Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=O)[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[N:18][NH2:19])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(=O)c1sc(-c2ccc(Cl)cc2)nc1C
Solvent: O
Solvent: CCO
Product: CC(=NN)c1sc(-c2ccc(Cl)cc2)nc1C
Yield: 90.6 %

Procedure:
In ethanol (10 ml), 1-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-ethanone (205 mg) prepared in the Step 30-1-1 was dissolved, and hydrazine monohydrate (1.2 g) was added thereto. The mixture was heated under reflux for 21 hours. The mixture was concentrated under a reduced pressure, and then water was added thereto. The precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (196 mg, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[N:18]1C=CC=C[CH:19]=1.CN>C(Cl)Cl>[CH3:19][NH:18][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: c1ccncc1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)Cc1cccc(O)c1
Reaction time: 1.5 h
Yield: 24 %

Procedure:
A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, poured into 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated, dissolved into 1M HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide 260 mg of the title compound. MS (DCI/NH3) m/e 166 (M+H)+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[C:41]([C:47]([F:50])([F:49])[F:48])[CH:40]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[C:41]([C:47]([F:48])([F:49])[F:50])[CH:40]=1
Reactant: COc1ccc(CN)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)NCc2ccc(OC)cc2C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Prepared using General Procedure 6: A solution of mono-methyl terephthalate (315 mg, 1.75 mmol), HOBt (395 mg, 2.92 mmol), EDC (562 mg, 2.92 mmol) and DIEA (509 μL, 2.92 mmol) in DMF (10 mL) was stirred at room temperature. After 30 min, 4-methoxy-2-(trifluoromethyl)benzylamine (300 mg, 1.46 mmol) was added as a solution in DMF (2 mL). After stirring for 18 h, the reaction mixture was diluted with NaHCO3 and extracted with EA. The combined organic layers were dried (Na2SO4) and purified by chromatography (EA/hexanes) to provide 418 mg (78%) of methyl 4-((4-methoxy-2-(trifluoromethyl)benzyl)carbamoyl)benzoate INT-52. LCMS-ESI (m/z) calculated for C18H16F3NO4: 367; no m/z observed, tR=3.42 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.13-8.04 (m, 2H), 7.85-7.75 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.05 (dd, J=8.5, 2.7 Hz, 1H), 6.44 (s, 1H), 4.75 (d, J=5.9 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:23]=[CH:22][C:21]3[CH:20]4[S:24](=[O:26])(=[O:25])[CH:16]([CH2:17][CH2:18][CH2:19]4)[C:15]=3[CH:14]=2)[N:3]=1.[NH2:27][CH2:28][C:29]1[C:30]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[N:31][CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C.ClC(Cl)C>[O:25]=[S:24]1(=[O:26])[CH:20]2[CH2:19][CH2:18][CH2:17][CH:16]1[C:15]1[CH:14]=[C:13]([NH:12][C:4]3[N:3]=[C:2]([NH:27][CH2:28][C:29]4[C:30]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=3)[CH:23]=[CH:22][C:21]=12
Reactant: O=S1(=O)C2CCCC1c1cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc12
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1CNc1nc(Nc2ccc3c(c2)C2CCCC3S2(=O)=O)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of C6 (51 mg; 0.126 mmol) and 1:1 (vol:vol) t-BuOH/dichloroethane (500 μL) was added to a mixture of N-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide (38 mg, 0.139 mmol) and diisopropyl ethylamine (66 μL, 0.378 mmol). The reaction mixture was heated to 85° C. in a sealed vial. After two hours, the hot reaction mixture was loaded directly onto silica under reduced pressure, purified via chromatography (99:1:0.1 CHCl3:CH3OH:NH4OH), and concentrated under reduced pressure to provide 1 as a white solid (13 mg, 0.0223 mmol, 18%). LC/MS (Method F) r.t.=2.26 min.; m/z 583.2. HPLC r.t.=6.40 min.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=[O:27].N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:19]1=[O:27]
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 68.6 %

Procedure:
3-(3-Dimethylaminopropyl)-2-formyl-4,5,6,7-tetrahydro-1H-indole (1.8 g), 1 g of 2-oxindole and 0.1 g of piperidine in 10 mL of ethanol was refluxed for 4 hours and then cooled to room temperature. The precipitate which formed was collected by vacuum filtration and washed with 4 mL of ethanol. The solids were slurry-washed with 8 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 3 mL of ethanol and vacuum dried to give 1.8 g (70% yield) of 3-[3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-ylmethylene]-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N:9]#[C:10]Cl.[CH2:12]([N:14](CC)CC)C>C(O)(C)C>[O:8]([C:4]1[CH:3]=[C:2]([NH:1][C:10]#[N:9])[CH:7]=[CH:6][CH:5]=1)[C:12]#[N:14]
Reactant: CCN(CC)CC
Reactant: N#CCl
Reactant: Nc1cccc(O)c1
Solvent: CC(C)O
Product: N#CNc1cccc(OC#N)c1
Temperature: 0 °C

Procedure:
55 g (0.5 mol) of m-aminophenol are dissolved in 500 ml of isopropanol in a 1 liter three-necked flask equipped with a stirrer, thermometer and dropping funnel. A solution, precooled to 0° C, of 55.0 ml (1.10 mol) of cyanogen chloride in 50 ml of isopropanol is slowly added dropwise with stirring to the resulting solution at a temperature of 0° C. On completion of the reaction, a solution of 106 g (1.05 mol) of triethylamine in 50 ml of isopropanol is pumped in below the surface at 0° C by means of a metering pump. The reaction mixture is then stirred for 2 hours at room temperature. The product which precipitates is filtered off under suction, washed with 50 ml of isopropanol, subsequently taken up in 500 ml of dichloroethane and the triethyl ammonium chloride is extracted with water. Removal of the solvent by distillation at room temperature leaves the crude m-cyanatophenyl cyanamide which, in the IR-spectrum, shows two absorption bands characteristic of the cyanamide and the cyanate group in the region of 4.5 μ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23](Cl)[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:14])[CH3:11].CCN(CC)CC>CCOC(C)=O>[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:14])[CH3:11]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Cl)c1ccc(C#N)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-4-fluoroaniline (6.40 mmol) was added at 0° C. to a solution of 2-[chloro-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H3) (3.20 mmol). Then Et3N (9.60 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc. The organic layer was washed successively with H2O (2×), brine, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography to afford the title compound. tR: 5.96 min (HPLC 4); ESI-MS: tR=1.35 min, [M+H]+ 440/442 (LC-MS 1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2C(=[CH:9][C:10]=1[F:11])N[CH:6]=[CH:5]2.Cl[CH:14]=[N+:15]([CH3:17])C.[OH-:18].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:17](=[CH:9][C:10]=1[F:11])[NH:15][CH:14]=[C:5]2[CH:6]=[O:18]
Reactant: C[N+](C)=CCl
Reactant: Fc1cc2[nH]ccc2c(F)c1Br
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4,6-difluoro-1H-indole (285 mg, 1.23 mmol) in DMF (2 mL) was added N-(chloromethylidene)-N-methylmethanaminium (236 mg, 1.84 mmol) at room temperature. The reaction mixture was stirred for 30 min, and treated with additional N-(chloromethylidene)-N-methylmethanaminium (100 mg). The mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was then treated with 1N aqueous NaOH (2.5 mL) and water (2.5 mL). The mixture was stirred at 100° C. for 30 min. After cooling to room temperature, the solvents were evaporated in vacuo, and the residue was diluted with THF (2 mL) and water (2 mL). The resulting mixture was stirred at room temperature for 2 hours, and the resulting solids were collected by filtration. The solids were washed with water and heptanes and dried in vacuo to give the title compound (157 mg) as a brown solid. MS (ES+) 261.8 ((M+2)+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41](Br)[CH:42]=1)C>>[C:9]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:41]1[CH:42]=[C:37]([CH2:36][C:35]([OH:44])=[O:34])[CH:38]=[N:39][CH:40]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Product: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)O)c1

Procedure:
N-Benzyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 17, Step 4 and the product was hydrolyzed to the acid as described in Example 17, Step 5.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[Br-:34].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCCOc1ccccc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 60.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0604 g, 0.206 mmol) and 4-bromobutyl phenyl ether (0.106 g, 0.463 mmol) in 2 CH3CN/3 CHCl3 (5.0 mL) were reacted to give the desired product (0.0649 g, 64.9%). EI-MS m/z 442(M+) Rt (2.13 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17].[Br:19]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:17])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Br:19])=[C:2]([F:1])[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)Nc1ccc(Br)c(F)c1
Reaction time: 8 h
Yield: 56152.5 %

Procedure:
To 33.3 g (0.3 mol) 3-fluoroaniline in 160 ml CH2Cl2 were added 450 ml of a 0.7 M aqueous NaHCO3-solution. The resulting mixture was treated dropwise with 34.6 ml (0.41 mol) methylchloroformate within a period of 20 min. After stirring overnight the layers were separated and the organic layer was washed with saturated aqueous NaCl and dried with MgSO4. After evaporation of ca.60% of the solvent, 600 ml of hexane were added, whereby (3-Fluoro-phenyl)-carbamic acid methyl ester precipitated as a colorless solid that was filtered off and dried i.v (41 g (81%)). The solid was dissolved in 600 ml acetonitrile and treated subsequently with 50 g (0.28 mmol) N-bromosuccinimide and 2.13 ml (0.024 mol) trifluormethane sulfonic acid. After stirring at room temperature during 12 hours ca 50% of the solvent were evaporated, the resulting mixture diluted with 1000 ml EtOAc, and washed subsequently with saturated aqueous NaHCO3 and saturated aqueous NaCl. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and column chromatography on silica gel with hexane/EtOAc 8:1 and then 2:1 gave 39 g (64%) (4-Bromo-3-fluoro-phenyl)-carbamic acid methyl ester as a colorless solid, that was dissolved in 390 ml acetonitrile, treated subsequently with 39 g (0.172 mol) N-iodosuccinimide and 1.4 ml (0.016 mol) trifluormethanesulfonic acid at 0° C. and left to stirr at room temperature during 10 hours. Cooling the reaction mixture to 0° C. led to precipitation of (4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester as colorless crystals that were filtered off and dried (26.7g, 44%). Dilution of the filtrate with 600 ml hexane followed by subsequent washing with saturated aqueous NaHCO3 and 0.5M aqueous NaS2O3, drying of the organic layer with MgSO4, evaporation of the solvent, and recrystallization of the residue in acetonitrile gave an additional 6.3 g (12%) of (4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester (total: 33 g, 56%), MS: 373 (M, 1Br).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][C:15]3[C:20]([C:6]=2[O:5]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.[CH3:21][NH:22][CH3:23]>C(O)C>[ClH:1].[CH3:21][N:22]([CH3:23])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][C:15]3[C:20]([C:6]=2[O:5]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2c(ccc3ccccc23)C1=S
Solvent: CCO
Product: CN(C)CCC1CN(C)C(=S)c2ccc3ccccc3c2O1
Product: Cl
Yield: 20 %

Procedure:
To a solution of 15.0 g (0.05 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]-oxazepine-5(4H)-thione in 50 ml of absolute ethanol was added 10 g of a 40% aqueous solution of dimethylamine. The resulting solution was heated in a steel bomb at 100° C. for 40 hr and concentrated under reduced pressure. The residue was partitioned between 15% aqueous sodium hydroxide and chloroform. The chloroform layer was evaporated and the residue partitioned between 3N hydrochloric acid and chloroform. The aqueous layer was made alkaline with 50% sodium hydroxide and extracted with chloroform. The chloroform extract was concentrated and the residue dissolved in isopropyl alcohol. Ethereal hydrogen chloride was added. Recrystallization of the precipitate from isopropyl alcohol/water gave 3.0 g (20%) of the product, m.p. 238°-240° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](=O)[CH2:22][O:23][CH3:24])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[BH4-].[Na+]>CC(O)C>[ClH:10].[ClH:10].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][CH:21]([C:17]2([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:18][CH2:19][CH2:20]2)[CH2:22][O:23][CH3:24])[CH2:3][CH2:2]1
Reactant: COCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: NCCN1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COCC(NCCN1CCOCC1)C1(c2ccc(Cl)cc2)CCC1
Product: Cl
Reaction time: 1 h

Procedure:
2-(Morpholino)ethylamine (20 g) was heated at 175°-180° C. and 1-(4-chlorophenyl)cyclobutyl-2-methoxyethanone (20 g) prepared as described in Example 206 was added dropwise with stirring over 1 hour. The mixture was stirred at 180° C. for a further hour. A stream of nitrogen was passed through the reaction mixture to remove any water formed. The mixture was cooled and added dropwise to a suspension of sodium borohydride (10 g) in propan-2-ol (800 ml). The mixture was then heated under reflux for 3 hours. Propan-2-ol was evaporated and an ice/water mixture was added to the residue which was cooled and acidified with 5N hydrochloric acid. The acidified mixture was basified and extracted with ether Hydrogen chloride gas was passed into the dried extract which was then evaporated to dryness. The residue was heated with propan-2-ol, filtered and the filtrate evaporated to dryness. The residue was partitioned between ether and 2N hydrochloric acid. The acid layer was washed with ether, basified and extracted with ether. Hydrogen chloride gas was passed into the ether extract which was then evaporated to dryness to give a residue which was recrystallised from propan-2-ol to give N-(2-morpholinoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-2-methoxyethylamine dihydrochloride (m.p. 234°-237° C.).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].CO[C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:14]=1>>[CH3:27][CH:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:28])=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Reactant: CC(C)CNCC(C)C
Product: CC(C)CCCC(C)Oc1ccc(C(=O)N(CC(C)C)CC(C)C)cc1

Procedure:
By the procedure given in Example 37, diisobutylamine is reacted with p-[(1,5-dimethyl-hexyl)-oxy]-benzoic acid methyl ester to produce p-[(1,5-dimethyl-hexyl)-oxy]-N,N-diisobutyl-benzamide (nD24 = 1.4968).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][C:6]=1[NH:16][C:17](=[O:19])[CH3:18])#[N:4].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].CN(C)C=O>O1CCCC1.CCOC(C)=O>[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][C:6]=1[N:16]([CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:17](=[O:19])[CH3:18])#[N:4]
Reactant: CC(=O)Nc1nc(N2CCOCC2)sc1C#N
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)N(c1nc(N2CCOCC2)sc1C#N)C(C)c1ccccc1
Temperature: 50 °C
Yield: 84.9 %

Procedure:
NaH (43.6 mg, 1.090 mmol) was added to a suspension of N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (250 mg, 0.991 mmol) in Tetrahydrofuran (THF) (8 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min. (1-Bromoethyl)benzene (183 mg, 0.991 mmol) was added dropwise. N,N-Dimethylformamide (DMF) (2 mL) was added. The reaction mixture was heated at 50° C. overnight. LCMS showed the reaction was almost completed. EtOAc was added and washed with H2O, brine and dried (Na2SO4). Removal of the solvent followed by flash column chromatography on a 25 g silica column, which was eluted with 50% EtOAc/hexane to give 300 mg of light yellow sticky/foamy solid as the product.
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]=[S:17]>>[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]1[N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][S:17]1
Reactant: NCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1c1ccccc1

Procedure:
N-(2-Hydroxyethyl)aniline was reacted with SOCl2 according to Method B7a to give N-2-chloroethyl)anilinium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl -4-nitrophenylimino)-3-phenyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
The product of Example 122, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.91 (s, 6H), 2.14 (s, 3H), 3.45 (br s, 4H), 3.93 (br s, 1H), 6.20 (br s, 1H), 6.31 (d, 1H, 3=9.7 Hz), 6.93 (m, 2H), 7.11 (m, 5H). LC MS (m/e)=449.0 (MH+). Rt=1.62 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[Cl:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CN(C=O)C.O>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:20]2[CH:21]=[CH:22][C:23]([OH:24])=[C:17]([Cl:16])[C:18]=2[O:19][C:23]2[C:22]1=[CH:21][CH:20]=[C:18]([OH:19])[C:17]=2[Cl:16]
Reactant: Oc1cccc(O)c1Cl
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC2(c3ccc(O)c(Cl)c3Oc3c2ccc(O)c3Cl)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 91.8 %

Procedure:
Treatment of tetrachlorophthalic anhydride (5 g, 17.49 mmol) and 2-chlororesorcinol (7.58 g, 41.98 mmol) according to the procedure described in Example 1, Step 1, provided 9.3 g of the crude product. Suspension of 8 g of the crude 9.3 g in DMF:water (1:1), followed by filtration provided 8.65 g (16.05 mmol, 91.7% AUC yield) of 4,4′,5,5′,6,7-hexachloro-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one that was isolated as an orange solid. 1H NMR (300 MHz; DMSO d6) δ 11.09 (S, 2H), 7.03 (d, J=9 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H).