaporated, and the residue was purified by chromatography on 300 gm of silicagel with cyclohexane/ethyl acetate = 1/4. Yield: 1.4 gm (87.6% of theory); oil, Rf -value: 0.5 on carrier 1 with cyclohexane/ethyl acetate = 1/4.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[CH3:11][NH2:12]>>[CH3:11][NH:12][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CN
Reactant: COC(=O)CCC[N+](=O)[O-]
Product: CNC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
To a sealed reaction vessel was added methyl 4-nitrobutyrate (1.00 g, 6.80 mmol) and methylamine (2.0 M methylamine in MeOH, 50.0 mL, 100 mmol). The resulting yellow solution was stirred at room temperature for 20 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, load: CH2Cl2, elution with EtOAc:Hexanes, 1:1) to give the title product (0.97 g, 98%) as a white solid. 1H NMR (CDCl3): 5.84 (br s, NH, 1H), 4.54-4.48 (m, 2H), 2.82 (d, J=4.7 Hz, 3H), 2.36-2.32 (m, 4H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].[C:8]1([O:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][NH:5][C:15](=[O:16])[O:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCl)Oc1ccccc1

Procedure:
1500 ml of an aqueous solution of 696 g (6 moles) of 2-chloroethylamine hydrochloride and 1500 g of sodium hydroxide solution containing 480 g (12 moles) of sodium hydroxide are simultaneously added dropwise to a solution of 936 (6 moles) of phenylchloroformate in 3 l of methylene chloride at 15° to 20° C. The mixture is worked up as described under Example 7 to give 1161 g of O-phenyl N-(2-chloroethyl)-carbamate of melting point 65° to 67° C.; purity according to gas chromatography: 95.7% (93% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[NH2:13][OH:14]>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]1
Reactant: O=C1CCN(CCCO)CC1
Reactant: NO
Agent: Cl
Product: OCCCN1CCC(=NO)CC1

Procedure:
1-(3-Hydroxypropyl)-4-piperidone oxime is prepared from 1-(3-hydroxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:12]=[C:13]([C:16]([Cl:19])=[CH:17][N:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[Cl:19][C:16]1[C:13]([C:14]#[N:15])=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: N#Cc1cc(-c2ccccc2)ncc1Cl

Procedure:
Tetralds(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol) was added to a stirred solution of phenylboronic acid (423 mg, 3.47 mmol), 2,5-dichloro-isonicotinonitrile (550 mg, 2.89 mmol) and sodium carbonate (3.5 mL of 2M aqueous solution) in dimethoxyethane (7 mL) and ethanol (3.5 mL). The resulting suspension was stirred at reflux for 3 hours, concentrated in vacuo and water (25 mL) added. The aqueous solution was extracted with ethyl acetate (×3) and the combined organic extracts were washed with brine, dried and concentrated. Purification by column chromatography using 2% v/v ethyl acetate in hexane as eluent afforded the title compound as a solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[N:30]=[C:31]=[O:32]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:31]([NH:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:32])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccs1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-thienyl isocyanate (0.153 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 257 mg (85.1%) of the desired product as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24](O)=[O:25])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:25]=[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([S:20][CH2:19][C:18]2[CH:30]=[CH:31][CH:32]=[C:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][C:9]=3[C:33]3[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:49])[F:50])[CH:43]=4)[CH:36]=[CH:35][N:34]=3)[CH:17]=2)[CH:22]=1)[NH:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66]
Reactant: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reaction time: 1 h

Procedure:
A solution of 25 mg of 3-(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)-benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzylthio)benzoic acid 8.1, 12 mg of tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate, and 17.8 mg of diisopropylethylamine in 1 mL of DMF was treated with 15 mg of HATU. The mixture was stirred for 1 h and then the product was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:12]2[C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[O:15][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:6])[CH:2]=[CH2:3].[CH3:31][NH:32][CH3:33].O>ClCCl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([O:20][C:8]2[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[C:12]3[C:13]([C:17](=[O:18])[N:32]([CH3:33])[CH3:31])=[C:14]([CH3:16])[O:15][C:11]3=[CH:10][CH:9]=2)[N:22]=1
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)Cl)c12
Reactant: CNC
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=O)N(C)C)c12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
3.0 g of 4-allyloxycarbonyl-5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-methylbenzofuran-3-carbonyl chloride was dissolved in 13 ml of dichloromethane, and 1.5 g of a 50% dimethylamine aqueous solution was dropwise added thereto under cooling with ice. After stirring for 30 minutes, the reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The oily substance obtained by concentration under reduced pressure, was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.84 g (yield: 60%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N)cc(Cl)c1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(3-amino-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.29 mmol) and N,N-diisopropylethylamine (75 mg, 0.58 mmol) in dichloro methane (4 mL) was added benzoyl chloride (49 mg, 0.35 mmol) slowly via syringe under nitrogen. The mixture was stirred at room temperature for 1 h. Solid precipitated and was collected by filtration to afford 65 mg of methyl 2-(3-benzamido-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 50%; MS (ESI+APCI) M+1-water=431.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH:18][CH3:35])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting glycine methyl amide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.81 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.99 (s, 2H), 2.74 (s, 3H), 2.21 (s, 3H). ESHRMS m/z 477.1141 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29]>O>[Cl:29][CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCCCl)cc2[nH]1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
After 7-hydroxy-1H-quinolin-2-one (10 g) and DMF (50 ml) were heated to approximately 30° C., an aqueous potassium carbonate solution (potassium carbonate: 8.6 g, water: 10 ml) was added. After the mixture was stirred at 30 to 40° C. for about 15 minutes, 1-bromo-4-chlorobutane (14.3 ml) was added and stirred at approximately 40° C. for 5 hours. Water (100 ml) was added dropwise over a period of 30 minutes or more while the temperature was maintained at 30° C. or more. After the mixture was stirred at approximately 30° C. for 30 minutes, stirring was continued at 10° C. or less for 1 hour, after which the precipitated crystals were collected by filtration. After methanol (100 ml) was added to the precipitated crystals, the mixture was stirred under reflux to ensure dissolution. This solution was cooled and stirred at 30 to 40° C. for 30 minutes and then at 5° C. or less for about 1 hour, after which the precipitated crystals were collected by filtration. The crystals were dried at 60° C. to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[CH:12]1([CH2:15][N:16]2[C:24]3[N:23]=[C:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=4)[NH:21][C:20]=3[C:19](=[O:34])[N:18]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[C:17]2=[O:43])[CH2:14][CH2:13]1>CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][C:22]3[NH:21][C:20]4[C:19](=[O:34])[N:18]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[F:42])[C:17](=[O:43])[N:16]([CH2:15][CH:12]5[CH2:14][CH2:13]5)[C:24]=4[N:23]=3)=[CH:27][CH:28]=2)[CH3:33])=[O:9])=[CH:5][N:4]=1)#[N:2]
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)c1ccc(C#N)nc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 6-cyanonicotinic acid (Lancaster) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.66 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 0.68 equivalents of 4-dimethylaminopyridine was added as the final reagent to the reaction mixture. The product was purified by chromatography using silica gel eluted with 5:95 hexanes/ethyl acetate followed by crystallization from acetonitrile. MS, m/z(M+)=564.2161.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH2:1][NH:22][CH3:21])[CH:4]=2)[CH:14]=1
Reactant: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(C)ccc2C#N)c1
Yield: 19.2 %

Procedure:
2-(3-Formyl-phenoxy)-4-methyl-benzonitrile (0.26 g, 1.1 mmol), methylamine (2M in methanol, 2.5 mL, 5.0 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-methyl-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (78 mg, 20%) as a tan solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:24][OH:25])=[CH:9][CH:8]=1)[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:26]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH:24]=[O:25])=[CH:9][CH:8]=1)[CH3:27]
Reactant: CCN(CC)CCNc1ccc(CO)c2sc3ccc(OC)cc3c(=O)c12
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCNc1ccc(C=O)c2sc3ccc(OC)cc3c(=O)c12
Yield: 79.7 %

Procedure:
A solution of 1-[[2-(diethylamino)ethyl]amino]-4-(hydroxymethyl)-7-methoxythioxanthen-9-one (8.8 g, 0.023 mol) in toluene (268 mL) was heated to 60° C. under nitrogen and then MnO2 (13.2 g) was added. The mixture was heated overnight, filtered, and the filtrate was concentrated in vacuo to afford 7.05 g (81%) of 1-[[2 -(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-carboxaldehyde (Formula II: R1 =R2 =Et; R8 =7-OCH3 ; n=2).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].Br[CH2:13][C:14]#[N:15]>O1CCOCC1>[C:14]([CH2:13][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])#[N:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: N#CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#CCSC[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
A 360 mL aqueous solution of commercially available (Aldrich) L-cysteine hydrochloride monohydrate (60.0 g, 341.7 mmole) and sodium hydroxide (27.33 g, 683.4 mmole), at room temperature, is treated with a solution of bromoacetonitrile (44.5 g, 370.6 mmole) in 130 mL of dioxane over 30 minutes. The reaction is stirred for 18 hours, during which time a thick precipitate will form. The solid is filtered off, washed with diethyl ether (100 mL) and dried under high vacuum at 40° C. to give the title compound.