Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.CN(C)[CH:26]=[CH:27][C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O.[ClH:37]>C(O)(=O)C.C(O)(C)C>[ClH:37].[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[C:6]([C:7]#[N:8])=[C:2]4[N:1]=[CH:26][CH:27]=[C:28]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[N:3]4[N:4]=3)[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: COc1cccc(CN2CCN(c3[nH]nc(N)c3C#N)CC2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cccc(CN2CCN(c3nn4c(-c5cccnc5)ccnc4c3C#N)CC2)c1

Procedure:
A mixture of 5.0 g of 3-amino-5-[4-[(3-methoxyphenyl)methyl]-1-piperazinyl]-1H-pyrazole-4-carbonitrile (prepared as described in Example 19) and 2.9 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (U.S. Pat. No. 4,281,000, Example 1) in 25 ml of glacial acetic acid was heated at reflux for 3 hours. The work procedure of Example 21 was followed to obtain a gummy solid. The solid was dissolved in isopropanol and was treated with 20 ml of 2.9N ethanolic hydrochloric acid. The yellow precipitate formed was collected by filtration, washed with isopropanol and dried in vacuo. The product was recrystallized from ethanol/water and gave 2.5 g of the desired product as a yellow solid, mp >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].Br[CH2:22][CH2:23][O:24][CH2:25]C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:25][O:24][CH2:23][CH3:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. of dimethylformamide is treated under nitrogen with 1.17 g. of sodium borohydride in 10 ml. of dimethylformamide at not greater than 30° C. The mixture is stirred at 15° to 20° C for 1 hour, then treated with 5 g. of 2-bromoethyl ethylether at 20°-25° C. The mixture is heated to 100° C for 2 hours, then cooled and diluted with water. The product is extracted with chloroform and after drying of the chloroform solution with sodium sulfate, 1-amino-2-nitro-4-(2-ethoxyethylthio) benzene is obtained by evaporation of the solution.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[CH:13]/[O:14][CH3:17])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=CO)c1ccccc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(\C(=O)OC)c1ccccc1C
Reaction time: 1 h

Procedure:
A solution of 44 g of the product of Step B in 400 ml of tetrahydrofuran was introduced at 20°-25° C. into a solution of 700 ml of tetrahydrofuran and 11 g of sodium hydride (50% in oil). The reaction mixture was stirred for one hour and 150 ml of methyl iodide were added. The mixture was stirred for 5 hours and poured into water. Extraction was carried out with methylene chloride and the extracts were dried and brought to dryness to obtain 47.2 g of product which was chromatographed on silica and eluted with hexane-ethyl acetate mixture (7-3) to obtain the following:
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])[C:9](=[O:15])[N:8]([CH2:16][CH2:17][CH2:18][Cl:19])[N:7]=[CH:6]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH3:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClC1C=CC=CC=1>[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([CH2:16][CH2:17][CH2:18][N:32]([CH3:33])[CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)[N:7]=[CH:6]2
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1cc2cnn(CCCCl)c(=O)c2cc1OC
Solvent: Clc1ccccc1
Product: COc1ccc(CCN(C)CCCn2ncc3cc(OC)c(OC)cc3c2=O)cc1OC
Product: Cl

Procedure:
1-[6,7-Dimethoxy-1(2H)-phthalazinone-2-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane hydrochloride was prepared analogous to Example 1 (b) by reaction of 1-[6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-methylamine in chlorobenzene. M.p.: 200° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[N:9]=[CH:10][C:3]=23)[CH2:32][CH2:33]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (308 mg, 1 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (257 mg, 1.2 mmol) and potassium carbonate (166 mg, 1.2 mmol) in THF (10 mL) was stirred at rt overnight. The mixture was purified by column chromatography to provide Compound A35 as a solid (76%). 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.74-2.04 (m, 8H), 3.09 (s, 3H), 3.73 (s, 1H), 4.62 (s, 1H), 8.07-8.09 (m, 3H), 8.49 (s, 1H), 8.57-8.59 (m, 2H). Exact mass calculated for C23H30N6O4S 486.2, found 487.2 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].S(Cl)(Cl)=O>CO>[CH:10]([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:15])[CH3:16])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=1)([C:9]1[C:8]([OH:13])=[C:7]([CH:14]([CH3:16])[CH3:15])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:12]=1)[C:25]1[C:24]([OH:27])=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=1
Reactant: CC(C)c1cc(C(C)(C)C)cc(C=O)c1O
Reactant: CC(C)c1cc(C(C)(C)C)ccc1O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C)c1cc(C(C)(C)C)cc(C(c2cc(C(C)(C)C)cc(C(C)C)c2O)c2cc(C(C)(C)C)cc(C(C)C)c2O)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Compound 3 was synthesized as described elsewhere with minor modifications.6 Briefly, a sample of 5-(tert-butyl)-2-hydroxy-3-isopropylbenzaldehyde (2) (5.08 g, 24.3 mmol) was combined with 2 equivalents of 4-(tert-butyl)-2-isopropylphenol (1) (9.17 g, 47.7 mmol) and 14 mL of methanol in a 100 mL schlenk flask. With a sodium carbonate trap connected to the reaction flask, the reaction mixture was cooled to 0° C. and thionyl chloride (11.4 mL, 157.7 mmol) was added dropwise causing an immediate change from orange/yellow to dark purple for the reaction mixture. The reaction was stirred overnight. The precipitate that was formed was collected by filtration. The residue was recrystallized from hexanes to afford 3 as a pale purple solid (6.88 g) in 48% yield with respect to the starting salicylaldehyde. 1H NMR (CDCl3-d) δ ppm 1.20 (27 H, s), 1.26 (18 H, d, J=6.9 Hz), 3.22 (3 H, spt, J=6.9 Hz), 4.91 (3 H, s), 5.83 (1 H, s), 6.81 (3 H, d, J=2.3 Hz), 7.18 (3 H, d, J=2.3 Hz). 13C-{1H} NMR, δ 22.7, 27.5, 31.4, 34.3, 41.8, 122.2, 123.7, 125.7, 135.0, 143.5, 148.9. Anal. calcd. for C40H58O3: C, 81.86; H, 9.96; N, 0.00. Found: C, 81.79; H, 10.32; N, 0.00.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>C(#N)C>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCN(C(=O)c2ccccc2)CC1

Procedure:
0.10 g (0.53 mmol) 1-benzoylpiperazine and potassium carbonate 0.22 g (1.58 mmol, 3.0 eq.) were added to 5 ml acetonitrile and 0.05 g (0.53 mmol, 1.0 eq.) chloroacetone was added dropwise slowly at room temperature. After mixing for one hour, 5 ml purified water was added, and the reaction mixture was extracted with 10 ml ethylacetate three times. After collecting organic layer, drying with anhydrous magnesium sulfate, and concentrating with decompression, residues obtained were purified with silicagel chromatography (mobile phase: dichloromethane/methnol=10:1) and 0.11 g (83%) target compound as yellow serup were yielded.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=3)[C:14]=2[C:15]([OH:17])=[O:16])[N:5]=1.[H-].[Na+].Cl[CH2:37][O:38][CH3:39]>CN(C)C=O>[F:33][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[N:24]=[C:25]([O:31][CH3:32])[CH:26]=[C:27]([O:29][CH3:30])[N:28]=3)[C:14]=2[C:15]([O:17][CH2:37][O:38][CH3:39])=[O:16])[N:5]=1
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC(F)F)n3)c2C(=O)O)n1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1Oc1nc(OC)cc(OC(F)F)n1
Yield: 82.5 %

Procedure:
0.9 g of (1.9 mmol) of 2-(4-difluoromethoxy-6-methoxypyrimidin-2-yl)oxy-6-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid, 0.1 g of 60% sodium hydride and 0.2 g of chloromethylmethylether were reacted in N,N-dimethylformamide, treated and purified in the same manner as in Example 1 to obtain 0.8 g of a colorless transparent viscous liquid having a refractive index of nD20 =1.5389.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[Br:19][C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: OB(O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Br)s2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (1.00 g, 2.75 mmol) and commercially available 5-bromthiophene-2-boronic acid (0.570 g, 2.75 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.480 g, 43%). MS (ISP) 398.0 [(M+H)+] and 400.0 [(M+2+H)+].
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.N1C=CN=C1.[CH2:18]([O:20][CH:21]([O:33][CH2:34][CH3:35])[CH2:22][O:23][C:24]1[CH:25]=[C:26]([NH2:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:19].CO[C:38](=[O:54])[C:39]([CH3:53])([NH:41][CH2:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=[CH:45][CH:44]=1)[CH3:40]>O1CCCC1>[CH2:34]([O:33][CH:21]([O:20][CH2:18][CH3:19])[CH2:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[C:38](=[O:54])[C:39]([CH3:40])([CH3:53])[N:41]([CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:46]=[CH:45][CH:44]=3)[C:6]2=[O:7])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:35]
Reactant: CCOC(COc1cc(N)ccc1OC)OCC
Reactant: COC(=O)C(C)(C)NCc1ccnc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOC(COc1cc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)ccc1OC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 317 mg di-imidazol-1-yl-methanone and 20 mg imidazole in 4 ml tetrahydrofuran a solution of 500 mg 3-(2,2-diethoxy-ethoxy)-4-methoxy-phenylamine in 2 ml tetrahydrofuran was slowly added at 0° C. After stirring at 0° C. for 1 hour 505 mg 2-methyl-2-[(quinolin-4-ylmethyl)-amino]-propionic acid methyl ester were added and the reaction mixture was allowed to warm up to room temperature. After 2 hours stirring at room temperature the solution was heated for 2 hours at 70° C. After cooling to room temperature the solvent of the mixture was removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid. Yield: 300 mg
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](N3CCOCC3)=[C:9]([C:19](=[S:22])[NH:20][CH3:21])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH2:24]>C(O)C>[CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:24])[CH:9]([C:19](=[S:22])[NH:20][CH3:21])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=S)C1=C(N2CCOCC2)CCC(C2CCCCC2)C1
Reactant: O
Agent: Cl
Solvent: CCO
Product: CNC(=S)C1CC(C2CCCCC2)CCC1=O
Reaction time: 0.5 h

Procedure:
1 g of 4-cyclohexyl 2-methylthiocarbamoyl 1-morpholyl cyclohex-1 ene is dissolved in 20 ml ethanol at room temperature. To this solution 2 ml 4 N hydrochloric acid solution are added and the mixture becomes pale yellow. The reaction mixture is kept under stirring for 1/2 hour. 60 ml water are then added and a brownish-red precipitate appears. It is sucction-filtered, washed with water and further taken up in benzene until complete solution. The benzenic solution is dried, filtered and evaporated to dryness. The dry residue is further washed with water then taken up with benzene. After distillation of the solvent 0.7 g of 4-cyclohexyl 2-methyl thio carbamoyl cyclohexanone are thus obtained which is used as such for the next step of the synthesis.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C-:13]#[N:14].[Na+].[Cu][C:17]#[N:18]>CC(C)=O>[C:1]([C:17]#[N:18])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]#[N:14])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CC(=O)c1ccc(C(=O)C#N)cc1
Temperature: 220 °C
Reaction time: 1.5 h

Procedure:
203 g (1 mol) of terephthalic acid dichloride, 97 g (1.94 mol) of sodium cyanide and 5.4 g of copper(I) cyanide were mixed in a reaction vessel, whilst stirring, and the mixture was slowly heated to 220° C. A distinctly exothermic reaction took place. After 90 minutes at 276° C., the mixture was allowed to cool and 400 ml of acetone were added. The residue was separated off by filtration and terephthalic acid dicyanide was obtained from the filtrate by fractional distillation.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:9]
Reactant: Cc1ccsc1C(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccsc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 95.1 %

Procedure:
3-Methyl-2-thiophenecarboxylic acid (28 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (42 mg, yield 95%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:35][C:34]3[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(CN[C@@H](CC(C)C)C(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 3,4,5-trimethoxybenzaldehyde (0.244 g, 1.25 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 15 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.46 and 0.15. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.15) was isolated by flash chromatography (50% EtOAc in hexanes). Eighty-four percent (0.61 g) of the pure titled compound was obtained as a white foam: mp 58-62° C. APCI-MS m/z 582.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1(CO)[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH:36]1[CH2:38][CH2:37]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: OCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CC4)c(Cl)c3)c2cc1OC
Yield: 75.6 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopropylmethanol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[C:12](Cl)=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)([O-:10])=[O:9]>N1C=CC=CC=1.CCOC(C)=O>[N+:8]([C:11]1[C:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(Nc2ccccc2)ccc2cccnc12
Temperature: 170 °C
Yield: 90.3 %

Procedure:
Aniline (2 ml, 21 mmol) was added to a solution of 8-nitro-7-chloroquinoline 40 (200 mg, 0.96 mmol) in pyridine (1 ml) and the mixture was heated in a microwave at 170° C. under nitrogen for 3 h. The residue was dissolved in EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 (30 ml) and concentrated in vacuo to give the title compound (230 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:19][C:20]([NH2:22])=[S:21].C([O-])(O)=O.[Na+]>CCO>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=2)[N:19]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2csc(N)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-bromoacetyl)-N-tert-butylbenzenesulfonamide (8.71 g, 26.1 mmol) in EtOH (45 mL) was added thiourea (2.38 g, 31.3 mmol). The reaction mixture was heated to 70° C. for 15 h and poured into an aqueous solution of NaHCO3. The mixture was stirred for 30 min. The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(2-aminothiazol-4-yl)-N-tert-butylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([NH-])C.Cl.C(N)C.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[N:40]=[CH:39][CH:38]=[CH:37][C:19]=3[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:36])([C:32](=[O:35])[NH:33][CH3:34])[CH3:31])=[CH:26][CH:25]=3)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[N:40]=[CH:39][CH:38]=[CH:37][C:19]=3[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:32](=[O:35])[NH:33][CH2:34][CH3:1])([CH3:36])[CH3:31])=[CH:26][CH:25]=3)=[O:21])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CNC(=O)C(C)(C)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Reactant: CC[NH-]
Agent: CCN
Agent: Cl
Product: CCNC(=O)C(C)(C)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1

Procedure:
The remaining portion of the tetrahydrofuran solution from Example 5a (10 mL) was converted to the ethyl amide with ethylamine hydrochloride using the same procedure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)=[N+]=[N-]>C1COCC1.O>[NH2:20][CH:23]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(COc2ccc(C(N=[N+]=[N-])c3ccccc3)cc2)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(C(N)c3ccccc3)cc2)o1
Temperature: 60 °C
Yield: 110.1 %

Procedure:
To a suspension of triphenylphosphine polymer supported (633 mg, 0.89 mmol) in THF (3 mL) was added a solution of methyl 5-((4-(azido(phenyl)methyl)phenoxy)-methyl)furan-2-carboxylate (293 mg, 0.81 mmol) in THF (6.1 mL) and H2O (0.12 mL). The reaction was stirred very slowly and heated at 60° C. for 18 h. Triphenylphosphine polymer supported (300 mg) and water (62 μL) were added and the heating was maintained at 60° C. for 5 h. The reaction was then allowed to cool to room temperature. The resin was removed by filtration, washed twice with THF and DCM. The combined organic phases were dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound (301 mg) which was taken on to the next step without further purification.