Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6][C:7]=1[CH3:8].O(Cl)[Cl:19].[P+5]>CN(C)C=O>[Cl:19][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1
Reactant: ClOCl
Reactant: Cc1nc(NCc2ccccn2)[nH]c(=O)c1C
Agent: [P+5]
Solvent: CN(C)C=O
Product: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Yield: 74 %

Procedure:
A solution of 5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4(3H)-one (7.0 g, 32.6 mmol, Step B) in phosphorus (V) oxychloride (30 mL) with addition of 1 drop of dimethylformamide was refluxed overnight under nitrogen. Then excess phosphorus (V) oxychloride was removed under reduced pressure. Toluene (30 mL) was added, and the reaction mixture was evaporated under reduced pressure. The residue was diluted with 5% aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (2×200 mL). The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography eluted with hexane/ethyl acetate (2:1). The titled compound 6.1 g (74%) was obtained as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 2.39 (s, 3H), 4.54 (s, 2H), 7.20-7.30 (m, 2H), 7.68-7.76 (m, 2H), 7.76 (bs, 1H).
Reaction SMILES: CC(N)COCC(OCC(OCC([NH2:16])C)C)C.[C:18]([O-:23])(=[O:22])[C:19]([CH3:21])=[CH2:20].C([C:27]([CH3:29])=O)CC>>[NH2:16][C:18]([O:23][CH2:27][CH3:29])=[O:22].[C:18]([O-:23])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: CCCC(C)=O
Reactant: CC(N)COCC(C)OCC(C)OCC(C)N
Agent: C=C(C)C(=O)[O-]
Product: CCOC(N)=O
Temperature: 25 °C

Procedure:
59.95 g-(0.010 m) α,β-di(1-methyl-aminoethyl) poly-(ethylene oxide-co-propyleneoxide) of MW 5995 (Jeffamine-ED 5000, TEXACO Corp.) and 59.95 g of anhydrous methyl propyl ketone are charged into a 3-necked round bottomed flask equipped with a stirrer, nitrogen inlet, condenser, thermometer and dropping funnel. The solution is stirred at room temperature under dry nitrogen. Then 3.10 g (0.020 mole) of 2-isocyanotoethyl methacrylate (MW 155) dissolved in 3.1 g of anhydrous methyl propyl ketone are added slowly from the dropping funnel. The mildly exothermic reaction is maintained at 35° C. and below by water bath cooling for 1 hour at which time an IR analysis shows the reaction to be complete.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:33]3[CH2:32][CH2:31][N:30]([S:27]([CH2:25][CH3:26])(=[O:28])=[O:29])[CH2:35][CH2:34]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 44.2 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol), ethanesulfonyl-piperazine hydrochloride (128 mg, 0.60 mmol) and sodium triacetoxyborohydride (83 mg, 0.39 mmol) to afford 66 mg (44%) of the desired product after purification.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:4](ON1C(=O)CCC1=O)=[O:5])[CH3:3].[NH2:31][C@H:32]([C:52]([OH:54])=[O:53])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[C:50]([CH3:51])=[C:48]([CH3:49])[C:45]([O:46][CH3:47])=[CH:44][C:42]=1[CH3:43])(=[O:40])=[O:39].C(=O)(O)[O-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.O.O.COCCOC>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@H:2]([C:4]([NH:31][C@H:32]([C:52]([OH:54])=[O:53])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[C:50]([CH3:51])=[C:48]([CH3:49])[C:45]([O:46][CH3:47])=[CH:44][C:42]=1[CH3:43])(=[O:40])=[O:39])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C

Procedure:
A solution of Fmoc-Ala-OSu 7c (15.31 mmol) in DME (100 mL) was added to a stirred solution of Lys(Mtr) 2 (6.4080 g, 1 equiv) and potassium bicarbonate (1.5331 mg, 1 equiv) in 2:1 water/DME (150 mL). After 16 h the DME was removed in vacuo and the resulting suspension was treated with citric acid (3.22 g, 1.1 equiv) in water (25 mL). The mixture was extracted with ethyl acetate. The organic phase was washed with water (2×) and brine, dried over sodium sulfate, and concentrated in vacuo, giving a yellow foam which was carried on without further purification. 1H-NMR (CDCl3/CD3OD) δ 1.25 (m, 2H), 1.32 (d, 3H), 1.57 (m, 3H), 1.73 (m, 1H), 2.41 (brt, 2H), 3.72 (s, 3H), 4.14 (m, 1H), 4.29 (m, 4H), 6.79 (d, 2H), 7.22 (m, 16H), 7.38 (d, 4H), 7.52 (m, 2H), 7.72 (d, 2H). MS (FAB) 712.2 (MH)+, 750.2 (M+K)+.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][S:2]([CH3:1])=[O:3])=[CH:8][CH:7]=1
Reactant: CS(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methanesulfinyl chloride (2.06 g) in dichloromethane (20 mL) is added drop wise to an ice-cooled mixture of 4-bromoaniline (3.00 g) and N,N-diisopropylethylamine (10.63 mL) in dichloromethane (20 mL). The reaction mixture is allowed to warm to room temperature and stirred for 5 h. Water is added to the mixture and the organic phase is separated, washed with water, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:500:100) to give the title compound. LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=234, 236 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[CH:18]1([NH:1][C:2]2[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7]3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCCC1
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc(NC2CCCC2)c2[nH]c(-c3ccccn3)cc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.8 %

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole (5 g, 22.4 mmol) prepared in Step A and cyclopentanone (1.88 g, 22.4 mmol) were added to dichloroethane (50 mL). NaBH(OAc)3 (9.5 g, 44.8 mmol) was added thereto, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, the reaction mixture was diluted with saturated aqueous NaHCO3 solution, and extracted with dichloromethane and EtOAc. The extracted organic material was washed with water and aqueous NaCl solution, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent EtOAc/n-Hex=1/5) to give the title compound (3.77 g, Yield 58%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:17](=[O:33])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)[C:36]([OH:38])=[O:37]>C(Cl)Cl>[O:37]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:6][N:8]3[CH2:13][CH2:12][CH:11]([NH:14][C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=5)[N:18]([CH2:26][C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)[C:17](=[O:33])[CH:16]=4)[CH2:10][CH2:9]3)=[CH:24][C:19]=2[O:38][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(=O)n(Cc3ccncc3)c3ccc(Cl)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)ccc2n1Cc1ccncc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4-(6-Chloro-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydroquinolin-4-ylamino)-piperidine-1-carboxylic acid t-butyl ester (1.22 g, 2.6 mmol) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred for 15 minutes before evaporating under reduced pressure. The crude amine was dissolved in acetone (25 mL), treated with cesium carbonate (1.26 g) and stirred for 15 minutes prior to addition of piperonyl chloride (50% wt solution in DCM, 1.4 mL). The mixture was heated to 50° C. for 8 hours at which time LC/MS analysis indicated the reaction was complete. The reaction was diluted with ethyl acetate and washed with 1 N NaOH. The organic layer was dried with sodium sulfate and concentrated to give the crude product which was purified by silica chromatography using DCM and methanol eluent to give the title compound (0.91 g). 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (2H, m), 2.23 (2H, m), 2.67 (2H, m), 3.19 (2H, m), 3.67 (1H, m), 3.81 (2H, s), 5.44 (3H, br s), 5.81 (1H, s), 5.95 (2H, s), 6.77 (1H, d, J=7.91 Hz), 6.93 (1H, m), 7.04 (4H, m), 7.30 (1H, m), 7.81 (1H, m), 8.48 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([O:24]CC)=[O:23])=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([OH:24])=[O:23])=[CH:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
100 mg ethyl 5-(3,5-dichloro-phenylsulphonylamino)-1H-indole-2-carboxylate are dissolved in 2 ml of tetrahydrofuran, combined with 2 ml 1 N sodium hydroxide solution and stirred for 48 hours at ambient temperature. Then the tetrahydrofuran is eliminated in vacuo, diluted with some water and combined with 2 ml of 2 N hydrochloric acid. The solid is suction filtered, washed with water and dried in vacuo.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#N)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O-:28].[Na+].C[OH:31]>>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:28][CH3:27])=[O:31])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: CO
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: [Na+]
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (Preparation 6) (5.0 g, 14.7 mmol) and sodium methoxide (4.0 g, 74.1 mmol) in methanol (300 ml) was heated under reflux for 24 hours. Further sodium methoxide (2.0 g, 37 mmol) and methanol (100 ml) was added and heating continued for a further 24 hours. The reaction mixture was allowed to cool and the solvent removed under reduced pressure. The residue was dissolved in tetrahydrofuran (THF) (375 ml), 2N aqueous hydrochloric acid (125 ml) added and the mixture stirred at room temperature for 24 hours. The THF was removed under reduced pressure and the suspension basified to pH 7 with saturated aqueous sodium bicarbonate solution Ethyl acetate (100 ml) was added and the white solid consisting mainly of the desired product filtered, washed with a little water and ethyl acetate and dried. Purification by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (90:10, by volume) gradually changing to dichloromethane:methanol (75:25, by volume) afforded the title compound as a white solid, 1.25 g (25%). Evaporation of the ethyl acetate filtrate provided 2.6 g of the starting material.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[Cl:12])[CH:8]([C:14]([OH:16])=[O:15])[CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)O.[CH3:23]O>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[Cl:12])[CH:8]([C:14]([O:16][CH3:23])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1c(Cl)c(N)c(Cl)c2c1C(C(=O)O)CCC2
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)C1CCCc2c(Cl)c(N)c(Cl)c(C)c21
Yield: 89 %

Procedure:
The product from Example 135 (0.5 g) was dissolved in methanol (50 ml) and concentrated sulfuric acid (3 ml) was added. The reaction was refluxed for 4 hours and solvent was evaporated to one-half the volume. The concentrated reaction mixture was diluted with benzene (50 ml) and washed with brine, and aqueous sodium bicarbonate. The organic layer was separated, dried and evaporated affording the desired ester in 89% yield.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(4-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 20, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si](CC)(CC)CC)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40].[NH4+].[Cl-]>C(Cl)Cl.CCOCC>[CH2:1]([N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:24])([C:20]([F:23])([F:21])[F:22])[C:16]([F:19])([F:17])[F:18])[CH2:11][CH2:10]1)[C:39](=[O:41])[CH3:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N(Cc1ccccc1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 50 mg (0.11 mmol) of trans benzyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine (example 3.1) in 1 mL of CH2Cl2 was treated with 0.1 mL of NEt3, cooled to 0° C. and treated with 0.14 mL (1.97 mmol) of acetylchloride. The mixture was stirred for 30 min and distributed between a saturated aqueous solution of NH4Cl and Et2O. The crude material obtained after drying of the combined organic phases over Na2SO4 and evaporation of the solvent was redissolved in 1 mL of THF, treated with an excess of TBAF and left to stir for 1 hr. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation of the solvent and chromatography on silica gel with EtOAc/heptane 1:1 gave 50 mg (95%) of trans N-benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-acetamide as a colorless viscous oil, MS: 398 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[N:42]1([CH2:48][CH2:49][NH2:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:50][CH2:49][CH2:48][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: NCCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (65 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (119 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:23]([O:25]C)=[O:24])=[N:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[N:4]=1.[OH-].[K+].CO.COCCOC>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[N:6]=1
Reactant: COC(=O)c1nc(N2CCCC2)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc(N3CCCC3)nc2C(=O)O)n1
Yield: 94 %

Procedure:
1.44 g (4 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate and 0.67 g (12 mmol) of potassium hydroxide were added to 30 ml of methanol, 30 ml of 1,2-dimethoxyethane and 10 ml of water, and the mixture was reacted at 40° C. for 4 hours. The solvent was distilled off, and water was added to the residue. The mixture was acidified (pH=4) by 10% hydrochloric acid, then extracted with chloroform and ethyl acetate, dried and concentrated, and then crystallized from diisopropyl ether to obtain the desired product.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:2]1([O:15][C:14]2[CH:16]=[CH:17][C:9]([CH:8]=[O:7])=[CH:10][C:11]=2[O:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C=O)ccc1OC1CCCC1
Yield: 97.7 %

Procedure:
Bromocyclopentane (7.0 mL, 66 mmol) was added to a suspension of vanillin (5.0 g, 33 mmol) and potassium carbonate (13.6 g, 99 mmol) in EtOH (75 mL) and treated according to Procedure 3. 4-Cyclopentyloxy-3-methoxybenzaldehyde (7.1 g, 98%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.62 (m, 2H, CH2), 1.78-2.04 (m, 6H, CH2), 3.89 (s, 3H, OCH3), 4.86 (tt, J=6.0, 3.2 Hz, 1H, OCH), 6.94 (d, J5,6=8.0 Hz, 1H, H5), 7.38 (d, J2,6=2.0 Hz, 1H, H2), 7.41 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.82 (s, 1H, CHO); δC (100 MHz, CDCl3) 24.1, 32.8, 56.0, 80.6, 109.4, 112.8, 126.6, 129.5, 150.2, 153.4, 190.9; vmax 977, 1260, 1504, 1580, 1680, 2869, 2956 cm−1.
Reaction SMILES: [Li][C:2](C)(C)C.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.C1COCC1.IC>CCOCC>[CH3:2][C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1
Reactant: c1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2ccccc2s1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
t-BuLi (1.7 M, 26 mmoles, 15 ml) was added to a stirred solution of benzo[b]thiophene (17 mmoles, 2.3 g) and THF (30 ml) at -50° C. The resulting bright yellow reaction mixture was warmed to -30° C., and iodomethane (26 mmoles, 1.6 ml) was added. After 10 min. at -30° C., the solution was warmed to ambient temperature and stirred an additional 30 min., then diluted with ether (100 ml) and washed with brine (2×100 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect 2.48 g (98%) of 2-methylbenzo[b]thiophene as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:12]([CH3:23])[C:11]([C:24](O)=[O:25])=[N:10]1.[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)=[C:12]([CH3:23])[C:11]([C:24]([N:31]2[CH2:30][CH2:29][C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([OH:27])[CH2:33][CH2:32]2)=[O:25])=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Yield: 49 %

Procedure:
1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 10 mg, 0.026 mmol), 4-hydroxy-4-phenylpiperidine (1 eq, 4.5 mg, 0.026 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq., 11.3 mg, 0.026 mmol), and triethylamine (0.02 mL) were stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-ol (7 mg, 50%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.73-1.95 (m, 2H) 2.09-2.29 (m, 5H) 2.85-3.04 (m, 3H) 3.34 (t, J=12.43 Hz, 1H) 3.66 (t, J=12.81 Hz, 1H) 4.34 (d, J=13.19 Hz, 1H) 4.74 (d, J=13.28 Hz, 1H) 6.61 (d, J=8.57 Hz, 2H) 6.99 (d, J=8.67 Hz, 2H) 7.09-7.57 (m, 8H).
Reaction SMILES: [NH2:1][C:2]([C@H]1[C@H]2C[C@H](C=C2)[C@H]1[NH:11][C:12]1[C:17](F)=[CH:16][N:15]=[C:14]([NH:19]C2C=CC(N3CCN(C)CC3)=C(C)C=2)[N:13]=1)=[O:3]>CO>[NH3:1].[CH3:2][OH:3].[NH2:19][C:14]1[N:13]=[C:12]([NH2:11])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(Nc2ncc(F)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc1N1CCN(C)CC1
Solvent: CO
Product: N
Product: Nc1ccnc(N)n1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A sealed tube charged with enantiomerically pure mono-SNAr product 57a (2.25 g, 8 mmol), aniline 7 (1.80 g, 8.8 mmol), TEA (1.12 mL) and methanol (18 mL) was stirred at 100° C. for 24 hours. The resulting viscous but homogeneous solution was concentrated and the residue was chromatographed (silica gel, CH2Cl2 then 2-5% 2N NH3/MeOH in CH2Cl2) to afford the expected 2,4-diaminopyrimidine derivative 60a (2.28 g, 63%; purity: 95% AUC; enantiomeric purity; greater than 99% as determined by chiral HPLC. The chiral analytical data, 1H NMR and LCMS analyses were found to be identical with the enantiomer designated E1; [α]DRI+44.4° (c 1.0, MeOH).