Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6]2)[NH2:2].[F:20][CH:21]([F:27])[C:22](OCC)=O.FC(F)C(O)=O.O>CN1C(=O)N(C)CC1>[F:20][CH:21]([F:27])[C:22]1[N:4]2[C:5]3[CH:6]=[C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]2=[N:1][N:2]=1
Reactant: NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Reactant: CCOC(=O)C(F)F
Agent: O=C(O)C(F)F
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=c1[nH]c2ccc3nnc(C(F)F)n3c2cc1-c1ccccc1
Temperature: 200 °C

Procedure:
A mixture of 6-hydrazino-3-phenyl-1,5-naphthyridin-2(1H)-one (7-2) (21 g, 83 mmol), ethyl difluoroacetate (31 g, 250 mmol), and difluoroacetic acid (200 mg, 2.08 mmol) in DMI (100 mL) was heated under microwave irradiation at 200° C. for 1 h. To the cooled mixture was added water, and the resulting solid was collected by filtration to give 1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (10-1) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:8]=[CH:7][N:6]=[C:5]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>ClCCl.O1CCCC1>[Br:30][C:26]1[CH:25]=[C:24]([NH:23][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:2]([NH:1][C:38]([CH:39]=[CH2:40])=[O:41])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CC(=O)Cl
Reactant: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2N)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCC1CCN(C)CC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 300 mg of 6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline in 7 ml of dichloromethane are added 0.28 ml of triethylamine. The reaction mixture is cooled to about −10° C. in an ice/sodium chloride cooling bath. Then a solution of 59 μl of acrylic acid chloride in 1 ml of tetrahydrofuran is added dropwise within 10 minutes. The cooling bath is removed and the mixture is stirred for a further 15 minutes at ambient temperature. For working up, the reaction mixture is poured on to 20 ml of ice water and mixed with 2-3 ml of 2 N sodium hydroxide solution, whereupon a light-colored precipitate is formed. The precipitate is suction filtered, washed with cold water and dissolved in dichloromethane. The solution is dried over sodium sulfate and concentrated by evaporation. The resin-like crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.5). Yield: 118 mg (35% of theory); Rf value: 0.35 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI+): m/z=524, 526 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-dichlorophenol and 4-fluoro-benzaldehyde.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([N:21]1[CH2:25][CH2:24][C@@H:23](O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>ClCCl>[F:11][C@H:23]1[CH2:24][CH2:25][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
Slowly add [bis(2-methoxyethyl)amino]sulfur trifluoride (2.40 mL, 13.03 mmol) to a solution of N-Boc-(R)-(−)-3-pyrrolidinol (2.00 g, 10.86 mmol) in anhydrous dichloromethane (10 mL), at −78° C. and under nitrogen. Allow the reaction mixture to warm to room temperature and stir overnight. Carefully add an aqueous solution of sodium hydrogen carbonate (saturated, 20 mL) and extract with dichloromethane. Concentrate the combined organic extracts under vacuum then purify using automated flash chromatography (ISCO® System, 120 g Redisep® SiO2 column; 0-40% ethyl acetate in cyclohexane gradient elution over 30 minutes at 85 mL/min) to give the title compound as a pale yellow liquid (1.67 g): MS (m/e): 212 (M+23).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[C:8]1(=O)[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CI.[Cl-].[NH4+:19]>O1CCCC1>[CH3:1][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:19][C:13]1=[O:14]
Reactant: [NH4+]
Reactant: CC(C)NC(C)C
Reactant: O=C1CCCCCO1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCCCNC1=O
Reaction time: 1 h
Yield: 66 %

Procedure:
1.6M n-butyllithium-hexane solution (28.9 ml, 46.2 mmole) was added dropwise to a solution of diisopropylamine (6.5 ml, 46.4 mmole) in tetrahydrofuran (50 ml) at -60° C. under an argon atmosphere, with stirring. 10 minutes later, a solution of caprolactone (5.0 g, 43.8 mmole) in tetrahydrofuran (10 ml) was added dropwise to the solution. After the reaction was allowed to proceed for 20 minutes under the same reaction conditions, a solution of methyl iodide (7.5 g, 52.8 mmole) in hexamethylphosphormaide (9.2 ml) was added gradually to the reaction solution, and stirring was continued for 1 hour after the dropwise addition while maintaining the reaction mixture at -40° to -45° C. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction solution to terminate the reaction, and water (100 ml) was added to the mixture, followed by extraction of the product with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was chromatographed on a column of silica gel, and development with isopropyl ether yielded 2-methylcaprolactam (3.7 g, 66%) [NMR (δ value): 1.18 (3H, d, 6 Hz), 2.5-2.9 (1H,m), 4.18-4.34 (2H,m)].
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.B1([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)OCCCO1>>[CH2:14]([N:13]([CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCN(CC)CCn1ccc2ccc(Br)cc21
Reactant: c1cncc(B2OCCCO2)c1
Product: CCN(CC)CCn1ccc2ccc(-c3cccnc3)cc21

Procedure:
(16.6 mg, 56%); from 6-bromo-1-(2-(N,N-diethylamino)ethyl)indole (30.7 mg, 0.101 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (33.0 mg, 0.202 mmol).
Reaction SMILES: O[C:2]1[N:11]=C(O)[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C([O-])(O)=O.[Na+].[CH2:33]([Cl:35])Cl>O>[Cl:23][C:2]1[N:11]=[C:33]([Cl:35])[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCCl
Reactant: COC(=O)c1ccc2c(O)nc(O)nc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(Cl)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 mL flask charged with methyl 2,4-dihydroxyquinazoline-7-carboxylate was added POCl3 (76 mL), PCl5 (12.1 g, 58.1 mmol), and the suspension heated at reflux overnight under nitrogen. In morning a dark orange solution has formed. The POCl3 was removed and the residue azeotroped with toluene to yield an orange solid that was taken into DCM (50 mL) and added slowly to stirred satd NaHCO3 (300 mL). The bi-phasic solution was then diluted with DCM (100 mL) and water (30 mL) and stirred for 1 hour at room temp. DCM (500 mL) was added and the mix transferred to a sep-funnel. The DCM layer was removed along with a large amount of ppt. The aq. was extracted with DCM (3×100 mL) and the combined organics dried over MgSO4, filtered and stripped to a orange solid that was purified by Biotage 65 flash chromatography eluting with DCM −3% MeOH/DCM over 3.5 L to reveal the title compound as a white solid, 4.4 g, 59%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.47 (1H, d, J=1.01 Hz) 8.43 (1H, d, J=8.84 Hz) 8.29 (1H, dd, J=8.72, 1.64 Hz) 3.96 (3H, s); MS (API+) for C10H6N2Cl2O2 m/z 257.0 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][CH2:11][NH:12][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NCCc1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.2 g, 0.85 mmol) in tetrahydrofuran (6 mL) was cooled to 0° C. and was treated with triethylamine (0.13 mL, 0.92 mmol) and methoxyacetyl chloride (0.078 mL, 0.85 mmol). The reaction was stirred under an argon atmosphere for 0.25 h, then was partitioned between methylene chloride and water. The extract was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 5% methanol/chloroform, provided an oil; additional 0.1 g of impure product also obtained).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.Cl.[CH3:21][NH:22][C:23](=[S:26])[NH:24][NH2:25]>C(O)C>[ClH:1].[C:16]([C:7]1[CH:6]=[C:5]([C:3]2[CH2:2][S:26][C:23]([NH:22][CH3:21])=[N:24][N:25]=2)[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)CCl)cc(C(C)(C)C)c1O
Reactant: CNC(=S)NN
Agent: Cl
Solvent: CCO
Product: CNC1=NN=C(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CS1
Reaction time: 0.5 h

Procedure:
10.7 g (0.038 mol) of 2-chloro-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone from step (a) and 4.8 g (0.034 mol) of 4-methylthiosemicarbazide hydrochloride were dissolved in 120 ml of ethanol, and the mixture was heated to boiling for 30 minutes. After cooling, the solvent was removed by distillation under reduced pressure, and the resinous residue was dissolved in 60 ml of warm ethyl acetate. On standing, the product immediately precipitated in crystalline form, and was filtered off and recrystallized again from 150 ml of a mixture of ethyl acetate and methylene chloride (10 : 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: Cc1cc(-c2ccc(CN)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4ccccn4)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-(2-methylpyridin-4-yl)phenyl)methanamine 13-3 (10 mg, 0.05 mmol), 4-(pyridin-2-yl)benzoic acid 13-4 (10 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(4-(2-methylpyridin-4-yl)benzyl)-4-(pyridin-2-yl)benzamide 13 as white powder. MS m/z 380.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.65-8.60 (m, 1H), 8.41 (d, 1H), 7.99-7.85 (m, 4H), 7.80-7.70 (m, 2H), 7.65-7.50 (m, 3H), 7.45 (d, 2H), 7.34 (bs, 1H), 7.32-7.27 (m, 2H), 4.66 (d, 2H), 2.56 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]1([CH3:25])[CH2:16][CH2:15][CH2:14][C:13]2[N:12]=[C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=[CH:9][C:8]1=2.[OH-:26].[Na+].[C:28](#[N:30])[CH3:29]>>[CH3:25][C:7]1([NH:30][C:28](=[O:26])[CH3:29])[CH2:16][CH2:15][CH2:14][C:13]2[N:12]=[C:11]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=[CH:9][C:8]1=2
Reactant: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [OH-]
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC1(C)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
Conc sulfuric acid (70 ml) was added dropwise over 45 mins to a solution of 5,6,7,8-tetrahydro-5-hydroxy-5-methyl-2-(phenylmethoxy)quinoline (14.0 g) and acetonitrile (200 ml) at 0° C. The solution was stirred at room temperature for 18 hrs, poured over ice, and basified to pH 8 with 50% sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by colmn chromatography (silica gel, elution with ethyl acetate). The appropriate fractions were collected and evaporated. Recrystallization (twice) of the residue from ethyl acetate/hexanes gave 2.60 g (16%) of product, mp 153°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][CH2:23][C:24](=[O:25])[C:9]=23)[CH:5]=[CH:6][CH:7]=1.CO.C(Cl)Cl.[BH4-].[Na+]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(=O)CCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(O)CCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione in 5 mL 1:1 MeOH:CH2Cl2 was added NaBH4 (17 mg). The reaction was stirred at room temp for 1 h, then diluted with bicarb and EtOAc and stirred for 30 min. The mixture was extracted once with EtOAc, and the organic solution was washed once with brine, dried (Na2SO4) and concentrated. Flash chromtaography (40 g silica, 50-100% EtOAc/hexanes) gave the titled compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[CH2:33][CH3:34].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH2:33][CH3:34]
Reactant: CCC=O
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 113 mg (0.27 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 2.5 mL chloroform was treated with 0.20 mL (2.7 mmol) propionaldehyde and 180 mg (0.82 mmol) NaBH3(CN), followed by addition of 2.5 mL methanol. The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 454 (M+H)+.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:27])=O>ClCCl>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:27])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 99 %

Procedure:
A solution of acid 1 (19.36 g), thionyl chloride (40 ml) and dichloromethane (200 ml) was stirred at 23° for 18 h. The solvent and excess thionyl chloride were evaporated in vacuo at 23° to give acid chloride 2 as an off-white solid, 20.5 g (99% yield). ##STR123##
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:18][C@@H:19]([C:24]([OH:26])=[O:25])[C:20]([SH:23])([CH3:22])[CH3:21].C(OCC)(=O)C>C(O)C.O>[CH:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]2[CH2:14][CH2:13][C:12]3([S:23][C:20]([CH3:22])([CH3:21])[C@H:19]([C:24]([OH:26])=[O:25])[NH:18]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(C)c1ccc(OC2CCC(=O)CC2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(OC2CCC3(CC2)N[C@@H](C(=O)O)C(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
In a mixture of 0.70 ml of ethanol and 0.30 ml of water were dissolved 0.30 g of 4-(4-isopropylphenoxy)-1-cyclohexanone and 0.21 g of D-penicillamine. The solution thus formed was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a solvent mixture consisting of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the deposited crystal was collected by filtration. Thus, 0.32 g of (3S)-8-(4-isopropylphenoxy)-2,2-dimethyl-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid was obtained as a colorless crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([NH:32][C:33](=[O:36])[CH2:34]Cl)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:34][C:33](=[O:36])[NH:32][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(CCl)Nc1cccc2ccccc12
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
A mixture of 290 mg of 1-[bis(4-fluorophenyl)methyl]piperazine and 400 mg of N-(1-naphthyl)chloroacetamide was dissolved in 10 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide. 1.2 g of anhydrous potassium carbonate were then added to the solution, after which the reaction mixture was stirred for 15 hours at 25° C. and then diluted with ethyl acetate. The organic layer was washed three times with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford 430 mg of 1-[bis(4-fluorophenyl)methyl]4-(1-naphthylcarbamoylmethyl)piperazine, melting at 173° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([OH:20])=[C:15]([F:21])[CH:14]=2)[CH:3]=1.C[Si]([C:26]#[C:27][Sn](CCCC)(CCCC)CCCC)(C)C>>[F:21][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]#[CH:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[C:17]([F:19])[C:16]=1[OH:20]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: Oc1ccc2nc(-c3cc(F)c(O)c(F)c3)cc(Br)c2c1
Product: C#Cc1cc(-c2cc(F)c(O)c(F)c2)nc2ccc(O)cc12
Yield: 87 %

Procedure:
This compound was prepared from 6c following a combination of method J using (trimethylsilylethynyl)tributyltin and method L. Yellow solid; Yield: 87%; mp 220° C. (dec.); 1H-NMR (300 MHz, acetone-d6) δ 4.39 (s, 1H), 7.45 (dd, J=9.1, 2.7 Hz, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.95 (d, J=10.1 Hz, 1H), 7.96 (d, J=7.1 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 8.14 (s, 1H), 9.18 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z 296 ([M−H]−), 298 ([M+H]+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:23]1([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:26][CH2:25]1
Reactant: BrCCBr
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(C2(CN3CC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 70 °C
Yield: 10 %

Procedure:
A mixture of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (482 mg, 1.50 mmol), 1,2-dibromoethane (0.13 ml, 1.50 mmol) and K2CO3 (420 mg, 3.0 mmol) in acetonitrile (50 ml) was heated to 70° C. for 3 days. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (93:7:1 to 91:9:1) to provide the title compound as a clear colourless oil (51 mg, 0.15 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 0.71 (m, 2H), 1.48 (m, 2H), 1.78 (m, 4H), 2.00 (m, 4H), 2.19 (m, 2H), 2.30 (s, 2H), 2.54 (m, 4H), 2.63 (t, 2H), 3.54 (m, 2H), 3.78 (m, 2H), 4.01 (t, 2H), 6.86 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 345.2534 [MH]+.