Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH2-].[Na+].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH3:15])[C:7]1[CH:2]=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=1)[CH3:12]
Reactant: Oc1ccccc1Cl
Reactant: CCNCC
Agent: [NH2-]
Agent: [Na+]
Product: CCN(CC)c1cccc(O)c1
Yield: 76 %

Procedure:
32.1 g (0.25 mol) of o-chlorophenol were slowly added dropwise under nitrogen to a mixture of 20.5 g (0.5 mol) of 95% by weight pure crystalline sodium amide and 750 ml of diethylamine. The reaction mixture was refluxed under nitrogen for 72 h with stirring. The workup comprised hydrolysis with 100 ml of saturated aqueous ammonium chloride solution, distillative removal of excess diethylamine, neutralization with dilute hydrochloric acid up to a pH of 7.5, extraction of the residue with a total of 600 ml of methylene chloride, drying over sodium sulfate and concentrating of the organic phase. Thereafter the crude oil thus obtained (46.3 g) was distilled, which yielded 31.5 g (76%) of 3-diethylaminophenol (purity>96% (GC)).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=1)[OH:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=1)=[O:3]
Reactant: CC(O)c1ccc2c(c1)SCCCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)SCCCC2
Reaction time: 8 h
Yield: 94.5 %

Procedure:
7.80 g of 2,3,4,5-tetrahydro-α-methyl-1-benzothiepine-8-methanol were dissolved in 100 ml of methylene chloride, treated with 50 g of manganese dioxide (MnO2) and the reaction mixture was stirred overnight. Thereafter, the mixture was filtered over a filter aid and the solution was evaporated. There were obtained 7.30 g of 2,3,4,5-tetrahydro-1-benzothiepin-8-yl methyl ketone as a colorless oil.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.Cl.CN1CCOCC1.Cl.[CH2:25]([O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:30])[CH3:26].[OH-].[Na+].[C:38]([O:42][C:43]([NH:45][C@H:46]([C:54](O)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C.O.CO>[CH2:25]([O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:30][C:54](=[O:55])[C@H:46]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH:45][C:43]([O:42][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:44])[CH3:26]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
N-α-t-Butoxycarbonyl-O-benzyl-L-tyrosine (7 g, 0.019 mol) was dissolved in tetrahydrofuran in a three-neck round bottom flask which was cooled to approximately -10° C. in an ice/acetone bath under a nitrogen atmosphere. N-methylmorpholine (6.3 ml, 0.06 mol) was added to the stirred solution, followed by 2.5 ml (0.019 mol) of isobutyl chloroformate. Immediately after the addition of isobutyl chloroformate, N-methyl morpholine hydrochloride precipitated. After 5 min, 3.7 g (0.019 mol) of L-leucine ethyl ester hydrochloride, dissolved in dimethylformamide, were added. The reaction mixture was stirred at this temperature for an hour, after which the solvent was evaporated. The residue obtained was dissolved in ethyl acetate/water and the organic layer was extracted with sodium bicarbonate solution, water, 0.01N HCl and water. The organic layer was dried over Na2SO4 and after evaporation of the solvent an oil was obtained. Crystallization from CHCl3 /petroleum ether yielded 7.4 g (0.014 mol, 76%) m.p. 104°-107° C., of N-α-t-butoxycarbonyl-O-benzyl-L-tyrosylglycylglycine ethyl ester. 1H NMR (CDCl3) δ 7.2 (5H, s), 6.9 (4H, doublet of doublets), 5.0 (2H, s), 1.1 (12H, m). The ethyl ester was cleaved by treating 6.2 g (0.012 mol) of it with an equivalent amount of 2N NaOH in methanol. The solution was stirred at room temperature for half an hour after which the solvent was evaporated. An equivalent amount of 2N HCl was added to the cooled residue and the solid obtained was filtered and dried to yield 3.5 g (96%), m.p. 118°-122° C., of the free (t-butoxycarbonyl-O-benzyl)tyrosylglycylglycine. t-Butoxycarbonylphenylalanylleucine ethyl ester was prepared starting with 6 g (0.019 mol) of t-butoxycarbonyl-L-phenylalanine, and 3.7 g (0.019 mol) of leucine ethyl ester hydrochloride. Work up and crystallization from CHCl3 /petroleum ether yielded 6.5 g (84%), m.p. 109°-112° C., of the desired compound. 1H NMR (CDCl3) δ 7.2 (5H, s), 6.4 (1H, bm), 5.1 (1H, bm), 4.3 (4H, bm), 3.1 (2H, bm), 1.3 (20H, m).
Reaction SMILES: C(OC1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18](O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:32](=[O:43])[N:31]=2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:14][CH2:13][N:12]4[CH2:15][CH2:20][CH2:19][CH2:18]4)=[CH:38][CH:37]=3)[C:32](=[O:43])[N:31]=2)=[CH:44][CH:45]=1
Reactant: O=c1nc(OCc2ccc(F)cc2)ccn1-c1ccc(O)cc1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Product: O=c1nc(OCc2ccc(F)cc2)ccn1-c1ccc(OCCN2CCCC2)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one was replaced with 4-(4-fluorobenzyloxy)-1-(4-hydroxyphenyl)-1H-pyrimidin-2-one, to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([CH:9]2[CH2:11][CH2:10]2)[C:3]=1Br.C1(C)C=CC=CC=1.C[O:21]CCO[AlH2-]OCCOC.[Na+]>C1C=CC=CC=1>[CH:9]1([C:4]2[CH:5]=[CH:6][C:7]([OH:21])=[CH:2][CH:3]=2)[CH2:11][CH2:10]1
Reactant: Oc1ccc(Br)c(Br)c1C1CC1
Reactant: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Oc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 ml flask equipped with a reflux condenser, and magnetic stirring bar under a nitrogen atmosphere were placed 11 g (37.6 moles) of dibromocyclopropylphenol, 100 ml of toluene, and 50 g of 70% solution of "Red-Al" [sodium bis(2-methoxyethoxy aluminum hydride)] in benzene. The solution was then heated to reflux for 6 hours and allowed to stir overnight at room temperature. The reaction was then quenched with water and acidified with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with 100 ml of ether. The organic layers were combined and washed with dilute base. The water layer was then acidified with concentrated hydrochloric acid and extracted with methylene dichloride. The methylene dichloride extract was dried over anhydrous magnesium sulfate and the solvent evaporated. A yield of 3 g of 4-cyclopropylphenol, an amber oil, was obtained.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[CH2:13][CH2:14][CH:15]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[NH4+].[OH-]>C(Cl)Cl>[OH:6][C:7]1[C:12]2[CH2:13][CH2:14][CH:15]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1CCC(C(=O)N1CCC(c3ccccc3)CC1)CC2=O
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c(O)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere, 2.2 mL (0.0234 mol) of BBr3 were added to 20 mL of CH2Cl2, then 1.47 g (0.0039 mol) of (±)-1-methoxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one dissolved in 25 mL of CH2Cl2 were added dropwise at room temperature. The reaction mixture was stirred for 2 h, then it was poured onto 25 g of crushed ice, basified with conc. NH4OH and extracted with CH2Cl2. The organic layer was dried and the solvent was removed in vacuo. The resulting crude solid was triturated with Et2O, filtered and dried, yielding 1.16 g of the title product.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11][C:10]=2[CH:21]=1)#[N:2].[NH:29]([C:31]1[N:36]=[N:35][C:34]2[C:37]3[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=3[CH2:39][CH2:40][CH2:41][C:33]=2[CH:32]=1)[NH2:30]>CC(O)C>[N:35]1[C:34]2[C:37]3[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=3[CH2:39][CH2:40][CH2:41][C:33]=2[CH:32]=[C:31]([N:29]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[CH2:15][CH2:14][C@@H:13]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH2:12][CH2:11][C:10]=4[CH:21]=3)=[N:30]2)[N:36]=1
Reactant: N#CN=C(Nc1ccc2c(c1)CCC(N1CCCC1)CC2)Oc1ccccc1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc3c(c2)CC[C@H](N2CCCC2)CC3)nn1-c1cc2c(nn1)-c1ccccc1CCC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Phenyl (S)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate and phenyl (R)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate were treated with 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine in a similar manner as described above in Synthetic Example 2 to yield 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine and 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine. For example, a suspension of a single enantiomer of phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate (0.06 g, 0.16 mmol) and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (0.036 g, 0.16 mmol) in 1 mL of IPA was stirred at 90° C. for 18 h. After cooling to ambient temperature, the solvent was evaporated and the residue was purified by HPLC to provide enantiomerically pure 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine as a yellow solid (0.04 g, 50%). 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.94 (s, 1H), 7.85 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.72 (m, 4H), 2.61 (m, 3H), 2.25 (m, 5H), 2.09-1.82 (m, 5H) ppm; MS (ES) 507 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[N:19]=[C:18]([CH3:28])[C:17]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].I[CH3:36].O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:15]([CH3:36])[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[N:19]=[C:18]([CH3:28])[C:17]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OC)ccc1Nc1c(-c2ccccc2)c(C)nn1-c1ccccc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)ccc1N(C)c1c(-c2ccccc2)c(C)nn1-c1ccccc1C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil; 0.28 g, 7 mmol) in DMF (10 mL) at rt was added a solution of methyl 5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]amino}benzoate (1.495 g, 3.5 mmol) in DMF (15 mL) dropwise. The mixture was stirred for 0.5 h, and then iodomethane (0.88 mL, 14 mmol) was added. The reaction mixture was stirred at rt for 1 h. Water (100 mL) was cautiously added, and the mixture was extracted with ethyl acetate (25 mL×3). The combined organic phases were washed with a saturated solution of sodium bicarbonate (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc/hexanes 1:12) to afford the title compound (1.18 g, 68%) as a pale yellow solid. 1H NMR (400 MHz, acetone-d6) δ 2.1 (s, 3H), 2.3 (s, 3H), 2.9 (s, 3H), 3.65 (s, 3H), 3.7 (s, 3H), 6.87-6.92 (m, 2H), 6.94-6.98 (m, 1H), 7.03-7.09 (m, 1H), 7.15-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.39-7.43 (m, 2H). ES-MS m/z 442.3 (MH+); HPLC RT (min) 3.96.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[Br:10]Br>[Fe].ClCCl>[Br:10][C:7]1[C:2]([Cl:1])=[C:3]([CH3:9])[C:4]([F:8])=[CH:5][CH:6]=1
Reactant: Cc1c(F)cccc1Cl
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: Cc1c(F)ccc(Br)c1Cl
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
2-chloro-6-fluorotoluene (5.00 g, 34.6 mmol) and iron (0.1 g, 0.17 mmol) was stirred in a 100 mL flask. Bromine (6.08 g, 38.1 mmol) was added slowly in 3 portions with 1 min between each addition. The reaction was stirred for additional 15 min. Then dichloromethane (50 ml) was added, the reaction mixture transferred to a separation funnel and washed with a sodium thiosulphate solution (10%, 30 mL) until it had turned colorless. The layers were separated and the organic layer was washed with sat. sodium hydrogen carbonate (30 mL), dried and evaporated to give the title compound as a colorless oil (7.57 g, 98%) containing 15% 3-bromo-5-chloro-2-fluorotoluene (calc. by 1H-NMR). The compound was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.O=C1N(C2CCNCC2)[C:25]2C=CC=C[C:24]=2N1.BrCC(OCC)=O.C(N(C(C)C)CC)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:24][CH3:25])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from amidines (V) or (VI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with amidine (V) or (VI), in the presence of an amine base, under peptide coupling conditions described above, to afford amidino benzimidazolinones (XV) of formula A in which Y=carbonyl and L=(N-methylene)piperidin-4-yl (Scheme 5).
Reaction SMILES: BrC1C2C(=NC(N)=NC=2)N(C)N=1.Br[C:14]1[C:22]2[C:17](=[N:18][C:19]([NH2:32])=[N:20][C:21]=2[NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:16]([CH3:33])[N:15]=1.[Cl:34][C:35]1[CH:40]=[C:39](B2OCC(C)(C)CO2)[CH:38]=[C:37]([Cl:49])[C:36]=1[OH:50]>>[NH2:32][C:19]1[N:18]=[C:17]2[N:16]([CH3:33])[N:15]=[C:14]([C:39]3[CH:40]=[C:35]([Cl:34])[C:36]([OH:50])=[C:37]([Cl:49])[CH:38]=3)[C:22]2=[C:21]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:20]=1
Reactant: CC1(C)COB(c2cc(Cl)c(O)c(Cl)c2)OC1
Reactant: Cn1nc(Br)c2c(NCCN3CCOCC3)nc(N)nc21
Agent: Cn1nc(Br)c2cnc(N)nc21
Product: Cn1nc(-c2cc(Cl)c(O)c(Cl)c2)c2c(NCCN3CCOCC3)nc(N)nc21

Procedure:
This compound is prepared analogously to Example 88 by replacing 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) with 3-Bromo-1-methyl-N*4*-(2-morpholin-4-yl-ethyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Intermediate 16) and by replacing 2-methoxy-5-trifluoromethylphenylboronic acid with 2,6-dichloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol to afford the title compound.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC1(C)C[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@@H](N)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Yield: 118.9 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (3R,4R)-4-azido-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (1.3 g, 3.5 mmol) and 10% palladium on carbon (200 mg) in methanol (10 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated to get the title compound (1.2 g, crude) as a yellow oil, which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].ClCCl.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>O>[CH3:26][S:23]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[CH3:1])(=[O:25])=[O:24]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(COS(C)(=O)=O)cccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 2 h

Procedure:
200 g 2-Methyl-3-nitro benzylalcohol is added to dichloromethane (2000 ml) and triethylamine (250 ml). Mesyl chloride is added drop wise while maintaining temperature between 0-10° C. and stirred until the completion of reaction. It is further stirred 2 hours at room temperature. Water is added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and washed with brine. Dichloromethane was evaporated to yield the oily brown 2-Methyl-3-nitrobenzyl methanesulfonate (207-210 g).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)nc1
Reaction time: 2 h

Procedure:
A suspension of 10% Pd on carbon (9.21 g, 8.66 mmol) in a solution of the ethyl (6-nitropyridin-3-yl)acetate (36.4 g, 173 mmol) in EtOH (364 mL) was hydrogenated at 20 psi and 25° C. for 2 h. The suspension was filtered through Solka Floc eluting with 200 mL EtOH. The filtrate was concentrated and solvent switched with EtOAc, then concetrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: N#CCc1ccc(Cl)cc1
Product: Fc1ccccc1-n1nccc1-c1ccc2noc(-c3ccc(Cl)cc3)c2c1

Procedure:
The title compound, light yellow solid (96 mg, 70%), MS (ISP) m/z=390.2 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:12]2[C:20]3[C:15](=[C:16]([O:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:29][CH3:30]>C1COCC1.CCO>[CH3:30][NH:29][S:25]([CH2:24][CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]2[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=1)(=[O:27])=[O:26]
Reactant: CN
Reactant: CCCCSc1nccc(-n2ccc3c(OCCCS(=O)(=O)Cl)cccc32)n1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCSc1nccc(-n2ccc3c(OCCCS(=O)(=O)NC)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[1-(2-Butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonyl chloride (10.97 mmol) was dissolved in THF (25 mL) and added dropwise to H2NMe (30 mL) in EtOH at 0° C. and stirred for 30 min, and then allowed to warm to RT The reaction mixture was then poured into ice water, extracted with EtOAc, washed with water and brine, dried with sodium sulfate, filtered, and the solvent removed in vacuo to yield 3-[1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid methylamide.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=O)CC(C3C=CC(F)=CC=3[C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)CC=2N=1.N1C=CC(B(O)O)=CC=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:44]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Agent: OB(O)c1ccncc1
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccncc1)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one using 4-pyridyl boronic acid instead of 3-pyridyl boronic acid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[Cl:6][CH2:7][CH:8]([OH:11])[CH2:9][SH:10]>>[Cl:6][CH2:7][CH:8]([OH:11])[CH2:9][S:10][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2]
Reactant: OC(CS)CCl
Reactant: ClCC1CO1
Product: OC(CCl)CSCC(O)CCl

Procedure:
Epichlorohydrin (5563 g, 60.12 mol) and methanol (2500 g) were put into a 10-liter reactor. The reaction temperature was adjusted to 6° C. When the reaction temperature reached 6° C., sodium hydroxide (50% aq., 5 g) was added to the mixture. NaSH.xH2O (70% NaSH, 3660 g, 45.75 mol), methanol (1000 g) and water (500 g) were completely dissolved with stirring in another 10-liter reactor, and hydrochloric acid was slowly added dropwise thereto to generate hydrogen sulfide gas. The hydrogen sulfide gas was added to the epichlorohydrin solution to obtain bis(3-chloro-2-hydroxypropyl)sulfide. The completion of the reaction was defined as the time when epichlorohydrin and 3-chloro-2-hydroxy-propane-1-thiol disappeared completely and bis(3-chloro-2-hydroxypropyl)sulfide was formed, which was confirmed by GC. When 3-chloro-2-hydroxy-propane-1-thiol was present, the content of the thiol compound was calculated from the relative integral ratio by GC and epichlorohydrin was further added in an amount corresponding to the calculated content. The reaction of epichlorohydrin and the thiol compound afforded bis(3-chloro-2-hydroxypropyl)sulfide (BCPS).