Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([CH3:27])[N:18]=1>ClCCl>[Cl:16][C:17]1[N:22]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([CH3:27])[N:18]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)nc(NC2CCCC2)c1[N+](=O)[O-]
Yield: 84.8 %

Procedure:
Cyclopentylamine (5.2 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylpyrimidine (10.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 1 hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (11.2 g) in a yield of 84.8%. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 2H), 4.41 (m, 1H), 2.64 (s, 3H), 2.01-2.15 (m, 2H), 1.61-1.76 (m, 4H), 1.45-1.63 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH:14]([NH2:16])=O>>[O:9]1[C:5]2=[CH:4][C:3]3[C:11](=[O:13])[NH:16][CH:14]=[N:1][C:2]=3[CH:10]=[C:6]2[O:7][CH2:8]1
Reactant: Nc1cc2c(cc1C(=O)O)OCO2
Reactant: NC=O
Product: O=c1[nH]cnc2cc3c(cc12)OCO3
Temperature: 140 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A mixture of 6-amino-benzo[1,3]dioxole-5-carboxylic acid (4.3 g, 23.7 mmol) and formamide (15 mL) was heated to 140° C. for 2 hours, then to 170° C. for 2 hours. After cooling to room temperature, precipitate was collected to give 7H-[1,3]dioxolo[4,5-g]quinazolin-8-one (1.11 g, 27%).
Reaction SMILES: O(Br)[Br:2].[P+5].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[N:13]1[CH:23]=[C:16]2[CH:17]=[N+:18]([O-])[CH:19]=[C:20]([CH3:21])[C:15]2=[N:14]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Br:2][C:17]1[C:16]2=[CH:23][N:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[N:14]=[C:15]2[C:20]([CH3:21])=[CH:19][N:18]=1
Reactant: Cc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Reactant: BrOBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [P+5]
Solvent: ClCCCl
Product: Cc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
Phosphorus(V) oxybromide (921 mg, 3.43 mmol) was slowly added to a suspension of 2-(2,6-dichlorophenyl)-7-methyl-2H-pyrazolo[4,3-c]pyridine-5-oxide (404 mg, 1.37 mmol) in DCE (9.0 mL) at 0° C., under an atmosphere of nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The orange suspension was poured onto saturated aqueous sodium carbonate solution and was stirred for 10 minutes. This was extracted with DCM and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in cyclohexane) to afford the title compound as a white solid (185 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.90-7.89 (m, 1H), 7.84-7.80 (m, 2H), 7.76-7.72 (m, 1H), 2.45 (d, J=1.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:28]=2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (1.72 g), 3-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.50 g), anhydrous iron (III) chloride (0.85 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (200 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent and washed with hexane to give 1.25 g of desired compound.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
tert-Butyl amine (14.6 g, 0.200 mole) was stirred in ethyl acetate (150 mL, purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and filtering through fluted filter paper) and cooled to 5° C. with an ice bath. Benzoyl chloride (14.0 g, 0.100 mole) in purified ethyl acetate (75 mL) was added dropwise at such a rate to maintain the temperature below 10° C. The ice bath was removed upon complete addition of benzoyl chloride solution and the reaction stirred for 4 hours. The reaction mixture was then filtered on a Buchner funnel, the filtrate washed three times with 5% HCl, once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered through fluted filter paper, and the solvent stripped off leaving white crystalline product. The product was dried in a vacuum oven at 24 mm and 45° C. for 14 hours. This procedure produced 15.46 g of crystals of the desired product N-tert-butyl benzamide (CPI1010) (87% yield), mp 133°-135° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.75 ppm (m, 2H; 2,6-aryl H); 7.45 ppm (m, 3H; 3,4,5-aryl H); 5.97 ppm (bs, 1H; N-H); 1.471 ppm (s, 9H, tert-butyl H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23]CCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([Li])[CH2:28][CH2:29]C.[CH3:32]C(C)C(=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:22]([OH:23])([CH3:32])[CH:28]([CH3:29])[CH3:27])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: CC(=O)C(C)C
Reactant: [Li]CCCC
Product: CC(C)C(C)(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 51 intermediate, from (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b), n-butyllithium and 3-methyl-2-butanone.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][CH2:15][C:16](Cl)=[O:17].CCN(C(C)C)C(C)C>>[Cl:14][CH2:15][C:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Yield: 81.1 %

Procedure:
The above-prepared tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol) was treated with chloroacetyl chloride (360 mg, 2.95 mmol) in the presence of DIEA (1.04 g, 8.05 mmol) to give tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (571 mg, 81% yield) after purification by flash chromatography on a silica gel column (hexane/EtOAc=1:2). C11H19ClN2O3; white solid; mp 68-70° C.; 1H NMR (400 MHz, CDCl3) δ 4.06 (2H, s), 3.58 (2H, m), 3.49 (4H, s), 3.44 (2H, m) 1.47 (9H, s); 13C NMR (100 MHz, CDCl3) δ 164.5, 153.7, 80.2, 46.2, 43.3 (2×), 42.1, 40.9, 28.5; ESI-HRMS calcd for C11H20ClN2O3: 285.0982. found: m/z 285.0985 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[N:35]=[CH:36][O:37][C:38]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:38]6[O:37][CH:36]=[N:35][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ncoc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:29]([CH3:40])[C:30](=[O:39])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36]CO)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:2][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:40])=[O:39]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)COCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
13 g of tetrabromo-methane and 10.3 g of triphenyl-phosphine were added at −10° C. to a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride. The reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate—cyclohexane 7-3) to obtain 7.49 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
2-Chloro-4-methylpyridine (1 g, 7.84 mmol) was dissolved in DCM (10 ml), cooled to 0° C., mCPBA (70%, 2.32 g, 9.41 mmol) was added and the mixture was stirred at 0° C. for several hours and allowed to reach room temperature overnight. The mixture was diluted with DCM and washed with saturated Na2S2O3 solution and saturated sodium bicarbonate solution. After drying (sodium sulfate) and concentration under reduced pressure, 1.0 g of a yellow oil was obtained (6.27 mmol, 80%) MS(ESI) m/z=144.0 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:48]>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:32])([C:28]([NH2:48])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@H]2CC[C@@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 68.3 %

Procedure:
Methyl (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-L-prolinate (Intermediate 10, 42 mg, 0.066 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml, 21.0 mmol) and the reaction mixture was stirred for 48 hours at 60° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (Companion system; eluent: from 99:1 Dichloromethane/MeOH to 95:5 Dichloromethane/MeOH; 12 g cartridge) affording the title compound (28 mg, 0.045 mmol, 68.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H) 8.04 (s, 1 H) 7.89-7.99 (m, 1 H) 7.60-7.87 (m, 2 H) 7.44 (s, 1 H) 6.90-7.24 (m, 4 H) 4.39-4.60 (m, 1 H) 3.21-3.32 (m, 1 H) 2.53 (s, 3 H) 2.21 (s, 3 H) 1.45 (s, 6 H) 1.38 (s, 3 H) 1.16-2.37 (m, 4 H), The relative stereochemistry syn was confirmed by dipolar correlations between CH3(8) and CH(5). HPLC: Rt 5.48 min. MS: m/z 625 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(I)chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:19][CH:17]([CH2:18]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:9][CH:8]=1.O>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:18][CH:17]([CH2:19]2)[C:16](=[O:20])[N:15]([CH2:21][CH2:22][CH3:23])[C:14]3=[O:24])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCN1C(=O)C2CC(c3ccc(NS(C)(=O)=O)cc3)(C2)C1=O
Reaction time: 5 h

Procedure:
A solution of 0.31 ml of methanesulphonic acid chloride in 3 ml of methylene chloride is added at room temperature to a solution of 1.03 g of 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione and 24 mg of 4-dimethylaaminopyridine in 10 ml of pyridine. After stirring for 5 hours, 50 ml of water are added, and the mixture is left to stand overnight at 0°-5°. Extraction is carried out with methylene chloride, and the organic phase is washed in succession with water, cold 2N hydrochloric acid, water, semi-saturated bicarbonate solution and water. After drying over magnesium sulphate, the mixture is filtered and concentrated by evaporation, and the residue is recrystallised from methanol. The title compound is obtained in the form of white crystals having a melting point of 159°-160°. Rf (hexane/ethyl acetate 1:1)=0.15.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)=[CH:14][CH:13]=1)[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH:3]([O:2][CH3:1])[C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[CH:17][CH:16]=1
Reactant: COC(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(c1ccc(CO)cc1)c1cccc(C#N)c1
Yield: 76 %

Procedure:
A solution of 3-[methoxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (0.4 g, 0.976 mmol), tetrahydrofuran (10 mL) and a 1M tetrahydrofuran solution of tetrabutylammonium fluoride (1.2 mL, 1.2 mmol) is stirred at room temperature 18 hr. The mixture is diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL) and the combined extracts are concentrated. The residue is purified via silica chromatography eluting with hexanes to 1:1 hexanes:ethyl acetate to give the title compound (188 mg, 76%) as a colorless oil. LCMS M+1 254.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:23])=[CH:7][CH:8]=1
Reactant: CSc1ccc(Nc2nc(C)nc3ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of (4-methylthio-phenyl)-(2-methyl-quinazolin-4-yl)-amine (263 mg, 0.94 mmol) in DMF (4 ml) at 0° C. was added sodium hydride (56.4 mg, 1.40 mmol, 60% oil dispersion) and followed by methyl iodide (0.09 ml, 1.40 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was diluted with EtOAc (15 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1:2 to 1:1) as eluent, yielding 120 mg of title compound (40.7%). 1H NMR (CDCl3): 7.76 (d, J=9.0 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.24-7.19 (m, 2H), 7.10-6.97 (m, 4H), 3.59 (s, 3H), 2.74 (s, 3H), 2.48 (s, 3H)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].C(=O)([O-])O.[Na+].Br[CH2:28][CH2:29][OH:30]>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:28][CH2:29][OH:30]
Reactant: CNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CN(C)CCO)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
A suspension of 10-[(2RS)-1-methylamino-2-propyl]-2-phenothiazinecarbonitrile (3.7 g), sodium hydrogen carbonate (1.6 g) and 2-bromoethanol (0.9 cc) in dimethylformamide (60 c ) is heated under reflux for 6 hours 15 minutes. After cooling, the mixture is concentrated to dryness under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc), washed successively with distilled water (2×50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (4.4 g) is purified by chromatography on a column (height: 35 cm; diameter: 2.6 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (70:30 by volume) (1.25 liters) of ethyl acetate and cyclohexane and collecting 50-cc fractions. The combined fractions 9 to 22 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-methyl-N-(2-hydroxyethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (3.1 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([F:15])[CH:3]=1.[H][H]>C(OCC)(=O)C.[Ir]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:15])=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: [H][H]
Agent: [Ir]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)c(Cl)cc1F
Yield: 98.1 %

Procedure:
To a supension of the title compound of Step A (116 g, 500 mmol) in 500 mL of ethyl acetate was added 3.63 g of iridium (5%) on charcoal. The hydrogenation was performed at 4 bar of hydrogen pressure in an autoclave for 4.5 h at 60° C. The reaction was then filtered and the solvent removed under reduced pressure. Drying of the crystalline product yielded the title compound of Step B (99.4 g, 98%) melting at 142-143° C. 1H NMR (CDCl3) δ 7.9 (d, 1H), 7.3-7.2 (br s, 1H), 7.1-7.0 (s, 2H), 2.2-2.1 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:8]([C:9]#[N:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:25]([C:8]1[C:7]2[C:6]([N:5]3[C:4]4[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=4[C:2](=[O:1])[NH:10][C:9]=13)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:26]
Reactant: N#CC1C(=O)c2ccccc2Nc2ccccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c2ccccc2n2c1[nH]c(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 11-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-10-carbonitrile (500 mg, 2.13 mmol), potassium carbonate (359 mg, 2.6 mmole) and ethyl iodide (0.202 ml, 2.5 mmole) in 4 ml DMF is stirred at r.t. for 18 h.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20]
Reactant: Nc1c(F)cccc1F
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NNc1c(F)cccc1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
To a solution of 2,6-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated hydrochloride solution, sodium nitrite (600 mg, 9.3 mmol) in 2.7 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture were added sodium acetate (1.78 g, 21.7 mmol) and acetylacetone (1 g, 10 mmol). The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give the title compound (400 mg, 21% yield): 1H NMR (400 MHz, CDCl3): δ ppm 2.43 (s, 3H), 2.61 (s, 3H), 6.97-7.03 (m, 2H), 7.05-7.15 (m, 1H), 14.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([P:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19]C2C=CC=CC=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:26]1([P:18](=[O:19])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]([NH:11][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])[CH2:2][CH2:3][CH3:4])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(OP(c2ccccc2)c2ccccc2)cc1
Reactant: NC(=O)Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCCC(NC(=O)Nc1ccc(Cl)cc1)P(=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 0.15 mole each of p-chlorophenylurea, phenyl diphenylphosphinite, and n-butylraldehyde in 150g of toluene is warmed at reflux for 5.5 hr, giving a reaction mixture having a 31P nmr signal only at -36.8 ppm. When the toluene is removed at reduced pressure, the residue solidifies. Recrystallization of a portion from benzene gives a white solid: mp 275°-278° C.; 31P nmr -37.4 ppm; 1H nmr δ9.1 (s, 1, NHC6H4Cl), 6.4-8.1 (m, 15, aryl and CHNH), 5.1 (m, 1, PCH), 0.6-2.0 (m, 7, CH2CH2CH3).