Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[CH:19]=[C:20]([NH:26][C:27]4[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[OH:71][CH:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>O>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[C:20]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([N:75]5[CH2:76][CH2:77][CH:72]([OH:71])[CH2:73][CH2:74]5)=[O:32])=[CH:34][CH:35]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)O)cc2)c(=O)n(C)c1
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)N3CCC(O)CC3)cc2)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
A solution of 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid (7) (56 mg; 0.11 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58 mg; 0.13 mmol) and N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 h. 4-Hydroxypiperidine (56 mg; 0.55 mmol) was added and the mixture was stirred at room temperature for 16 h. Water (15 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL) and brine (1×30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was slurried with diethyl ether and filtered to give 4-tert-butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide (8) as a light brown solid (40 mg), MS 593.41 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=2)[CH2:41]Cl)[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([C:30]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH:39]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCCCOc1ccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[CH:4]=[O:5].[Li+].[CH3:19][CH:20]([N-:22]C(C)C)C>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:19][C:20]#[N:22]
Reactant: CC(C)[N-]C(C)C
Reactant: O=Cc1cc(OCC2CCCCC2)ccc1Br
Agent: [Li+]
Solvent: CC#N
Product: N#CCC(O)c1cc(OCC2CCCCC2)ccc1Br

Procedure:
Reaction of 2-bromo-5-(cyclohexylmethoxy)benzaldehyde with acetonitrile in the presence of LDA was conducted following the procedure given for Example 4 to give 3-(2-bromo-5-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile. Yield (0.49 g, 79%): 1H NMR (400 MHz, MeOD) δ 7.40 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.4 Hz, 1H), 5.20 (dd, J=6.8, 4.4 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.91 (dd, J=16.8, 4.0 Hz, 1H), 2.74 (dd, J=16.8, 6.8 Hz, 1H), 1.66-1.88 (m, 6H), 1.18-1.36 (m, 3H), 1.02-1.16 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-fluorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:1]([NH:9][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)Nc1ccccc1
Yield: 98.3 %

Procedure:
A solution of octyl amine (22.79 g, 176 mmol) and phenyl isocyanate (21 g, 176 mmol) in THF (200 ml) at 0° C. was stirred for 2 hours. The solvent was evaporated in vacuo and the residue was triturated with hexane to give 43 g of final product (173 mmol).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH3:32][O:33][C:34](=[O:40])[CH2:35][CH2:36][C:37](O)=[O:38]>CN(C=O)C>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([O:33][CH3:32])=[O:40])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)CCC(=O)O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 109.2 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 400 mg; 0.86 mmol) and succinic acid monomethyl ester (249 mg; 1.88 mmol) in DMF (10 mL), 506 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EA).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[Na+]>O.CC(C)=O>[F:24][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)S1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
7 g (18.7 mmole) of 4-[2-(4-formylphenoxy)ethyl]phenyl trifluoromethanesulfonate, 2.74 g (23.4 mmole) 2,4-thiazolidinedione and 3.8 g (46.8 mmole) sodium acetate were mixed and heated under vacuum to 140° C. when it melted. It was kept at 140° C. for 20 minutes and thereafter taken off the heat, water:acetone (2:1) was added, the formed crystals were filtered off and recrystallization in dichloromethane gave 2.09 g (yield 24%) 5-(4-[2-(4-trifluoromethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[O:12][C:11]([C:13](=[NH:16])OC)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[CH2:20][NH2:21]>C(#N)C>[ClH:1].[C:2]1([C:8]2[O:12][C:11]([C:13]3[NH:16][CH:19]=[CH:20][N:21]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: COC(=N)c1ccc(-c2ccccc2)o1
Agent: Cl
Solvent: CC#N
Product: c1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1

Procedure:
A mixture of methyl 5-phenyl-2-furimidate hydrochloride (33 g, 0.14 mole), absolute alcohol (500 ml) and aminoacetaldehyde dimethyl acetal (15 g, 0.14 mole) was refluxed for 3 hr. The solvent was removed in a rotary evaporator and the residue was heated for 20 hr. at 63°-73° C with 3N HCl (400 ml). The solvent was decanted and the black viscous material was washed with water. It was purified by stirring with boiling acetonitrile and collected by filtration to give 4.1 g (9%). An analytical sample was prepared by recrystallization from acetonitrile m.p. >277° dec.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:21]([CH2:28][O:29][CH2:30][CH3:31])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(#N)C>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][C:24]([CH3:25])([OH:27])[CH3:26])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cc(CCCOS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Reactant: C1COCCN1
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(CCCN4CCOCC4)ccc3c2n1CC(C)(C)O
Temperature: 75 °C
Yield: 42.7 %

Procedure:
A round bottom flask, equipped with a stir bar, was charged with 3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl methanesulfonate (0.24 g, 0.53 mmol) and acetonitrile (10 mL). Morpholine (0.23 g, 2.7 mmol) was added in one portion. The reaction mixture was heated at 75° C. for 18 hours and then cooled to ambient temperature. After concentrating under reduced pressure, the resulting solid was dissolved in dichloromethane (50 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness. The solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-25% CMA/chloroform). The material was further purified by a second chromatography treatment using a HORIZON HPFC system (silica cartridge, 10% methanol/dichloromethane). A final recrystallization from acetonitrile provided 0.1 g of 1-[4-amino-2-(ethoxymethyl)-7-(3-morpholin-4-ylpropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white crystalline solid, mp 132-133° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH2:13])[C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:27]([O-])=O)=[CH:16][CH:15]=2)=[CH:5]1)([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[C:7]3[C:12]([NH2:13])=[N:11][CH:10]=[N:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[CH:19][CH:18]=1
Reactant: CC(C)n1cc(-c2ccc(Oc3ccccc3[N+](=O)[O-])cc2)c2c(N)ncnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)n1cc(-c2ccc(Oc3ccccc3N)cc2)c2c(N)ncnc21

Procedure:
A mixture of 7-isopropyl-5-[4-(2-nitrophenoxy)phenyl]-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine (0.15 g), ammonium formate (3 equivalents), 10% palladium on charcoal (15 mg) and ethanol (5 ml) was boiled under reflux under nitrogen for 2 hours. Further ammonium formate (100 mg) was added after one hour. The mixture was cooled and filtered through silica. The filter bed was washed with industrial methylated spirit (2×10 ml). The filtrate was evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was removed under reduced pressure to give a residue which was purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 5-[4-(2-aminophenoxy)phenyl]-7-isopropyl-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine. The structure was confirmed by 1H nmr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38]([NH:37][CH2:35][CH3:36])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Solvent: ClCCl
Product: CCNC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 2 ml of dichloromethane, 35 mg of ethyl isocyanate was added, and the mixture was stirred at room temperature for 15 hours. Then, 117 mg of ethyl isocyanate was added, the mixture was stirred at room temperature for 6 hours, and then the reaction solution was evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (65:35) as the eluent to give 154 mg of 1-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-1-[(7-cyano-2-naphthyl)methyl]-3-ethylurea.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O.[Ni]>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(SCc2ccccc2)nc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc(SCc2ccccc2)nc1

Procedure:
91.4 g of 2-benzylthio-5-nitropyridine is dissolved in 1 liter of dimethylformamide and, after addition of 20 g of Raney nickel, hydrogenated at room temperature and at 20°-30° until the reaction is completed. The Raney nickel is filtered off under nitrogen by suction; the solvent is then evaporated off under vacuo to obtain 2-benzylthio-5-amino-pyridine, which is used direct for the subsequent thiophosgenisation.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9]([CH2:14][CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:25])[CH2:10]2)[CH2:6]1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:15][CH2:14][N:9]2[CH2:10][CH:11]3[O:13][CH:7]([CH2:6][N:5]([CH2:4][CH2:3][NH:2][S:34]([C:28]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=4[F:26])(=[O:36])=[O:35])[CH2:12]3)[CH2:8]2)=[C:18]([F:25])[CH:19]=1)#[N:22]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: N#Cc1ccc(OCCN2CC3CN(CCN)CC(C2)O3)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(OCCN2CC3CN(CCNS(=O)(=O)c4ccc(F)cc4F)CC(C2)O3)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}-3-fluoro-benzonitrile hydrochloride salt (0.266 g, 0.6 mmol; prep N above) and 2,4-difluorobenzenesulfonyl chloride (0.170 g, 0.80 mmol) were dissolved in DCM (6 mL). Triethylamine (0.416 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature for 20 h under a nitrogen atmosphere. The reaction mixture was concentrated and then redissolved in DCM (3 mL) and transferred to a phase separator. The DCM layer was washed with water (3 mL) and the layers were separated. The retained water was extracted with DCM (3 mL) and the layers were separated. The combined DCM fractions were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 173 mg (56%) of the title compound.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CC([O-])(C)C.[K+].Br[C:17]1[CH:22]=[CH:21]C=C[N:18]=1>C1COCC1.O>[N:18]1[CH:17]=[CH:22][CH:21]=[CH:9][C:2]=1[O:3][CH2:4][CH:5]([OH:6])[CH2:7][OH:8]
Reactant: CC1(C)OCC(CO)O1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCC(O)COc1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
Following a literature procedure2, a solution of solketal (1.25 mL, 0.01 mol) in THF (20 mL) was stirred and cooled to 0° C. under N2 and KOtBu (1.349 g, 0.012 mol) was added. The mixture was stirred 15 min, 2-bromopyridine (1.1 mL, 0.011 mol) was added, and the mixture was stirred 18 h at room temperature, diluted with H2O, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), filtered, and evaporated to give the crude title product (288.1 mg, 17%).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:37][O:36][CH2:35][CH2:34][O:33][CH3:32])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 55.7 %

Procedure:
Following the procedure of Example 1(a), but reacting 980 mg (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 330 μl (28.6 mmol) of methoxyethoxymethyl chloride, 650 mg (55%) of the expected compound were obtained in the form of an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CN4CCOCC4)cc3)cc2n1

Procedure:
The title compound was prepared from morpholine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 141-152° C.; LC-MS: 442 (MH+); HPLC RT: 4.10 minutes.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[O:20][CH3:21])=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>C1(C)C(C)=CC=CC=1>[CH3:21][O:20][C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[NH:7][C:5](=[S:24])[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)C(=O)Nc1cc(N2CCOCC2)ccc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Product: COc1ccc(N2CCOCC2)cc1NC(=S)C(=O)O
Temperature: 25 °C
Yield: 170.4 %

Procedure:
To 33.9 g (110 mmol) N-(2-methoxy-5-morpholin-4-yl-phenyl)-oxalamic acid ethyl ester in 652 ml boiling xylene was added 8.80 g (40 mmol) phosphorus pentasulfide in small portions over a period of 30 minutes. The mixture was refluxed for 5 hours, cooled to room temperature and filtered. The solution was extracted 7 times with 100 ml 1N NaOH. The aqueous phase was washed twice with 100 ml toluene, filtered, and treated at 0–5° C. with concentrated hydrochloric acid until pH 1 was reached. Filtration of the precipitate yielded 20.2 g (62%) (2-methoxy-5-morpholin-4-yl-phenylamino)-thioxo-acetic acid as yellow crystals with M.p.: 156–158° C., MS m/e (%): 297 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[Cl:17]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([CH3:10])[CH:12]=2)(=[O:19])=[O:20])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (4.12 g, 20 mmol) in anhydrous pyridine (100 mL) was added 3-methyl-4-chlorobenzenesulfonyl chloride (6.35 g, 26 mmol) and the progress of the reaction was followed by LCMS. The reaction mixture was stirred overnight (18 h), then concentrated to remove as much of the pyridine as possible. The residue was dissolved in THF and was stirred 18 h with aqueous sodium hydroxide (20 mL) in THF to cleave the bis-sulfonamide. The reaction mixture was subsequently neutralized with aqueous HCl and extracted with EtOAc; the organic phase was washed with water (2×100 mL), brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using EtOAc-hexane to provide N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamide as a white crystalline solid. MS m/z 397.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:25]([CH2:26][CH2:27][CH2:28][OH:29])[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: NCCCO
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3CCCO)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminopropane-1-ol, the desired compound was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:15]([NH2:16])[CH2:14][C@H:13]2[CH2:17][C@@H:11]1[C:12]2([CH3:19])[CH3:18].C(N(CC)CC)C.[C:27](Cl)(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][C@H:13]2[CH2:17][C@@H:11]1[C:12]2([CH3:19])[CH3:18]
Reactant: CCCCCC(=O)Cl
Reactant: CC1(C)[C@H]2C[C@H](N)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)N[C@H]1C[C@H]2C[C@@H]([C@@H]1CCOC1CCCCO1)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a atmosphere of argon, to a mixture of (1S,2S, 3S,5R)-10-(tetrahydropyran-2-yloxy)methylpinan-3-ylamine (20 g; prepared in reference example 8), triethylamine (25 ml) and anhydrous tetrahydrofuran (200 ml), a solution of caproyl chloride (13 ml) in anhydrous tetrahydrofuran (30 ml) was dropped and the mixture was stirred for 2 hrs at room temperature. The diluted solution with diethyl ether was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to give the title compound (28 g) having the following physical data: