Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][C:22]\2=[O:23])=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.CO.[BH4-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21][CH:22]\2[OH:23])=[N:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of (E)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (6.41 g) in a mixed solvent of dichloromethane (40 ml) and methanol (40 ml) was added sodium borohydride (436 mg) at 0° C. After the resulting mixture was stirred at 0° C. for 30 minutes, water was added to the mixture to stop the reaction and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (3:7 to 7:3) as eluents to afford the title compound as a colourless solid (5.35 g, yield: 84%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N:12]#[C:13]Br>C(OCC)C>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:6][CH:7]=1)[C:13]#[N:12]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#CBr
Solvent: CCOCC
Product: N#CNc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-aminobenzotrifluoride (15.0 g, 93.1 mmol), cyanogen bromide (12.2 g, 129 mmol) and diethyl ether was stirred at reflux for 40 h. The crude mixture was purified by chromatography using silica gel and a mixture of petroleum ether and dichloromethane as eluent (1:1). The product was isolated as the free base. Yield 5.2 g, 25%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N:12]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22]>O.Cl.C(O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][N:12]=[C:24]([C:25](=[O:27])[CH3:26])[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C(=NNc1ccc(C(F)(F)F)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 4-(trifluoromethyl)aniline (1090 mg, 6.80 mmol) in 5 mL of water and 5 mL of concentrated hydrochloride solution, sodium nitrite (563 mg, 8.16 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1670 mg, 20.40 mmol) and acetylacetone (748 mg, 7.48 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-{[4-(trifluoromethyl)phenyl]hydrazono}pentane-2,4-dione (580 mg, 31%).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].ClC([O:25][C:26]1C=CC(Cl)=CC=1)=O.[CH3:33][S:34]([NH:37][NH2:38])(=[O:36])=[O:35].CCN(C(C)C)C(C)C>O1CCOCC1>[O:25]=[C:26]1[N:38]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])[C:3](=[O:21])[C:4]2[C:5](=[CH:6][C:7]([C:16]([F:17])([F:18])[F:19])=[C:8]([C:10]3[N:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:9]=2)[NH:20]1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2cccnn2)c(C(F)(F)F)cc1N
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3cccnn3)cc2c1=O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a solution of 2-amino-5-pyridazin-3-yl-4-trifluoromethyl-benzoic acid methyl ester (79 mg, 0.266 mmol) in dioxane (4 mL) under argon was added 4-chlorophenyl chloroformate (44.6 μL, 0.319 mmol). The solution was stirred at 85° C. for 30 min and cooled to r.t. CH3SO2NHNH2 (58.5 mg, 0.531 mmol) and i-Pr2NEt (46.4 μL, 0.266 mmol) were added and the reaction mixture was heated back to 85° C. for 3 h. The mixture was concentrated in vacuo and the residue was purified by two consecutive flash chromatographies (silica gel, DCM 5% MeOH in DCM) then (silica gel, 7:3 EtOAc/hexanes). The product was suspended in a minimum amount of EtOAc, sonicated then taken into hexanes. The solid was collected by vacuum filtration to furnish the title compound (13 mg, 12%) as a white solid. API-ES: m/z 402.0 [M+H]+, rt 3.36 min, Method N—05—100: 5%→100% (6 min), 100% (1.5 min), 100%→5% (0.5 min)
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](=[O:13])[CH3:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C1CNC(=O)C1.[Br:20][Br-]Br>CO>[Br:20][CH2:12][C:11]([CH:8]1[CH2:9][CH2:10][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:13]
Reactant: CC(=O)C1CCC2(CCCC2)CC1
Agent: O=C1CCCN1
Solvent: CO
Product: O=C(CBr)C1CCC2(CCCC2)CC1
Yield: 70.2 %

Procedure:
1-Spiro[4.5]dec-8-yl-ethanone (120 mg, 0.66 mmol) was treated with pyrrolidone hydrotribromide (360 mg, 0.72 mmol) in methanol (3 mL) following a method analogous to General Procedure B1 to produce 2-bromo-1-spiro[4.5]dec-8-yl-ethanone (120 mg). This bromo ketone was used without further purification. It was treated with 3-[1-(5-methyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (158 mg, 0.5 mmol) following a method analogous to General Procedure C to afford 3-[(5-methyl-thiophen-2-ylmethyl)-(4-spiro[4.5]dec-8-yl-thiazol-2-yl)-amino]-propionic acid tert-butyl ester after workup and purification (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[O:20]=[C:21]1[CH2:30][CH:29]2[CH2:31][N:32]([CH2:33][C:34]([O-])=[O:35])[C:27]3[C:28]2=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH:22]1.[Li+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:20]=[C:21]1[CH2:30][CH:29]2[CH2:31][N:32]([CH2:33][C:34]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)=[O:35])[C:27]3[C:28]2=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH:22]1
Reactant: O=C([O-])CN1CC2CC(=O)Nc3cccc1c32
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CC2CC(=O)Nc3cccc1c32)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of (−)-5-amino-1,3-dihydrospiro [indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (108 mg, 0.431 mmol, described in Intermediate 3), lithium (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B (100 mg, 0.431 mmol, described in Intermediate 12), EDC (107 mg, 0.560 mmol), HOBT (86 mg, 0.560 mmol), and N,N-diisopropylethylamine (0.113 mL, 0.646 mmol) was stirred in DMF (3 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated in vacuo. The residue was added to saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=466 (M+1). HRMS: m/z=466.1913; calculated m/z=466.1874 for C27H24N5O3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:27])[O:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[O:27])[CH2:13][CH2:14]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A reaction mixture comprising tert-butyl(piperidin-4-ylmethyl)carbamate (1 g, 4.67 mmol), 3,5-dichlorobenzyl carbonochloridate, (1.117 g, 4.67 mmol) and sodium bicarbonate (15 mL, 4.67 mmol) in DCM (15.55 mL) was stirred at room temperature for 18 hours. The reaction mixture was separated and the organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure to give the title compound as a yellow oil;
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:7](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH2:8][O:9][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2]>CC#N.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5]/[C:6](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)=[C:7](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of 50.5 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl acetate in 125 mL of MeCN, 10 mL of PyHF was added and the resulted mixture was stirred at rt for 1.5 hr. The reaction mixture was diluted with 600 mL of toluene and then loaded on silica gel column and eluted with EtOAc. The solvent was evaporated to afford 38.3 g of the titled compound. 1H NMR (acetone-d6, 500 M Hz): δ 7.68 (d, 2H), 7.32 (d, 2H), 7.15–7.00 (m, 5H), 5.20 (s, 2H), 4.62 (d, 2H), 4.09 (t, 1H, OH), 3.02 (s, 3H), 1.92 (s, 3 H),
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[CH:9]=3)=[CH:36][CH:35]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CCC(n3cc(-c4ccc(CC(=O)Nc5ccccc5)cc4)c4c(Cl)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
A mixture of cis-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.18 mmol), N1-phenyl -2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (0.81 g, 2.40 mmol), tetrakis(triphenyl-phosphine)palladium (70 mg, 0.131 mmol) and sodium carbonate monohydrate (0.65 g, 2.40 mmol) in ethylene glycol dimethyl ether (16 mL) and water (8 mL) was heated at 85° C. under an atmosphere of nitrogen for 18 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane/methanol (9:1) as an eluent to give N1-phenyl-2-(4-{4-chloro-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-5-yl}phenyl)acetamide (0.74 g, 62%): 1H NMR (DMSO-d6, 400 MHz) 10.20(s, 1H), 8.66(s, 1H), 7.81(s, 1H), 7.62(d, 2H), 7.52(d, 2H), 7.41(d, 2H), 7.31(t, 2H), 7.04(t, 1H), 4.83(m, 1H), 3.70(s, 2H)<2.05-2.5(m, 13H), 2.17(s, 3H), 1.59-1.77(m, 4H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-100% acetontrile over 10 min, 1 mL/min) tr 8.23 min.; MS:MH+ 543.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 72.5 %

Procedure:
Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 9.1 g (0.03 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 6.7 g (0.03 mole) of 1-(3-chloropropoxy)-4-nitrobenzene were reacted to give 10.5 g of the title compound which was recrystallized from isopropyl ether, m.p. 93.5°-94.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[C:21]1(C)C=[CH:25][C:24](S(O)(=O)=O)=[CH:23][CH:22]=1.C([O-])(O)=[O:33].[Na+]>ClCCl>[O:33]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C

Procedure:
100.26 g (0.35 mol) of methyl 16-hydroxyhexadecanoate, 0.60 g (3.5 mol) of p-toluenesulfonic acid and 350 ml of dichloromethane were introduced into a 1-l flask equipped with a stirrer and a dropping funnel and 32.39 g (0.385 mol) of dihydropyan was dropped thereto under stirring at 0° C. After the completion of the addition, the mixture was stirred at room temperature for additional 1 hour to thereby complete the reaction. Next, the reaction mixture was neutralized by adding 0.59 g (7 mmol) of NaHCO3 and filtered. After distilling off the solvent, crude methyl 16-(2-tetrahydropyranyloxy)hexadecanoate (III-a) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:6](=[S:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:6](=[S:14])[NH:5][C:4](=[O:15])[C:3]=1[N:16]=[O:17]
Reactant: Nc1cc(=O)[nH]c(=S)n1CC1CCCO1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)[nH]c(=S)n1CC1CCCO1
Temperature: 75 °C
Yield: 90.6 %

Procedure:
6-Amino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.3 g, 5.6 mmol) was suspended in 10% aqueous acetic acid (25 mL). Sodium nitrite (0.43 g, 6.2 mmol) was added and this mixture was heated at 75° C. for 1 h. The purple solid was collected by filtration, washed and dried, giving the title product (1.3 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]=1[C:20](O)=[O:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]=1[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:21]
Reactant: COc1cc(-c2ccccc2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: COc1cc(-c2ccccc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (26 mg, 0.18 mmol) and 3-methoxy-1,1′-biphenyl-4-carboxylic acid (D59) (50 mg, 0.22 mmol) as an off-white solid. MS (ES): MH+ 355.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: ClCCCBr
Reactant: Sc1ccccc1Cl
Product: ClCCCSc1ccccc1Cl

Procedure:
Prepared by Procedure R and Scheme Z using 2-chlorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:33])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)=[O:43])=[CH:37][CH:36]=1.C(N(CC)CC)C.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>[C:1]1([O:7][C:8](=[O:33])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:47]([C:44]4([C:42](=[O:43])[NH:41][C:38]5[CH:37]=[CH:36][C:35]([F:34])=[CH:40][CH:39]=5)[CH2:45][CH2:46]4)=[O:48])=[CH:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reaction time: 15.5 h
Yield: 70.4 %

Procedure:
A crude product of [4-(4-aminophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (820 mg) was dissolved in N,N-dimethylformamide (15 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (830 mg), triethylamine (0.519 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.65 g) were added in this order under a nitrogen atmosphere at room temperature, followed by stirring for 15.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The resultant organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white foam (845.8 mg).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>C(O)C.CCOCC>[CH2:1]([S:13][CH2:15][CH:17]([OH:19])[CH2:18][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: BrCC1CO1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCCCCCCSCC(O)CSCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
26.6 ml Dodecanethiol was added to an ethylate solution of 2.6 g sodium in 100 ml ethanol and the solution was stirred for 1 hour at room temperature. Then 8.5 ml epibromohydrin was added dropwise within 30 min and stirred overnight. The residue was taken up in ether after removing the solvent, washed twice with water and dried. The desired compound crystallized on evaporation of the solution. Yield 28.5 g (62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[NH:3]1.[CH3:10][C:11]1[C:12]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:1][C:2]1([CH3:9])[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[C:29]1[CH:30]=[CH:31][C:26]([C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:12]3[C:11]([CH3:10])=[CH:16][C:15]([CH3:17])=[CH:14][N:13]=3)[CH2:19][CH2:20]2)=[O:25])=[CH:27][CH:28]=1
Reactant: CC1(C)CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(C)(C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 1.3 %

Procedure:
Using 3,3-dimethylisothiazolidine 1,1-dioxide (130 mg) described in Preparation Example 11 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (367 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (4.9 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c(Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 94 %

Procedure:
4-Benzyloxyphenyl 2-chloro-4-trifluoromethylphenyl ether (25 g., 0.066 mole), purified by recrystallization from methanol, ethyl acetate (200 ml.) and 10% palladium on charcoal (1.0 g.) are charged to a 2-liter Paar hydrogenation bottle and shaken in a hydrogen atmosphere (40-45 psi) until hydrogen uptake ceases. The catalyst is then removed by filtration and the solvent and toluene are removed in vacuo to give 17.9 g. (94% yield) of 4-(2-chloro- 4-trifluoromethylphenoxy)phenol, mp 55°-6 ° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[C:25]=1[N+:32]([O-:34])=[O:33].C(N(CC)CC)C>C(O)(C)C>[ClH:1].[ClH:1].[ClH:1].[CH3:31][C:26]1[C:25]([N+:32]([O-:34])=[O:33])=[C:24]([NH:23][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][N:7]([CH:10]([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)[CH2:6][CH2:5]2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: ClCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc(N)c([N+](=O)[O-])c(C)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(NCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c(C)n1
Product: Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In accordance with process variant (c), 10 g (0.08 mol) of 1-(2-chloroethyl)-4-diphenylmethylpiperazine, 13.4 g (0.08 mol) of 4-amino-2,6-dimethyl-3-nitropyridine and 10 g (0.1 mol) of triethylamine were dissolved in 300 ml of isopropanol in a 500 ml round-bottomed flask, and the solution was heated to boiling for 10 hours. It was then cooled to room temperature, and the precipitate was filtered off with suction. The latter was extracted by stirring with ethyl acetate, and the mixture was filtered and the filtrate was evaporated to dryness. The remaining residue was taken up in ethanol, and ethanolic HCl was added. The solution was evaporated to dryness in vacuo, and the residue was recrystallized from Isopropanol/diisopropyl ethyl (4:1; vol.).