Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:6][N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[CH3:1][S:2]([C:3]1[S:4][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:6][N:7]=1)=[O:23]
Reactant: CSc1nnc(-c2ccc3ccccc3c2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nnc(-c2ccc3ccccc3c2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylsulfanyl-5-naphthalen-2-yl-[1,3,4]thiadiazole (1.3 g, 5.03 mmol) in dichloromethane (50 ml) was added 50% moisten 3-chloro peroxybenzoic acid (1.9 g, 5.53 mmol) at 0° C. After stirred for 1 h at 0° C. the reaction was diluted with dichloromethane (50 ml) and quenched with addition of saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase was separated and washed with water (50 ml), dried (MgSO4), filtered and evaporated in vacuo. The residue (1.4 g) was purified by column chromatography on silicagel (400 ml) using a mixture of ethyl acetate and heptane (1:1) as eluent. This afforded after drying in vacuo at 50° C. 0.9 g (65%) of the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][S:12][CH:13]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[N:14]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][S:12][CH:13]=1)=[N+:15]=[N-:16]
Reactant: BrCc1ccccc1-c1csnn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccccc1-c1csnn1

Procedure:
A solution of 4-(2-bromomethyl-phenyl)-[1,2,3]thiadiazole (7.0 g, 0.027 mol) and sodium azide (5.3 g, 0.081 mol) in N,N-dimethylformamide (200 ml) was stirred at room temperature overnight. Ethyl acetate was added and the reaction mixture was washed with water and brine. Drying and solvent evaporation gave an oil; flash chromatography (silica gel, hexane-ethyl acetate, 96:4) gave 4-(2-azidomethyl-phenyl)-[1,2,3]thiadiazole; 1H NMR (CDCl3, 300 MHz) δ8.74 (s, 1H), 7.76 (m, 1H), 7.53 (m, 3H), 4.54 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[CH2:28][C:27](=O)[CH2:26][CH2:25]2>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][CH:27]2[CH2:26][CH2:25][C:24]3[C:29](=[C:30]([F:32])[CH:31]=[C:22]([F:21])[CH:23]=3)[CH2:28]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CD3OH) 13.0, 18.1, 24.5, 25.4, 25.8, 27.5, 32.8, 53.1, 53.2, 57.9, 64.7, 100.8, 101.1, 109.9, 110.4, 110.8, 115.8, 128.4, 131.6, 132.3, 139.1, 139.3, 159.5, 160.2, 166.8, 171.2; MS 449.3 m/z (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:22]1([NH:28][C:29]2[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]3[N:40]=C(C4SC=CN=4)O[N:37]=3)[N:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:22]1([NH:28][C:29]2[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]3[N:37]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[O:9][N:40]=3)[N:30]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3nccs3)n2)n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: c1ccncc1
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ccccn3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of picolinic acid (90 mg, 0.73 mmol) and carbonyl di-imidazole (0.12 g, 0.73 mmol) in pyridine (1 ml) was stirred for 2 h. N-Phenyl-6-(5-thiazol-2-yl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Intermediate 4, 100 mg, 0.41 mmol) was added and the resulting mixture was heated to 100 C and stirred for 24 h. In a separate vessel, a second mixture of picolinic acid (90 mg, 0.73 mmol) and carbonyl di-imidazole (0.12 g, 0.73 mmol) in pyridine (1 ml) was stirred for 90 minutes and added to the first mixture, which was stirred for a further 24 h at 100 C. The mixture was cooled to room temperature, concentrated under vacuum and suspended in aqueous sodium hydrogencarbonate solution. The solid was filtered off, washed with water, ethyl acetate and methanol and dried under vacuum to give the title compound (73 mg, 54%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:42]([O:44][CH3:45])=[O:43])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][C:23]([CH2:26][CH2:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:42]([O:44][CH3:45])=[O:43])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]4[O:22][C:23]([CH2:26][CH2:27][C:28]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[O:29])=[CH:24][N:25]=4)[CH2:18][C:17]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(c1ncc(CCC(=O)N2CCOCC2)o1)=Cc1cc(OC)ccc1-3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(c1ncc(CCC(=O)N2CCOCC2)o1)Cc1cc(OC)ccc1-3
Temperature: 25 °C
Reaction time: 22 h
Yield: 93 %

Procedure:
Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (610 mg, 1.00 mMol)) was dissolved in 15 ml of THF and 5 ml of methanol. To this reaction was added 83 mg of 10% palladium on carbon. The reaction was placed under hydrogen atmosphere (1 atm, balloon pressure) and stirred at room temperature for 22 hrs. The reaction was filtered through a celite plug and rinsed with THF. Volatiles were removed from the filtrate in vacuuo to yield 569 mg (93%) of the title compound as a yellow solid. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=3 min; Runtime=4 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=2.55 min, MS m/z 612(MH+).
Reaction SMILES: C([N:8]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)[CH2:9][C@H:10]([OH:32])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:24]CC2C=CC=CC=2)=[C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:24][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C@@H:10]([OH:32])[CH2:9][NH:8][C@H:33]2[CH2:38][CH2:37][C@H:36]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)[CH2:35][CH2:34]2)=[CH:18][C:17]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(O)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(O)cc3)CC2)ccc1O
Reaction time: 2 h

Procedure:
A mixture of 0.8 g (1.26 mmol) of trans-N-[5-[((2S)-3-{benzyl[4-(4-hydroxyphenyl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]methanesulfonamide and of 0.2 g of 10% palladium-on-charcoal (50% in water) in ethanol (40 ml) is placed under hydrogen atmosphere and stirred for 2 h. The reaction mixture is filtered through celite. The solvents are evaporated under reduced pressure and trans-N-{2-hydroxy-5-[((2S)-2-hydroxy-3-{[4-(4-hydroxyphenyl)cyclohexyl]amino}propyl)oxy]phenyl}methanesulfonamide is obtained in the form of a white solid (0.24 g, 67%) after purification on silica gel (eluent: dichloromethane/methanol, 95/5 to 80/20 gradient in 15 min).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:26])=[C:13]([C:15]2[NH:24][C:23](=O)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH:14]=1.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:26])=[C:13]([C:15]2[N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH:14]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: Nc1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(Br)cc1-c1nc(Nc2ccncc2)c2nccnc2n1
Reaction time: 12 h
Yield: 32.9 %

Procedure:
Triethylamine (1.04 mL, 7.17 mmol) was added to a solution of 2-(5-bromo-2-fluoro-phenyl)pteridin-4-one 104 (800 mg, 2.49 mmol), 4-aminopyridine (469 mg, 4.98 mmol) and PyBOP (2.59 g, 4.98 mmol) in CH2Cl2. After 12 h, the reaction mixture was partitioned between CH2Cl2/Petroleum ether (2:1, 300 mL) and ice-cold 1N HCl (300 mL). The pH of the water phase was adjust to 12 with conc. NaOH and extracted with AcOEt, dried (Na2SO4) and evaporated. The residue was triturated in CH2Cl2/Petroleum ether (2:1, 15 mL), filtered off, and washed with ether. The product was purified by column chromatography (AcOEt/CH2Cl2/MeOH, 5:4:1) to give 325 mg of the title product 1 as a yellow powder (LCMS analysis).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11](C)[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[ClH:26]>C1COCC1.O1CCOCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[NH:11][C:10](=[O:25])[C:9]=2[Cl:26])[CH2:3]1
Reactant: Cl
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at RT for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): 8 ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1 H), 7.68 (t, J=7.7 Hz, 1 H), 7.49 (t, J=7.7 Hz, 1 H), 7.36 (d, J=7.8 Hz, 1 H), 5.09-5.21 (m, 2 H), 3.17 (m, 2 H), 2.96 (t, J=11.1 Hz, 1 H), 2.86 (d, J=10.6 Hz, 1 H), 2.65 (m, 1 H), 1.90 (d, J=11.6 Hz, 1 H), 1.57 (d, J=13.1 Hz, 1 H), 1.19-1.31 (m, 1 H), 1.03-1.15 (m, 1 H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: COc1ccc(CN)cc1
Reactant: C#Cc1cccc(Nc2ncnc3cnc(F)cc23)c1
Solvent: CS(C)=O
Product: C#Cc1cccc(Nc2ncnc3cnc(NCc4ccc(OC)cc4)cc23)c1
Temperature: 70 °C
Reaction time: 158 h
Yield: 80.1 %

Procedure:
A mixture of compound 164 (8.90 g, 33.7 mmol) and 4-methoxybenzylamine (44.2 mL, 337 mmol) in dry DMSO (80 mL) was stirred under nitrogen at 70° C. (bath temperature) for 158 h. The resultant solution was cooled briefly and then stirred with petroleum ether (2×400 mL) at room temperature for 15 min before the petroleum ether layer was decanted. Water (400 mL) was added to the DMSO layer and the mixture was stirred at room temperature for 3 h. The solid thus precipitated was collected by filtration and washed with water (5×100 mL), before being suctioned dry and then washed with petroleum ether (2×100 mL) and suctioned dry again. The resultant brownish orange solid was dissolved in warm acetone (400 mL) and water (500 mL) was added. The mixture was then stirred at room temperature for 1 h and the resultant solid was collected by filtration, washed with acetone/water (1:1, 5×80 mL) and dried in vacuo over silica-gel, to give N4-(3-ethynylphenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (167) (10.3 g, 80%) as a yellow/orange solid, mp 200-203° C.; 1H NMR δ [(CD3)2SO] 9.63 (s, 1H), 8.75 (s, 1H), 8.38 (s, 1H), 8.03 (br s, 1H), 7.94-7.88 (m, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.34 (br d, J=8.6 Hz, 2H), 7.28-7.21 (m, 2H), 7.19 (s, 1H), 6.92-6.85 (m, 2H), 4.50 (d, J=6.3 Hz, 2H), 4.19 (s, 1H), 3.71 (s, 3H). Anal. Calcd for C23H19N5O: C, 72.42; H, 5.02; N, 18.36%. Found C, 72.28; H, 5.05; N, 18.22%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([C:22](OC)=[O:23])[CH2:10]1.[Li+].[BH4-]>C1COCC1.CO>[OH:23][CH2:22][CH:11]1[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: COC(=O)C1CC(c2ccccc2OC)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)C(CO)C1
Reaction time: 8 h

Procedure:
At 0° C., to a solution of 1-tert-butyl 2-methyl 4-(2-methoxyphenyl)piperidine-1,2-dicarboxylate 124 (640 mg, 1.83 mmol) in THF (10 mL) and MeOH (0.5 mL), LiBH4 (60 mg, 2.74 mmol) was added. The reaction solution was stirred at r.t overnight, The reaction was quenched with water and the mixture was extracted with ethyl acetate. After removal of solvent, the crude product of tert-butyl 2-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate 125 was obtained without further purification. LC/MS RT (5 min method)=2.027 min. Mass observed: 222.2 (M-Boc+H).
Reaction SMILES: CSSC.CSC1C(N)=C(C)C=CC=1N.[CH3:16][S:17][C:18]1[C:19]([NH2:28])=[C:20](SC)[C:21]([NH2:25])=[C:22]([CH3:24])[CH:23]=1>>[CH3:16][S:17][C:18]1[C:19]([NH2:28])=[CH:20][C:21]([NH2:25])=[C:22]([CH3:24])[CH:23]=1
Reactant: CSc1cc(C)c(N)c(SC)c1N
Agent: CSc1c(N)ccc(C)c1N
Solvent: CSSC
Product: CSc1cc(C)c(N)cc1N
Reaction time: 16 h

Procedure:
This example demonstrates preparation of a chain extender having the inventive aromatic diamine as a minor proportion. The reaction time was shorter. A sample was prepared using a single equivalent of methyl disulfide (95.4 g) under similar reaction conditions and the reaction was completed in 16 hours. The product was predominantly mono(methylthio)-2,4-diaminotoluene containing a minority portion of di(methylthio)-2,4-diaminotoluene. A distilled fraction (b.p. 156-161 @ 1.0 mm) had the following analysis:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]([N:35]2[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]2)[N:7]=1
Reactant: CCN1CCNCC1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2nc(Cl)c(C(=O)OC)c(Nc3cccc(C)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.3 %

Procedure:
A mixture of methyl 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylate (502.6 mg, 1.610 mmol), N-ethyldiisopropylamine (0.3 mL, 1.718 mmol) and N-ethylpiperazine (0.21 mL, 1.653 mmol) in THF (8 mL) was stirred at RT for 12 h. Saturated aq NaHCO3 was added and the resulting mixture was extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound (152.6 mg, 24%). 1H NMR (500 MHz, CDCl3) δ ppm 1.12 (t, J=6.5 Hz, 3H), 2.35 (s, 3H), 2.48 (br s, 6H), 3.82-3.97 (m, 7H), 6.92-6.93 (m, 1H), 7.21-7.22 (m, 1H), 7.37-7.42 (m, 2H), 10.45 (s, 1H). [M+H] calc'd for C19H25ClN5O2, 390; found, 390.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1cccc(OC[C@H]2CO2)c1
Solvent: CC(C)O
Product: CC(O)c1cccc(OC[C@H]2CO2)c1
Reaction time: 14 h
Yield: 98 %

Procedure:
Chiral hydrogenation of (R)-glycidyl 3-acetylphenyl ether was carried out (see formula (12) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using (R)-glycidyl 3-acetylphenyl ether (481 mg; 2.5 mmol) as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 14 hours. As a result, one of the stereoisomers of (R)-glycidyl 3-(1-hydroxyethyl)phenyl ether was obtained at a conversion rate of 99%, isolation yield of 98% (475 mg; 2.45 mmol), and enantiomeric excess of 99%. GC (column: Chirasil-DEX CB; column temperature: 135° C.; injection and detection temperature: 250° C.; helium pressure: 60 kPa; tR of (R)-glycidyl (R) or (S)-3-(1-hydroxyethyl)phenyl ether: 94.9 minutes (98.6%); tR of the stereoisomers: 109.6 minutes (0.5%); tR of (R)-glycidyl 3-acetylphenyl ether: 46.5 minutes (0.9%); [α]29D: +32.0° (c: 1.36; CHCl3); The absolute structure was not determined.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:23][CH:24]=1.O>CN(C)C=O>[CH3:31][C:25]1([C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:3][C:4]3[CH:17]=[CH:16][C:7]([CH2:8][CH:9]4[S:13][C:12](=[O:14])[NH:11][C:10]4=[O:15])=[CH:6][CH:5]=3)[N:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC1(c2nc(CCl)co2)CCCCC1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)co2)CCCCC1
Reaction time: 0.5 h

Procedure:
60% sodium hydride in oil (1.32 g) was added to solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (3.35 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred for 30 minutes. Then, solution of 4-chloromethyl-2-(1-methylcyclohexyl)oxazole (3.85 g) in N,N-dimethylformamide (5 ml) was added dropwise thereto at room temperature. After being stirred at 60° C. for 1 hour, the reaction solution was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The oily residue was chromatographed on a column of silica gel (70 g). Elution with hexaneethyl acetate (2:1, V/V) gave 5-{4-[2-(1-methylcyclohexyl)-4-oxazolylmethoxy]benzyl}-2,4-thiazolidinedione as an oily substance. A solution of sodium 2-ethylhexanoate in isopropanol (2N, 3 ml) was added to the oily substance, and treated with ether. The crystals which separated out were collected by filtration to give 5- {4-[2-(1-methylcyclohexyl)-4-oxazolylmethoxy]benzyl}-2,4-thiazolidinedione.sodium salt (2.3 g, 36.3%). Recrystallization from methanol afforded colorless plates. m.p. 285°-287° C. (decomp.) Elemental analysis for C21H23N2O4SNa, Calcd.: C, 59.70; H, 5.49; N, 6.63. Found: C, 59.76; H, 5.56; N, 6.82.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)[OH:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[CH:35][C:31]=2[C:32](O)=O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>O>[CH3:29][O:28][C:27]1[C:26](=[O:16])[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[C:30]1[C:31](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:39][CH3:40])[CH:38]=1)[CH:32]=2
Reactant: COc1ccc(-c2cc(OC)c(OC)cc2C(=O)O)cc1OC
Reactant: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COC1=C(OC)C(=O)C2=Cc3cc(OC)c(OC)cc3C2=C1
Temperature: 100 °C

Procedure:
Polyphosphoric acid which had been newly prepared from diphosphorus pentaoxide (50 g) and phosphoric acid (50 ml) was heated at 100° C. With stirring, 2-(3,4-dimethoxyphenyl)-4,5-dimethoxybenzoic acid (7.5 g) was added thereto as it is (in the crystal form) in several portions. After stirring at 100 to 120° C. for 2 hours, the reaction solution was poured into water (1.5 liter) and extracted with chloroform. The extract was washed with 2% aqueous sodium hydroxide solution, water and a saturated saline solution, then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethyl acetate-n-hexane to give 5.0 g of 2,3,6,7-tetramethoxyfluorenone as an orange needle-like crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: Brc1ccccn1
Product: CC(=O)c1ccc(Oc2ccccn2)cc1
Yield: 73 %

Procedure:
4'-Hydroxyacetophenone was condensed with 2-bromopyridine by Ullmann reaction to obtain 4'-(pyridine-2-yloxy)acetophenone (yield 73%). This was converted to Mannich base with dimethylamine hydrochloride and paraformaldehyde (yield 56%), which was then cyclized by reacting with 1-ethoxycarbonylmethylpyridinium chloride and ammonium acetate in N,N-dimethyl formamide, (as described in Synthesis (1976), pages 1-24) to obtain 6-[4-(pyridine-2-yloxy)phenyl]-2-pyridone (yield 32%).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=5)[CH:25]=4)[CH:20]=[CH:19]3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.O.[Sn](Cl)Cl.O.N.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=5)[CH:25]=4)[CH:20]=[CH:19]3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-n3ccc4ccc(-c5cccc([N+](=O)[O-])c5)cc43)ncnc21
Agent: Cl[Sn]Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)OCn1ccc2c(-n3ccc4ccc(-c5cccc(N)c5)cc43)ncnc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
(4-(6-(3-Nitrophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (166 mg, 0.35 mmol) was dissolved in ethanol (5 mL). After adding tin(II) chloride dihydrate (SnCl2.2H2O; 80 mg, 1.75 mmol), the reaction mixture was stirred at 80° C. for 1.5 hours. After cooling to room temperature and alkalinizing the reaction mixture to pH 8 with ammonia water, ethyl acetate and sodium carbonate were added. The mixture solution was filtered through a diatomite pad and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, DCM:MeOH=20:1) yielded (4-(6-(3-aminophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (120 mg, 0.27 mmol) as ivory solid.