Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl>[O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, condenser, and nitrogen bubbler was charged with 351 g (1.61 mol) of benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate (Intermediate 1, Step A), 6 L of dichloromethane, 500 g of powdered molecular sieves, and 400 g (3.41 mol) of N-methylmorpholine-N-oxide. The resultant suspension was stirred at ambient temperature and to this was added 12.9 g (0.0367 mol) of tetrapropylammonium perruthenate. The reaction temperature was kept at ≦30° C. with a cold water bath. The mixture was stirred at ambient temperature for 2 h. The mixture was poured onto a plug of 5 kg of silica gel and eluted with 10% ethyl acetate/dichloromethane to give the title compound as an orange oil.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].B(F)(F)F.[CH2:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:10]1[O:12][CH2:11]1.C(OCC1OC1)C1OC1.C(=O)(O)[O-].[Na+]>CCOCC>[CH3:1][C:2]1([CH3:4])[O:12][CH:10]([CH2:9][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:3]1
Reactant: CC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC1CO1
Agent: C(OCC1CO1)C1CO1
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCOCC1COC(C)(C)O1
Reaction time: 1 h
Yield: 90 %

Procedure:
Into a round bottom flask having a capacity of 500 ml and equipped with a reflux condenser, a thermometer, a dropping funnel, a nitrogen gas supply tube, and a stirring means, 81.2 g (1.4 moles) of acetone, and 2.0 g (0.014 mole) of boron trifluoride etharate were charged and stirred while supplying a nitrogen gas. Then, 64.9 g (0.2 mole) of oleyl glycidyl ether was gradually added dropwise while supplying a nitrogen gas. The reaction mixture generates heat as the glycidyl ether is added. Therefore, the reaction mixture was cooled to maintain a temperature of from 20° to 30° C., and it took about one hour for the addition of the glycidyl ether. The stirring was continued for further one hour. After confirming by the gas chromatograph of the reaction mixture that the glycidyl ether completely disappeared, the reaction mixture was poured into a dilute aqueous solution of sodium bicarbonate whereby the acid was neutralized. Ether was added thereto and the mixture was stirred, and thereafter the ether layer was collected by separation. Anhydrous sodium sulfate was added for dehydration, and the solvent was removed by distillation under a reduced pressure thereby to obtain 68.8 g (yield: 90%) of colourless, transparent 2,2-dimethyl-4-oleyloxymethyl- 1,3-dioxolan.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(CC)=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2CCCN2)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCN1CCCC1Cc1ccc(Cl)cc1

Procedure:
Boil 5 g of 2-(4-chlorobenzyl)pyrrolidine, 3.53 g of anhydrous potassium carbonate, 4.6 g of 1-bromohexane and 50 ml of ethyl methyl ketone under reflux for 18 hours. Work up according to the procedure o Example 67 to obtain 5.82 g (81% of theory) of the title compound as a colorless liquid of b.p. 110° to 112° at 0.005 mm of Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[C:8]([CH:9]=[N:10][C@H:11]([CH3:30])[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[OH:13])[C:7]([OH:32])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1>CCCCCCC>[N+:1]([C:4]1[CH:31]=[C:8]([CH:9]=[N:10][CH:11]([CH3:30])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[OH:13])[C:7]([OH:32])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](C)N=Cc1cc([N+](=O)[O-])ccc1O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COc1ccccc1C(O)(c1ccccc1OC)C(C)N=Cc1cc([N+](=O)[O-])ccc1O
Temperature: 10 °C
Yield: 99 %

Procedure:
19.6 g (44.9 mmol) of (R)-N-(5-nitrosalicylidene)-2-amino-1,1-di(2-methoxyphenyl)-1-propanol, 8.96 g (44.9 mmol) of cupric acetate, and 160 g of toluene were mixed in a flask and reacted at 80° C. for 1 hr under stirring. 100 g of n-heptane were added to the reaction solution to precipitate blue-green chrystals. The precipitated reaction mixture was cooled to 10° C. and filtered to collect the crystals. Collected crystals were washed with 100 g of n-heptane, and dried at room temperature to give 22.1 g of a copper complex of (R) N-(5-nitro-salicylidene)-2amino-1,1-di(2-methoxyphenyl)-1-propanol in a yield of 99.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:4][C:3]=1[N+:44]([O-])=O>CO.[Pd]>[NH2:44][C:3]1[CH:4]=[C:5]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:33][CH2:34][CH2:35]3)=[CH:28][CH:27]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1N
Reaction time: 6.5 h
Yield: 60.4 %

Procedure:
10% Pd/C (50.0 mg) was added to a solution of tert-butyl (1-{4-[2-(4-methyl-3-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (49.1 mg, 0.0799 mmol) in MeOH (5 mL), and the mixture was stirred for 6.5 hours under hydrogen atmosphere. The catalyst was filtered off and washed with MeOH. The combined filtrate and washings were concentrated, and the residue was purified by silica gel column chromatography (EtOAc/hexane=1:2→1:1→2:1→EtOAc) to afford desired product (28.2 mg, 60.4%) as pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.17 (dd, J=7.8, 1.4 Hz, 1H), 8.00 (dd, J=5.0, 1.4 Hz, 1H), 7.39-7.31 (m, 2H), 7.27 (td, J=7.7, 1.5 Hz, 1H), 7.21-6.69 (m, 8H), 6.58 (dd, J=7.8, 4.6 Hz, 1H), 6.52-6.46 (m, 1H), 5.24 (br s, 1H), 3.56 (br s, 2H), 2.63-2.27 (m, 4H), 2.19-2.06 (m, 1H), 2.14 (s, 3H), 1.95-1.74 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:27]([O:34][CH2:35][C:36](=[CH2:39])[CH2:37]O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[I:1][CH2:37][C:36](=[CH2:39])[CH2:35][O:34][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C=C(CO)CO[Si](C)(C)C(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(CI)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of iodine (1.49 g, 5.85 mmol) in anhydrous CH2Cl2 (3×10 mL, then 4×1 mL to rinse) was added dropwise to a stirred mixture of imidazole (0.441 g, 6.48 mmol) and triphenylphosphine (1.50 g, 5.71 mmol) in anhydrous CH2Cl2 (3 mL) at 0° C. under N2. After stirring at 0° C. for 30 min, a solution of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-propen-1-ol (164) (reported by Chen et al., US 2007213341 A1, by monosilylation of 2-methylene-1,3-propanediol) (1.00 g, 4.94 mmol) in anhydrous CH2Cl2 (4 mL, then 4×1 mL to rinse) was added, and the mixture was stirred at 0-8° C. for 5 h. The resulting mixture was concentrated carefully under reduced pressure, and the residual oil was chromatographed on silica gel. Elution with pentane firstly gave foreruns, and then further elution with 10% CH2Cl2/pentane gave tert-butyl(dimethyl)silyl 2-(iodomethyl)-2-propenyl ether (165) (1.46 g, 95%) as a volatile pink oil that was used directly in the next step; 1H NMR (CDCl3) δ 5.31 (br s, 1H), 5.19 (d, J=1.3 Hz, H), 4.31 (s, 2H), 3.95 (s, 2H), 0.92 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2>>[OH:44][C@H:29]([CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:26])[CH3:1])=[N:10][C:9]3=[O:11])=[CH:18][CH:17]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and 5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Intermediate 12) according to the procedure of Example 1 as a yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 6 H), 2.40 (t, J=7.9 Hz, 2 H), 2.55-3.20 (m, 12 H), 3.70-3.95 (m, 6 H), 6.44 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 7.00 (d, J=8.9 Hz, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H), 8.82 (brs, 1 H); MS (ES) m/z: 304.6 ((M+2H)2+, 100%); 608.1 (MH+, 10%); HRMS Calcd. for C30H38N7O5S (MH+): 608.2655. Found: 608.2655.
Reaction SMILES: N[C:2]1[S:3]C=C[C:6]=1C#N.[CH3:9][CH2:10][O:11][C:12]([CH2:14][C:15]#[N:16])=[O:13]>>[NH2:16][C:15]1[S:3][CH:2]=[CH:6][C:14]=1[C:12]([O:11][CH2:10][CH3:9])=[O:13]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccsc1N
Product: CCOC(=O)c1ccsc1N

Procedure:
The same procedure as 2-aminothiophene-3-carbonitrile was used except replacing malononitrile with ethyl cyano acetate. 1H-NMR (CDCl3, 400 MHz): 6.95, 6.15, 4.26, 1.32.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>O=[Pt]=O.CO>[NH2:9][C:5]1[C:6]([OH:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1O
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1cnc(Cl)nc1O

Procedure:
25 g (126 mmol) 2-chloro-5-nitro-pyrimidin-4-ol, 2.0 g PtO2 and 2.5 L MeOH are hydrogenated (50 psi) for 1 h. The mixture is filtered and concentrated and dried to yield 5-amino-2-chloro-pyrimidin-4-ol.
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)[C:20]([O:22]C)=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1
Agent: BrCc1ccccc1
Product: O=C(O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OCc2ccccc2)c1

Procedure:
18 g (63 mM) of the ester obtained in Example 9(a) are treated with benzyl bromide under the conditions described in Example 5(a) to lead, after the same treatment, to 17.5 g (74%) of methyl 3-benzyloxy-4-(1-adamantyl)benzoate. The derivative obtained is then saponified under the conditions described in Example 7(b) to lead, after the same treatment, to 13.6 g (96.6%) of the expected derivative, of melting point 240° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:24]>CO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:24])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Reactant: N
Solvent: CO
Product: Cc1cc(OCc2ccccc2)c2cc(C(N)=O)[nH]c2c1
Yield: 46 %

Procedure:
20.0 g 4-benzyloxy-2-ethoxycarbonyl-6-methyl indole (see preparation of the primary products in connection with Example 1) are heated together with 200 ml each of methanol and liquid ammonia in the autoclave for 16 hours, to 100° C. The solution is evaporated and the residue is chromatographed on silica gel (fluxing agent: chloroform/methanol 98:2). There is obtained 8.5 g (~46% of theory) 4-benzyloxy-2-carbamoyl-6-methyl indole; m.p. 185°-187° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12](=[O:15])[N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(C)c(F)c2)n[nH]c1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)c(F)c2)nn(CC(C)C)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one (5.28 g, 20.0 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (5.53 g, 40.0 mmol) and isobutyl bromide (3.29 g, 24.0 mmol), and the mixture was stirred at 80° C. for 1 hour. The temperature of the reaction mixture was allowed to drop back to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel [silica gel 100 g, chloroform/methanol (100/1→50/1)) to yield the title compound as an orange oil (5.41 g, 84.9%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[N:25]>N1C=CC=CC=1>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:23][C:19]2[CH:20]=[N:21][CH:22]=[C:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[N:16]4)[CH:18]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1)#[N:25]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cc(-c2cnc3ccc(-c4cncc(N)c4)cc3n2)cn1
Solvent: c1ccncc1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccc(C#N)cc5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 5-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-3-pyridinamine (52 g, 0.172 mmol) in pyridine (1.7 mL) was added 4-cyanobenzenesulfonyl chloride (56 mg, 0.278 mmol). The reaction mixture was stirred at room temperature overnight. Monitoring by LCMS still showed 30% of starting material. An additional portion of 4-cyanobenzenesulfonyl chloride (17 mg, 0.084 mmol) was added to the reaction mixture and after stirring for a further 30 minutes, all starting material was consumed. Cold water was poured into the reaction resulting in precipitate formation. This solid was collected by filtration, washed with water and dried under vacuum to give the title compound (54 mg, 67%) as a brown colored solid. MS(ES)+ m/e 468 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH2:3](I)[CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1>C(O)C>[CH2:3]([S:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1)[CH3:4]
Reactant: COc1cccc(S)c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSc1cccc(OC)c1
Reaction time: 72 h
Yield: 100.2 %

Procedure:
Solid potassium hydroxide (2.2 g, 39 mmol) and ethyl iodide (3.14 ml, 39 mmol) were added to a solution of 3-methoxybenzenethiol (5.0 g, 35 mmol) in ethanol (35 ml) (Caution—exotherm). The mixture was stirred for 72 h, then partitioned between water and ethyl acetate. The organic phase was dried over MgSO4 and the solvent removed under reduced pressure to give 1-(ethylsulfanyl)-3-methoxybenzene (5.9 g) as a yellow liquid.
Reaction SMILES: OC1C=CC([C:8]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:17][C:15]2[CH:16]=[CH:8][C:9]([O:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:16][C:15]([O:17][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=4)=[CH:14][CH:13]=3)=[CH:13][CH:14]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C([O-])c1ccc(O)cc1-c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(Oc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(Cl)cc3)cc2)cc1)c1ccc(Cl)cc1

Procedure:
4-(4-chlorobenzoyloxy)-benzoic acid-4-(4-chlorobenzoyloxy)-phenyl ester is prepared as in Example 5 from 4-hydroxyphenyl-4-hydroxybenzoate and p-chlorobenzoic acid chloride. Yield: 250 g (98% of the theoretical). A liquid crystalline phase is observed under a polarization microscope in the temperature range from 160° to 350° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.O>CS(C)=O>[C:1]([CH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(OC)nc(CCl)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(CC#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
16.7 g of dried sodium cyanide are dissolved in 850 ml of dimethyl sulfoxide at 90° C. under N2 protective gas. At this temperature, 52.8 g of 2-chloromethyl-4,6-dimethoxypyrimidine, dissolved in 280 ml of dimethyl sulfoxide, are added dropwise over the course of 2 hours. Stirring is continued for 1 hour at 90° C., and the mixture is cooled to room temperature and poured into 300 ml of water. The aqueous phase is extracted seven times using ether, and the combined organic phases are washed using saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in a rotary evaporator. This gives 29.1 g of crude product, from which 2-cyanomethyl-4,6-dimethoxypyrimidine of melting point 65°-67° C. are obtained after column chromatography (SiO2 ; CH2Cl2 /CH3OH; 98.5/1.5).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(C)ccc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 5-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.CCOCC.Cl.[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.Cl>[N:23]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:8])[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)nc1)N1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
DMF (2 drops) was added to a solution of 6-chloronicotinic acid (1.00 g, 6.35 mmol) and oxalyl chloride (0.67 mL, 7.62 mmol) in DCM (20 mL) and 2M hydrogen chloride in ether (3.15 mL, 6.35 mmol). The mixture was stirred at RT for 4 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride was dissolved in DCM (10 mL) and added to a mixture of azetidine hydrochloride (0.66 g, 6.99 mmol) and triethylamine (2.14 mL, 13.97 mmol) in DCM (10 mL) then stirred at RT for 24 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and 1M citric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL), dried (MgSO4), and the solvent removed in vacuo to give a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (0.73 g). 1H NMR δ (CDCl3) 2.43 (quin, 2H), 4.2-4.4 (brm, 4H), 7.42 (d, 1H), 7.97 (d, 1H), 8.63 (s, 1H). m/z 197 (M+H)+
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32].C(O)CC>CC(N(C)C)=O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CC(=O)N(C)C
Solvent: CCCO
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 25 °C

Procedure:
2 g of sunitinib base were suspended in 6 ml of DMA under stirring at RT. 0.673 g of Malic acid were added to the mixture and the temperature was set at 40° C. 40 ml n-propanol were dropped in 30 minutes, the suspension was cooled to 0° C., filtered and washed with 10 ml n-propanol. Dried at 70° under vacuum for 16 h.