Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.Cl>CO>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CC(C)N1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
1-Isopropyl-4-(5-nitro-pyridin-2-yl)-piperazine (0.9 g, 3.6 mmol) is dissolved in MeOH (20 mL) and tin (II) dichloride dihydrate (4 g, 18 mmol) is added. The mixture is cooled using a water bath and conc. HCl is added (4 mL). The reaction is stirred at room temperature overnight. After removing the methanol, the resultant light yellow solution is basified using conc. NaOH (pH 11) and a white precipitate is formed. The solid is collected by filtration and the water is extracted with diethyl ether (5×). The organic layers are combined, dried over MgSO4, filtered, concentrated under vacuum to afford an orange oil which crystallizes on standing to afford an orange solid (0.68 g, 86%).
Reaction SMILES: [CH:1]1([CH:7]2[NH:12][NH:11][C:10](=[S:13])[N:9]([CH3:14])[C:8]2=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:18]I.CBr>O>[CH:1]1([C:7]2[C:8](=[O:15])[N:9]([CH3:14])[C:10]([S:13][CH3:18])=[N:11][N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: CN1C(=O)C(C2CCCCC2)NNC1=S
Agent: CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nnc(C2CCCCC2)c(=O)n1C

Procedure:
30 ml of 3-benzyl-4-hydroxy-biphenyl polyglycol ether, as an emulsifier, and 5,805 g (25.8 mol) of 6-cyclohexyl-4-methyl-5-oxo-3-thioxo-tetrahydro-1,2,4-(2H,4H)-triazine were added to a solution of 1,033 g of NaOH in 52 liters of water. 3,881 g (27.3 mol) of methyl iodide were added dropwise (or 2,620 g of methyl bromide were passed in) and the mixture was subsequently stirred until the slightly exothermic reaction had ended and the pH value had reached 7-8. After filtering off the product, washing it with water and drying it at 50° C., 5,860 g (95% of theory) of the compound (IIc) of melting point 84°-88° C. were obtained. The crude product was sufficiently pure for further reaction. A sample recrystallized from methanol or petroleum ether melted at 90° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:35])[C:8]([C:30]([O:32]CC)=[O:31])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH:20]C(OC(C)(C)C)=O)[C:17]([F:28])=[CH:16][C:15]=2[F:29])=[CH:5][C:4]=1[O:36][CH3:37]>>[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:35])[C:8]([C:30]([OH:32])=[O:31])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([F:28])=[CH:16][C:15]=2[F:29])=[CH:5][C:4]=1[O:36][CH3:37]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(N)c(OC)cc2c1=O
Agent: Cl
Product: COc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c(C)c1N

Procedure:
12N Hydrochloric acid (2 ml) was added to ethyl 7-amino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6-methoxy-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 3 hours. After the reaction mixture was allowed to cool, solids deposited were collected by filtration, washed successively with water and ethanol and then dried to obtain the title compound (52 mg) as a yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([O:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[C:17]#[N:18].[OH-].[Na+]>CO>[C:17]([C:8]1[CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH:4]([O:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([OH:27])=[O:2])#[N:18]
Reactant: COC(=O)C(COc1ccc(C(F)(F)F)cc1C#N)Oc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cc(C(F)(F)F)ccc1OCC(Oc1ccccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
60 g (0.15 Mol) of the methyl ester obtained in Example 1 are dissolved in 400 ml of methanol and 100 ml of 2 n methanolic sodium hydroxide solution is added thereto. This reaction mixture is stirred for 3 hours at room temperature. The solvent is then evaporated under reduced pressure and the residue dissolved in water. After acidifying with concentrated hydrochloric acid, the acid separates as viscous oil. After extraction with a mixture of ethyl acetate and toluene 1:1, and evaporation of the solvent, there remains 61.5 g of the above acid as a clear viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][C:46]([O:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:43]3[CH:42]=[CH:41][C:40]([CH2:45][C:46]([O:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47])=[CH:39][CH:44]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC(C)COC(=O)Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCC(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, isobutyl 2-(2-bromophenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded isobutyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([NH:20][C:21](=[O:24])[CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH2:13]([NH:20][C:21](=[O:24])[CH2:22][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-benzyl-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.58 (m, 4H), 3.05 (s, 2H), 3.52 (m, 4H), 4.35 (d, J=5 Hz, 2H), 6.63 (t, J=5 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 7.28 (m, 5H), 7.55 (t, J=6 Hz, 1H), 8.12 (t, J=5 Hz, 1H), 8.35 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)([Cl:23])=O>ClC1C=CC=CC=1>[C:1]([Cl:23])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C

Procedure:
170.4 g (0.6 mol) of stearic acid and 890 g of monochlorobenzene are introduced into the reactor and 594 g (6 mol) of phosgene are then added over about 30 minutes, while maintaining the temperature of the reaction medium at a maximum of 25° C. The set pressure is adjusted to 10.5 bar relative. The reaction medium is heated to 120° C. and is maintained at this temperature for 1 hour 30 minutes and is then heated to 150° C. and maintained at this new temperature for 1 hour. The level of residual acid is then about 1.4 mol %, the level of residual anhydride is zero and the level of stearoyl chloride obtained 98.6 mol %. The maximum pressure reached was 9 bar relative.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)(=[O:12])=[O:11])[C:7](=[O:21])[N:6]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([S:10]([N:8]2[CH2:9][CH:5]([C:3]([OH:4])=[O:2])[N:6]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]2=[O:21])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1CN(S(=O)(=O)c2cccc(OC)c2)C(=O)N1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid methyl ester (0.043 g) in tetrahydrofuran (0.5 ml) and methanol (0.5 ml) was added a 1 M aqueous NaOH solution (0.13 ml) at 0° C. The mixture was stirred at 0° C. for 30 min. 1 M HCl (0.15 ml) was added and the organic solvents were evaporated. The colorless precipitate was collected by filtration, washed with water and dried to give (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (0.040 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:39][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:40][C:41]([CH3:43])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:39][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][N:36]([CH:41]([CH3:43])[CH3:40])[CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(C4CCNCC4)cc3-5)cc2Cl)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(n2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
To a solution of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-piperidin-4-yl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (40 mg, 0.07 mmol, 1 eq) in THF (1 mL) was added acetone (8 mg, 0.14 mmol, 2 eq), sodium triacetoxyborohydride (23 mg, 0.11 mmol, 1.5 eq) and trace amount of acetic acid. It was stirred at rt for 16 h. The mixture was purified by preparative HPLC to yield the desired product (15.4 mg, 36%). 1H-NMR (DMSO-d6) δ 8.41 (broad, 1H), 8.32 (d, 1H), 8.01 (d, 1H), 7.74 (d, 1H), 7.5 (dd, 1H), 7.44 (m, 1H), 7.29 (m, 2H), 7.20 (d, 1H), 7.15 (m, 1H), 5.24 (s, 2H), 4.04 (m, 1H), 3.36 (m, 4H), 2.92 (m, 3H), 2.74 (m, 1H), 2.25 (m, 1H), 2.02 (m, 2H), 1.89 (m, 2H), 0.99 (d, 6H). LCMS RT=2.87 min; [M+H]+=603.2.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([CH3:18])=[CH:11][N+:10]=2[O-])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-].[Na+]>CC(O)=O.[Fe]>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([CH3:18])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(-c2cc([N+](=O)[O-])c(C)c[n+]2[O-])n1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(F)c(-c2cc(N)c(C)cn2)n1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-fluoro-6-methylpyridin-2-yl)-5-methyl-4-nitropyridine 1-oxide (2.7 g, 10.2 mmol) in AcOH (54 mL) was added iron (2.3 g, 40.9 mmol) and the mixture was stirred at 100° C. for 30 minutes, cooled to room temperature, adjusted pH to about 8 with NaOH (1N) and extracted with ethyl acetate. The organic layers were concentrated to give 3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-amine. 1HNMR (CDCL3) δ ppm 8.32 (s, 1H), 7.43-7.38 (m, 1H), 7.19-7.15 (m, 2H), 4.19 (s, 2H), 2.65 (s, 3H), 2.19 (s, 3H). MS [M+H] found 218.0.
Reaction SMILES: [Cl-].[C:2]1([O:12][C:13]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][NH2+:23][CH2:22][CH2:21]3)[S:18][CH:19]=2)=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:30]([CH2:37][C:38](O)=[O:39])[N:29]=1>>[F:42][C:27]([F:26])([F:41])[C:28]1[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[N:30]([CH2:37][C:38]([N:23]2[CH2:24][CH2:25][CH:20]([C:17]3[S:18][CH:19]=[C:15]([C:13]([O:12][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:5]=[CH:4][CH:3]=4)=[O:14])[N:16]=3)[CH2:21][CH2:22]2)=[O:39])[N:29]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Oc1cccc2ccccc12)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Product: O=C(Oc1cccc2ccccc12)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1

Procedure:
4-{4-[(1-Naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (X-2, 375 mg) is reacted analogously to Example I-772 with [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (288 mg). This gives, after chromatographic purification, 1-naphthyl 2-(1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (356 mg, 61%).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].S(Cl)(Cl)(=O)=O.[CH:10]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:24]#[N:25]>ClCCCl>[Cl:1][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:22][C:23]1[CH:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][C:14]=1[S:15]2
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(c1)Nc1ccc(Cl)cc1S2
Temperature: 25 °C
Reaction time: 48 h
Yield: 7143.1 %

Procedure:
Aluminium chloride (0.5 g) and sulphuryl chloride (39.7 cc) are added in the course of 4 hours to a solution, heated to 50° C., of 2-phenothiazinecarbonitrile (100 g) in 1,2-dichloroethane (3000 cc). The reaction mixture is brought to reflux for 2 hours, and then stirred for 48 hours at 25° C. The precipitate formed is filtered off, washed with 1,2-dichloroethane (2×200 cc) and then with ethyl ether (200 cc) and dried at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-2-phenothiazinecarbonitrile (69.3 g) in the form of a yellow-green solid, m.p. 235° C.
Reaction SMILES: O=[C:2]([CH2:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[NH2:21]O.Cl>CO>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:20][N:21]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Yield: 95.9 %

Procedure:
A mixture of methyl 2,4-dioxo-4-(4-(trifluoromethoxy)phenyl)butanoate (6.85 g, 23.6 mmol) and NH2OH.HCl (4.92 g, 70.8 mmol) in MeOH (120 mL) was refluxed for 4 h. The volatiles were removed under reduced pressure, the residue was taken up in CHCl3 (200 mL) and washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.50 g, 95.6%), which was used in the next step without further purification. MS (ES+) C12H8F3NO4 requires: 287. found: 288 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12]2[C:4](=[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]1=O.[BH4-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:13][C:12]2[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]3[C:6](=[C:5]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:4]=2[CH:3]=1)[CH2:7][CH2:8][CH2:9]3
Reactant: CC1Cc2c(c(-c3ccccc3)c3c(c2-c2ccccc2)CCC3)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1=Cc2c(c(-c3ccccc3)c3c(c2-c2ccccc2)CCC3)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
17.4 g (51 mmol) of 2-methyl-4,8-diphenyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (4b) and 3.8 g (100 mmol) of sodium borohydride in 100 ml of toluene were placed in a reaction vessel. The solution was heated to 50° C. and 22 ml of methanol was slowly added and the reaction mixture was stirred at 50° C. for 3 hours and then at room temperature overnight. During stirring solids were precipitated. 12 ml of water and 80 ml of 1 N sulfuric acid were added and the mixture was stirred at 35° C. for 30 minutes. 200 ml of methylene chloride was added and organic phase was separated and evaporated and the residue (18.0 g) was taken up in 200 ml of toluene and mixed with 100 mg of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 1 hour on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. This gave 18 g of pale brawn solid. The crude product was purified by column chromatography.
Reaction SMILES: [C:1]1([C:7]2([CH3:14])[CH2:11][O:10][C:9](C)([CH3:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C1C=CC=CC=1)(CC=C)C=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:14][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH2:8][CH:9]=[CH2:12])[CH2:11][OH:10]
Reactant: CC1(C)CC(C)(c2ccccc2)CO1
Agent: C=CCC(C)(C=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=CCC(C)(CO)c1ccccc1
Yield: 96 %

Procedure:
Following the procedure of part (a) of Example I a 400 g sample of 2-methyl-2-phenyl-4-pentenal was reduced with 30 g of lithium aluminum hydride in 1200 ml of anhydrous ether. Usual workup and distillation afforded 386 g (96% yield) of the desired 2-methyl-2-phenyl-4-penten-1-ol (bp 112°-114° C./0.5 mm Hg) with a purity of 97%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[C:3]([O:2][CH3:1])=[O:24]
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Yield: 86.8 %

Procedure:
A solution of 2-(4-benzyloxy-benzylidene)-malonic acid dimethyl ester (14.5 g, 44.5 mmol) in methanol (300 mL) was hydrogenated at 3 atm. in the presence of 5% palladium on charcoal (1.1 g). The solution was filtered, and the filtrate evaporated under a vacuum to give 9.2 g (77%) of 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester: 1H NMR (300 MHz, CDCl3): δ3.15 (d, 2H), 3.65 (t, 1H), 3.70 (s, 6H), 6.70 (d, 2H), 7.05 (d, 2H).
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1.C(N(CC)CC)C.C(#N)C>O>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:1]([O:2][C:3]4[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=4)=[O:12])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC4)nc(N)n2)CC1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
4-Nitrophenyl carbonochloridate (0.14 g, 0.69 mmol) was added to 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (0.30 g, 0.69 mmol) and triethylamine (0.38 mL, 2.8 mmol) in acetonitrile (8.0 mL, 150 mmol) at 0° C. After 1 h., the mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dicloromethane (0-10%) to afford the desired product (0.32 g, 94%). Analytic LCMS (M+H)+: m/z=490.2.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cccnc1
Product: CCOC(=NC(=O)c1cccnc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and nicotinoyl chloride, there is obtained ethyl N-(nicotinoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 371 (5), 42 (26), 194 (100), 106 (38);
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[S:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[CH3:2].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[S:16][C:17]1[CH:18]=[C:19]([NH:20][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Reactant: CCOc1cc2c(Sc3cccc(N)c3)ncnc2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a stirred solution of 3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)aniline (100 mg, 0.305 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (144 mg, 0.458 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (35 mg, 21%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (brs, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.85 (m, 1H), 7.28-7.51 (m, 5H), 6.88 (s, 1H), 4.23 (q, J=7 Hz, 2H), 3.99 (s, 3H), 1.54 (s, 6H), 1.45 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 548 (M+H)+.