Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 32.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added N-methyl piperazine (0.122 mL, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (72 mg, 32%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.25 (m, 2H), 3.88 (s, 3H), 2.50-2.25 (m, 10H), 2.15 (s, 3H), 1.95 (m, 2H), 1.23 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][N:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1)#[N:2].[CH2:21]([Mg]Br)[CH3:22].FB(F)F.[OH-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:2][C:1]1([C@@H:3]2[CH2:7][CH2:6][N:5]([CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:4]2)[CH2:22][CH2:21]1
Reactant: CC[Mg]Br
Reactant: N#C[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Product: NC1([C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)CC1
Reaction time: 18 h
Yield: 48 %

Procedure:
(3R)-3-Cyano-1-(1,1-diphenylmethyl)pyrrolidine (0.70 g) was dissolved in tetrahydrofuran under an argon atmosphere. Titanium(IV) tetraisopropoxide (0.86 mL) and ethylmagnesium bromide (1.78 mL, 3 mol/L ether solution) were added to the solution at room temperature. After 05 h, trifluoroboron.diethyl ether complex (0.67 mL) was added dropwise to the mixture, and the resultant mixture was stirred at room temperature. After 18 h, 2 mol/L aqueous sodium hydroxide (30 mL) was added to the reaction mixture, and the resultant mixture was stirred for 0.25 hours. The product that precipitated was collected through filtration and then extracted. The formed aqueous layer was again extracted with ethyl acetate, and the organic layers were combined together, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystals. The residue was subjected to silica gel chromatography, to thereby give the target compound (0.374 g, yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[C:17]([NH:19][C:20](=[O:29])[CH2:21][C:22](O)(O)[C:23]([F:26])([F:25])[F:24])[C:16]([F:30])=[CH:15][C:14]=1[Cl:31].O1CCCC1.C(O)(=O)C.[O-:42][C:43]#[N:44].[K+]>O>[Cl:31][C:14]1[CH:15]=[C:16]([F:30])[C:17]([N:19]2[C:20](=[O:29])[CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[NH:44][C:43]2=[O:42])=[CH:18][C:13]=1[O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([O:2][CH3:1])=[O:32]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(=O)CC(O)(O)C(F)(F)F)c(F)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a solution of 1.0 g of crude methyl[2-(5-{3,3-dihydroxy-4,4,4-trifluorobutyryl}amino-2-chloro-4-fluorophenoxy)phenoxy]acetate and 3 ml of tetrahydrofuran were added 4 ml of acetic acid and 0.87 g of potassium cyanate, and the mixture was stirred at room temperature for 6 hours and then heated at reflux at 120° C. for 2 hours. After cooling, 30 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of methyl [2-{2-chloro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-4-fluorophenoxy}phenoxy]acetate.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH2:11][C:12](OC)=[O:13])=O)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]2[NH:3][N:2]=[C:12]([OH:13])[CH:11]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2ccc(Cl)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Hydrazine monohydrate (0.80 g, 20 mmol) was added to a solution of methyl 4-chlorobenzoylacetate (3.19 g, 15.0 mmol) in ethanol (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 days. After completion of the reaction, a precipitated solid was filtered and washed with diethyl ether, to give a white solid of 5-(4-chlorophenyl)-3-hydroxypyrazole (2.02 g, yield: 55.1%). mp: 240-241° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 5.92 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 9.30-10.60 (br s, 1H), 11.60-12.70 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[OH:5][CH2:4][CH:3]([NH:2][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH2Cl2 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2Cl2. The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2Cl2 and the solution washed with H2O, 1N NaHCO3, 2N citric acid, brine and dried (with Na2SO4). The solvent was removed under vacuum to give a solid. The aqueous 2N citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2Cl2. The solvent was removed to give a solid. The two crops of solid were combined, washed with H2O and then hexane. The solid was dried at 80° C. to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]propionate as white crystals, mp. 137-139° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([OH:16])=[O:15])[C:3]1=[O:17].[CH2:18]([CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].[ClH:37]>C(O)(=O)C.CO>[ClH:37].[C:14]([CH2:13][N:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8][CH:2]([NH:1][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]1=[O:17])([OH:16])=[O:15]
Reactant: NC1CCc2ccccc2N(CC(=O)O)C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (10.0 g) and ethyl benzylpyruvate (26.4 g) in acetic acid (75 ml) and methanol (75 ml) was stirred at room temperature under nitrogen for 1 hour. Sodium cyanoborohydride (3.4 g) in methanol (25 ml) was added dropwise over 4 hours. The reaction mixture was stirred at room temperature for 24 hours. Concentrated hydrochloric acid (4 ml) was added dropwise, and the mixture stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. The residue was partitioned between 150 ml of water and 50 ml of ether and adjusted to pH 9 with 40% sodium hydroxide. The layers were separated and the ether layer was discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with 3×75 ml of ethyl acetate. The organic portions were dried (magnesium sulfate) and concentrated to dryness. Hydrogen chloride gas was bubbled into a solution of the crude product in 310 ml of methylene chloride for 5 minutes. The solution was evaporated and the residue was stirred in 225 ml of ether. The product was collected by filtration to give a 70:30 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from ethanol/ethyl acetate (1:3) to give 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride melting at 246°-8° (dec.) and corresponding to the racemic isomer B.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:35].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2](=[O:35])[NH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:31][CH:30]=1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (400 mg, 0.88 mmol.) was dissolved in 3.5 M H2SO4 (10 mL), and 2 M NaNO2 (6 mL) was added at 0° C. The reaction mixture was stirred at rt for 20 min. The reaction mixture was then treated with aqueous NaOH solution (8%), and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (350 mg, 0.78 mmol). 1H NMR (CDCl3): δ=1.10-1.25 (m, 8H), 1.37 (m, 1H), 1.42-1.55 (m, 2H), 1.78-1.93 (m, 2H), 2.10-2.38 (m, 2H), 2.87 (m, 2H), 3.52-3.58 (m, 1H), 3.31-3.97 (m, 1H), 4.12-4.19 (m, 1H), 5.53-5.63 (m, 1H), 6.85-7.15 (m, 3H), 7.35-7.55 (m, 1H), 7.75-7.89 (m, 1H), 8.10-8.12 (m, 1H).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH3:6])#[N:2].[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][C:4](=[N:3][C:1]#[N:2])[NH:5][CH3:6])=[CH:16][N:15]=1
Reactant: CNC(=NC#N)SC
Reactant: NCc1ccc(Cl)nc1
Product: CNC(=NC#N)NCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 3-cyano-1-methyl-2-methylisothiourea (0.65 g) and 5-aminomethyl-2-chloropyridine (0.72 g) was stirred under heating at 100° C. for three hours. Then, the reaction product was cooled to room temperature and then purified on silica gel column chromatography (eluent: ethanol/chloroform) to obtain the desired 3-(2-chloro-5-pyridylmethyl)-1-methyl-2-cyanoguanidine (0.5 g) having a melting point in the range of from 193° to 197° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH3:19].O=[C:21]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:22][C:23](OCC)=[O:24].Cl.O1CCOCC1>C(O)C>[CH3:19][C:10]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:3]1[C:4]([OH:7])=[N:5][N:6]2[C:23]([OH:24])=[CH:22][C:21]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:1][C:2]=12
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: Cc1c(Cc2c(N)[nH][nH]c2=O)cccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(Cc2c(O)nn3c(O)cc(C4CCOCC4)nc23)cccc1C(F)(F)F

Procedure:
To a suspension of 5-amino-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (136 mg, 0.5 mmol) in ethanol (1 mL) were added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.5 mmol) and 4 M HCl solution in dioxane (25 uL, 0.1 mmol). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes. Reaction was cooled down. The precipitate was collected by filtration. It was washed with acetic acid (1 mL), then methanol (1 mL) and dried. The titled compound was obtained. (52 mg, 25%); LC/MS: MS (ES+) m/e 408 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (dd, J=12.51, 4.17 Hz, 1H) 1.73-1.80 (m, 3H) 2.46 (s, 3H) 2.72 (s, 1H) 3.34-3.45 (m, 2H) 3.83 (s, 2H) 3.93 (br. s., 2H) 5.51 (s, 1H) 7.15 (d, J=7.58 Hz, 1H) 7.29 (t, J=7.71 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 11.46 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9]Br)[C:4]=1[F:11].C[O:13][P:14]([O:17][CH3:18])[O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][O:15][P:14]([CH2:2][C:3]1[C:4]([F:11])=[C:5]([CH2:9][P:14](=[O:13])([O:17][CH3:18])[O:15][CH3:16])[CH:6]=[CH:7][CH:8]=1)(=[O:13])[O:17][CH3:18]
Reactant: Fc1c(CBr)cccc1CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cccc(CP(=O)(OC)OC)c1F)OC
Yield: 89 %

Procedure:
A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:13])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:13]
Reactant: COc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccccc1CCl

Procedure:
In a nitrogen atmosphere, 2.00 g (14.5 mmol.) of 2-methoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 1.06 ml (14.6 mmol.) of thionyl chloride in 2 ml of dichloromethane.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1.C([SiH](CC)CC)C>CO.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([N:2]([CH3:1])[CH3:15])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: CN(C)C(=O)Cc1cccc(N)c1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of N,N-dimethyl-2-(3-nitrophenyl)acetamide (1.6 g, 7.68 mmol) in methanol (20 ml) was added 10% Pd—C (0.327 g,) followed by slow addition of triethylsilane (12.3 ml, 77 mmol) at RT. Reaction was stirred at same temperature for 30 min. The reaction mixture was filtered through celite bed. The filtrate was concentrated to get 2-(3-aminophenyl)-N,N-dimethylacetamide (1.21 g, 88% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:17])[CH2:12][NH:13][CH2:14][CH2:15][CH3:16])=[CH:5][C:4]=1[Cl:18]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:17])[CH2:12][NH:13][CH2:14][CH2:15][CH3:16])=[CH:5][C:4]=1[Cl:18]
Reactant: CCCNCC(=O)c1cc(Cl)c(N)c(C#N)c1
Agent: Cl
Product: CCCNCC(O)c1cc(Cl)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 187°-189° C., was prepared from 4'-amino-3'-chloro-5'-cyano-2-propylamino-acetophenone analogous to Example 48.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18]>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([CH2:16][C:15]2[CH:23]=[CH:24][CH:25]=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and 3-trifluoromethylbenzylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[3-(trifluoromethyl)benzylsulfonyl]acrylonitrile
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[I:12].[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[F:13][CH:2]([F:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:9])=[CH:5][C:4]=1[I:12]
Reactant: O=C(O)c1ccc(C(F)F)c(I)c1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)c1ccc(C(F)F)c(I)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 4-(difluoromethyl)-3-iodobenzoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 539.
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:18][NH2:19]>C1C=CC=CC=1.CO>[CH3:17][C:3]1([CH:1]=[N:19][CH3:18])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: Cn1c2c(c3ccccc31)C(C)(C=O)CCS2
Solvent: CO
Solvent: c1ccccc1
Product: CN=CC1(C)CCSc2c1c1ccccc1n2C
Reaction time: 2 h

Procedure:
To a solution of the product (2.0 g) of the above (1) in benzene (20 ml) is added a 30% solution (14 ml) of methylamine in methanol. The solution is stirred for 2 hours and evaporated to give 4,9-dimethyl-4-methyliminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (IR: νmaxCHCl3 1660 cm-1). The product is dissolved in methanol (20 ml) and sodium borohydride (930 mg) is added thereto on ice bath. The mixture is stirred at room temperature for 1 hour and evaporated to remove the solvent. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The ethereal extract is again extracted with hydrochloric acid. The extract is made alkaline with an aqueous solution of sodium hydroxide and extracted with ether. The extract is washed with a saline solution, dried and evaporated to give an oil. Crystallization from hydrochloric acid--ethanol gives the hydrochloride (2.06 g) of the title compound melting at 274° C. (decomp.). Yield: 86%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=1.[CH2:17]1[O:25][C:24]2[CH:23]=[CH:22][C:21]([N:26]=[C:27]=[O:28])=[CH:20][C:19]=2[O:18]1>N1C=CC=CC=1>[O:25]1[C:24]2[CH:23]=[CH:22][C:21]([NH:26][C:27]([NH:16][C:12]3[CH:11]=[C:10]([C:2]4[O:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=[CH:14][N:13]=3)=[O:28])=[CH:20][C:19]=2[O:18][CH2:17]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: Nc1cc(-c2nc3ccccc3o2)ccn1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1cc(-c2nc3ccccc3o2)ccn1

Procedure:
A microwave vial was charged with 4-benzoxazol-2-yl-pyridin-2-ylamine (0.05 g, 0.2 mmol), 3,4-(methylenedioxy)phenyl isocyanate (0.04 g, 0.2 mmol) and 1 mL of pyridine. The mixture was subjected to microwave irradiation at 160° C. for 15 minutes. Upon cooling, a precipitate formed. The solid was filtered and then triturated with hot methanol. The undissolved material was filtered, and the precipitate that formed in the mother liquor was filtered and dried to afford the desired product as a white solid. (Calc'd for C20H14N4O4: 374.36, [M+H]+ found: 375.1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[BrH:27]>O>[OH2:7].[BrH:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:25][CH:26]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:25][CH:26]=1.[BrH:27]
Reactant: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)(c2ccccc2)CC1
Agent: Br
Solvent: O
Product: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 14 parts of ethyl 4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate and 150 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 30 minutes. The reaction mixture was diluted with 100 parts of water and the whole was stirred while the mixture was allowed to cool to room temperature. The precipitated product was filtered off (filtrate I was set aside), washed with methylbenzene and stirred in 2-propanone. It was filtered off again (filtrate II was set aside) and dried, yielding a first fraction of 4.3 parts of (4-fluorophenyl)(4-phenyl-4-piperidinyl)methanone hydrobromide hemihydrate. Filtrates I and II were evaporated and the solid residue was stirred in 4-methyl-2-pentanone. The product was filtered off and dried, yielding a second fraction of 6.2 parts of (4-fluorophenyl) (4-phenyl-4-piperidinyl)methanone hydrobromide hemihydrate; mp. 173.4° C. Total yield: 73%. (intermediate 17).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:23][NH2:24]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:24][CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Yield: 111.7 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.573 mmol), and methanamine (0.286 mL, 0.573 mmol) in MeOH (5 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford crude 2-chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (220 mg, 0.640 mmol, 112% yield). LC-MS (M+H)+=343.9.