Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:20])[CH:8]([CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][NH2:22]>C1(C)C=CC=CC=1>[C:1]1([C:7](=[O:20])[CH:8]([CH3:19])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([NH:22][CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: CC(Cc1ccc(N=C=O)cc1)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(CC(C)C(=O)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A solution of 13.25 g of 4-(3-phenyl-2-methyl-n-propan-3-onyl)-phenyl isocyanate in 20 ml of toluene was added dropwise to a solution of 3 g of methylamine in 100 ml of toluene, at from 20° to 25° C. The mixture was stirred for 6 hours at 40° C., after which the toluene was stripped off under reduced pressure. 13.3 g (90% of theory) of a slightly yellow oil were obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Cl-:9].[Al+3].[Cl-].[Cl-].ClCl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: [Cl-]
Reactant: O=Cc1ccc(Cl)s1
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(Cl)s1

Procedure:
To a mechanically stirred solution of 31.8 grams (0.217 mole) 5-chloro-2thiophenecarboxaldehyde in 150 ml of methylene chloride, 65 grams (0.487 mole) of anhydrous aluminum chloride was added in small portions. The mixture exothermed and turned purple. To this mixture 20.6 grams (0.29 mole) of chlorine in 250 ml of carbon tetrachloride was added dropwise. The reaction mass was refluxed for about 15 hours, and an additional 15 grams (0.21 mole) of chlorine in 200 ml of carbon tetrachloride was added. The mixture was refluxed for an additional 7 hours. The reaction was quenched by pouring over one liter of ice water. The aqueous layer was extracted with chloroform. The chloroform solution was washed with water and sodium bicarbonate. After drying with anhydrous sodium sulfate and concentration under vacuum, a yellow-brown oil was obtained. The crude 4,5-dichloro-2-thiophenecarboxaldehyde crystallized on standing and was recrystallized from hexane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCN(CCN1CCCCC1)C3
Yield: 80.2 %

Procedure:
In the same way as described in example 3, 4.2g of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 4.05g of N-chloroethylpiperidine hydrochloride and 4.4g of triethylamine gave 5.0g of crude base. Crystallization from actronitrile gave analytical material, m.p. 142°-5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[C:14]3([CH3:22])[N:18]([CH2:19][CH2:20][C:8]2=1)[C:17](=[O:21])[CH2:16][CH2:15]3.[CH3:23]I>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:23])[C:9]1[C:14]3([CH3:22])[N:18]([CH2:19][CH2:20][C:8]2=1)[C:17](=[O:21])[CH2:16][CH2:15]3
Reactant: CI
Reactant: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)CCC31C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2C)C2(C)CCC(=O)N2CC1

Procedure:
Sodium hydride (1.06 g. of about a 50% dispersion in mineral oil) is stirred under nitrogen with 5.41 g. 1,2,5,6,11,11b-hexahydro-8-methoxy-11b-methyl-3H-indolizino[8,7-b]indol-3-one [S. Wawzonek and J. D. Nordstrom, J. Med. Chem., 8, 265 (1965)] in 100 ml. dry dimethylformamide for one-half hour. The brown solution is cooled in an ice-water bath as 3.41 g. methyl iodide (1.50 ml.) is added. After one-half hour of cooling, the reaction mass is allowed to stand at about 25°C. for sixteen hours. The dimethylformamide is removed in vacuo and the residue is twice triturated with 50 ml. hexane, dissolved in chloroform and washed with water. After drying (sodium sulfate), the solvent is removed and the solid is twice recrystallized from ethyl acetate, thus affording 4.30 g. of the title compound, m.p. 164°-7°C.; λmaxCHCl3 6.02, 6.19 μ; NMR (CDCl3); δ 1.60 (singlet, 11b-methyl), 3.68 (singlet, 11-methyl), 3.83 (singlet, methoxyl) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J=7.6 Hz, 1 H), 7.91 (s, 1 H), 7.85 (d, J=7.6 Hz, 1 H), 7.74-7.67 (m, 2 H), 7.59-7.56 (m, 2 H), 6.09 (s, 1 H), 5.29 (s, 2 H), 4.51 (s, 2 H), 3.83 (t, J=5.6 Hz, 2 H), 3.74-3.72 (m, 2 H), 3.62 (t, J=5.6 Hz, 2 H), 2.47 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25](OC)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>C1COCC1>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([CH2:25][OH:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1cccc2cc(Oc3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(CO)cccc4c3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g (5.1 mmol) of methyl 6-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthoate (prepared in Example 1(a)) and 60 ml of THF were introduced into a three-necked flask. 300 mg (7.7 mmol) of lithium aluminum hydride were introduced under a stream of nitrogen, and the mixture was stirred at room temperature for two hours. Sodium sulfate hydrate was added, and the mixture was stirred until the excess hydride had hydrolysed. The salt was filtered off and the filtrate was evaporated. 1.91 g (99%) of the expected alcohol was recovered, having a melting point of 131°-3° C.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10]3[CH:20]=[CH:21][CH:22]=[C:23]([CH2:24][CH3:25])[C:9]=3[NH:8][C:7]2=[O:26])C(=O)C2=CC=CC=C12.O.NN>CO.O1CCCC1.C(OCC)(=O)C>[NH2:5][CH:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]2[CH:20]=[CH:21][CH:22]=[C:23]([CH2:24][CH3:25])[C:9]=2[NH:8][C:7]1=[O:26]
Reactant: CCc1cccc2c1NC(=O)C(N1C(=O)c3ccccc3C1=O)N=C2c1ccccc1F
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cccc2c1NC(=O)C(N)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A mixture of (3RS)-3-phthalimido-9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (6.0 g) and hydrazine hydrate (1.05 g) in a mixture of methanol and tetrahydrofuran (1:1, 60 ml) was refluxed with stirring for 3 hours. The reaction mixture was allowed to cool to room temperature, and the resultant precipitates were filtered off. The filtrate and the washings were combined and evaporated in vacuo to give a residue, which was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water and brine successively. The solvent was dried over sodium sulfate and evaporated in vacuo to afford a pale yellow powder, which was washed with diisopropyl ether and collected by filtration to give (3RS)-3-amino-9-ethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.37 g, 81.0%).
Reaction SMILES: CN(C)C=O.[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[NH:11]([CH2:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[C:12]([NH2:14])=[NH:13].[CH3:24][S:25]([O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=2)[CH:30]=1)(=[O:27])=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[NH:11]([CH2:15][C:16]1[O:20][C:19]([C:21]([O:23][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=3)[CH:30]=2)=[O:22])=[CH:18][CH:17]=1)[C:12]([NH2:14])=[NH:13]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)NCc1ccc(C(=O)O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Reaction time: 0.5 h

Procedure:
##STR50## In a solvent mixture of 8 ml of dry N,N-dimethylformamide (DMF) and dry pyridine, were dissolved 2.0 g of 5-guanidinomethyl-furan-2-carboxylic acid methanesulfonate and 1.8 g of 6-amidino-2-naphthol methanesulfonate. To the resulting solution, while being cooled in ice, were added 1.8 g of DCC and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 30 minutes with cooling in ice and then overnight at 30° C. The insolubles were removed by filtration and ethyl ether was added to the filtrate. The supernatant was removed by decantation. The residue was dissolved in a small amount of methanol and the methanol solution was added dropwise to ethyl ether. After precipitation the supernatant was removed by decantation. These procedures were repeated twice. Finally, the precipitate was collected by filtration and dried to obtain 1.2 g of a pale yellow substance of 6-amidino-2-naphthyl 5-guanidinomethyl-furan-2-carboxylate dimethanesulfonate.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([NH2:20])=O)=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O>>[C:18]([C:15]1[CH:14]=[N:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=2)=[N:17][CH:16]=1)#[N:20]
Reactant: CCCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
9.1 G. of 2-(p-n-pentylphenyl)-5-pyrimidinecarboxamide are reacted with 100 ml. of phosphorus oxychloride with the exclusion of moisture, worked up and purified in a manner analogous to that described in Example 7. The pure, colorless 5-cyano-2-(4-n-pentylphenyl)-pyrimidine has a melting point of 96.0°-96.2° C. and a clearing point of 109.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH:9]([NH:24]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:24][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:22])([F:23])[F:21])(=[O:19])=[O:18])[CH:12]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:32]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}-ethylcarbamate (620 mg, 1.30 mmol) was added trifluoroacetic acid (5 ml), and mixture was stirred at 0° C. for 10 min. After the reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate (30 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (0.52 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][N:13]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)nc1
Temperature: 90 °C
Yield: 42.2 %

Procedure:
To a round-bottom flask was added 2-fluoro phenylboronic acid (271 mg, 1.94 mmol), palladium tetrakis(triphenylphosphine) (22.4 mg, 0.0194 mmol)) and tert-butyl 6-bromonicotinate (500 mg, 1.94 mmol) and the mixture was evacuated 3× with N2. The solids were dissolved in 25 mL of DMF, followed by addition of 2.9 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. The mixture was cooled to room temperature and then poured into a seperatory funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO4, filtered and concentrated to afford an orange oil. The crude mixture was purified by chromatography (silica, 10% EtOAc:Heptane) to afford the desired product (224 mg, 40%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.16 (1H, d, J=2.2 Hz), 8.34 (1H, dd, J=8.3, 2.3 Hz), 7.90-8.05 (2H, m), 7.50-7.62 (1H, m), 7.33-7.44 (2H, m) 1.59 (9 H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:29])[C:11]([N:14]1[C:19](=[O:20])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([CH2:27][OH:28])[O:16][CH2:15]1)([CH3:13])[CH3:12].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:29])[C:11]([N:14]1[C:19](=[O:20])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([CH:27]=[O:28])[O:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)(C(=O)Nc1cc(F)ccc1F)N1COC(CO)=C(c2ccccc2)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1cc(F)ccc1F)N1COC(C=O)=C(c2ccccc2)C1=O
Yield: 83.4 %

Procedure:
A solution of N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.0 g) in dichloromethane was added to a stirred mixture of pyridinium chlorochromate (0.8 g) and powdered 4A molecular sieve (1.6 g) in dichloromethene. After 2 hours the mixture was purified directly by dry column chromatography on silica gel, eluting with dichloromethane to give N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-formyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 129, 0.83 g) as a pale green solid, m.p. 76-77.5° C.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:8][C:2]([F:9])([CH:10]([OH:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=CCCc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Product: CCOC(=O)C(F)(F)C(O)CCc1ccccc1

Procedure:
According to the procedure of Thaisrivongs et. al. (J. Med. Chem., 1986, 29, 2080), ethyl bromodifluoroacetate was condensed with hydrocinnamaldehyde to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].CO[C:20](OC)(OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: CC(=O)O
Product: Cc1ccsc1C1Cc2ccccc2N=C(c2ccccc2)N1C
Yield: 91.4 %

Procedure:
A stirred solution of 2.19 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 9.88 g of trimethyl orthobenzoate was treated rapidly with 2.4 ml of glacial acetic acid, and heated under reflux for 8 hours. The solution was concentrated at 75° C. on a rotary evaporator (vacuum pump) to a syrup. The syrup was then partioned between 10% hydrochloric acid solution (50 ml) and ether. The aqueous phase was extracted again with ether, basified with 10% sodium hydroxide solution (60 ml) and extracted with dichloromethane (2×100 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, sample applied in dichloromethane, 2% triethylamine in methanol as the eluent). Concentration of the appropriate fractions yielded 2.70 g of 4,5-dihydro-3-methyl-4-(3-methyl-2-thienyl)-2-phenyl-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1N.C(C(CC)(CC)C([O-])([O-])[O-])C.[C:31](#[N:33])[CH3:32]>>[ClH:1].[CH3:32][C:31]1[N:4]([CH3:3])[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:33]=1
Reactant: CNC(Cc1ccccc1N)c1ccccc1
Reactant: CC#N
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cl
Product: CC1=Nc2ccccc2C=C(c2ccccc2)N1C
Temperature: 70 °C
Yield: 83 %

Procedure:
A heterogeneous mixture of N-methyl-2-amino-α-phenylphenethylamine dihydrochloride (150 g, 0.5 mol) in acetonitrile (500 ml) was treated with triethylorthoacetate (202 ml, 1.1 mol) and heated to 70° C. for 2 hours with stirring under a dry nitrogen atmosphere. The reaction mixture was filtered, concentrated in vacuo, and the residual solid recrystallized from 2-propanol at -10° C. to give 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine hydrochloride (118 g, 0.413 mol) in 83% yield. The product had a melting point of 239.5°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16].[H][H]>C(O)C.O=[Pt]=O>[CH3:16][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=1)[NH2:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1cc(N)ccc1OCc1cccc(F)c1
Yield: 100.3 %

Procedure:
A mixture of 1-[(3-fluorobenzyl)oxy]-2-methyl-4-nitrobenzene (3.2 g, 12.2 mmol) and PtO2 (320 mg) in ethanol (250 ml) was stirred under an atmosphere of hydrogen (1.2 bar) until completion of the reaction (the reaction being complete when 3 mole equivalents of hydrogen have been reacted). The mixture was then filtered over celite and the solvent evaporated to give 3-methyl-4-[(3-fluorobenzyl)oxy]aniline as a yellow oil (2.83 g, 100%);
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([O:6][C:7](=[O:34])[C@@H:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][N:9]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH3:5]>CS(C)=O.[Cl-].[Na+].O.O>[CH2:4]([O:6][C:7](=[O:34])[C@@H:8]1[CH2:12][C@@H:11]([C:1]#[N:2])[CH2:10][N:9]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH3:5]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Finely powdered NaCN (0.49 g, 10 mmol) was suspended in a stirring mixture of 5 (3.0 g, 6.7 mmol) in DMSO (7 mL). The reaction flask was heated in an oil bath at 80° C. for 3 h, during which time the NaCN had completely dissolved and the reaction mixture had turned a deep orange color. After cooling to room temperature, the reaction was diluted with brine (3 mL) and H2O (4 mL), then extracted with Et2O (5×11 mL). The combined organic layers were dried (MgSO4) and concentrated to a yellow syrup which was purified by flash chromatography (silica gel, using 1:1 ethyl ether-petroleum ether) yielding 1.42 g (70%) of the N-CBZ-trans-4-cyano-L-proline ethyl ester as a colorless viscous oil: TLC Rf 0.22 (4:2 ethyl ether-petroleum ether); [α]24D -39° (c 1.05, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.38-7.27 (m, 5 H), 5.21-5.03 (m 2 H, PhCH2), 4.55-4.45 (m, 1 H, H-2), 4.21 (q, J=7.1 Hz, 1 H, CO2CH2CH3, one of two rotamers), 4.09-3.94 (m, 2 H, CO2CH2CH3 and H-5), 3.80-3.67 (m, 1 H, H-5), 3.35-3.21 (m, 1 H, H-4), 2.62-2.34 (m, 2 H, H-3), 1.28+1.13 (t, J=7.1 Hz, CO2CH2CH3, two rotamers); IR (CHCl3) 2995, 2900, 2250, 1740, 1705, 1420, 1355, 1195, 1125, 1020 cm-1 ; LRMS (CI, 70 eV, isobutane) m/e 303 (MH+, 66), 259 (44), 91 (100); HRMS (EI, 21 eV) m/e 302.1264 (302.1266 calcd for C16H18N2O4).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[C:27]([O:32]C)=[N:28][CH:29]=[CH:30][CH:31]=3)[N:19]=2)[CH3:16])=[N:13][CH:14]=1>C(#N)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=3)[N:19]=2)[CH3:16])=[N:13][CH:14]=1
Reactant: COc1ncccc1Nc1ncc(C)c(N[C@@H](C)c2ccc(F)cn2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(Nc2ccc[nH]c2=O)nc1N[C@@H](C)c1ccc(F)cn1
Temperature: 80 °C
Yield: 101.1 %

Procedure:
Trimethylsilyl chloride (0.20 mL, 1.58 mmol) and sodium iodide (235 mg, 1.57 mmol) were added to a stirred solution of (S)—N4-(1-(5-fluoropyridin-2-yl)ethyl)-N2-(2-methoxypyridin-3-yl)-5-methylpyrimidine-2,4-diamine (Preparation 2b, 185 mg, 0.52 mmol) in acetonitrile (5 mL) and the mixture was stirred and heated at 80° C. for 45 min. After cooling to ambient temperature, the mixture was concentrated and treated with saturated aqueous sodium thiosulphate solution. After stirring for 10 minutes, the precipitate was filtered, washed with water and diethyl ether and dried to give the title compound (179 mg, 100%) as a solid.
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[Br-:18].[Br-].[Br-].P>C1(C)C=CC=CC=1>[Br:18][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: [Br-]
Reactant: CC(O)c1ccc(-c2ccccc2C#N)cc1
Agent: P
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution (15 mL) of 4′-(1-hydroxyethyl)biphenyl-2-carbonitrile (3.52 g) in toluene was added phosphine tribromide (5.00 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate 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 pale-yellow oil (3.93 g, 87%).