Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>>[CH2:4]([SiH:2]([Cl:3])[Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Cl[SiH2]Cl
Reactant: CCCCCC
Product: CCCCCC[SiH](Cl)Cl
Temperature: 90 °C

Procedure:
Dichlorosilane in an amount of 74.7 g (0.74 mol), 63.0 g of 1-hexane (0.75 mol) and as a catalyst 0.684 g of RhCl(PPh3)3 (7.4×10-4 mol) were charged in a 500 ml pressure proof stainless steel reaction tube and after sealing, reaction was carried out by heating in an oil bath at a temperature of 90° C. for 13 hours. Then reaction liquid was subjected to vacuum distillation to obtain 110 g (0.59 mol) of n-hexyldichlorosilane. The boiling point of this product was 100°-102° C./100 mmHg and the refractive index nD20 was 1.4412. Further, the infrared spectrum of this product is shown in FIG. 1 indicating characteristic absorptions of Si--H at 2213 cm-1. The NMR spectrum of this product is shown in FIG. 5. Thus it was confirmed that the product corresponded to the formula (n--C6H13)SiHCl2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[SH:86][CH2:87][CH2:88][C:89]([O:91][CH3:92])=[O:90]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[CH3:92][O:91][C:89](=[O:90])[CH2:88][CH2:87][S:86][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1cnc(Nc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 94.4 %

Procedure:
The atmosphere above a mixture of tert-butyl 4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (1.52 g, 2.79 mmol), N-ethyl-N-isopropylpropan-2-amine (0.971 mL, 5.57 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.161 g, 0.279 mmol), and dioxane (25 mL) was purged with nitrogen. Methyl 3-mercaptopropanoate (0.332 mL, 3.07 mmol) and Pd2dba3 (0.128 g, 0.139 mmol) were added, and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and filtered through celite. The filtrate was concentrated and purified by MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (1.54 g, 94.5% yield) as a tacky white solid: 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.16 (s, 1H), 7.40 (t, 2H), 7.24 (t, 1H), 7.14 (s, 1H), 7.06 (d, 2H), 6.46 (s, 1H), 4.08 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 2.55 (t, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=1>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:33](=[O:34])[CH2:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CO
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(C(C)C)cc4)c3c2C)cc1
Yield: 42 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxyphenylacetyl chloride, the title compound was synthesized according to Example 1b. Yield: 42%. Melting point: 202-204° C. (Methanol)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C=O.[C:22](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)cc(N(C)C2CCOCC2)c1C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (1.20 g, 3.66 mmol) in DCE (10 ml) under a nitrogen atmosphere was added paraformaldehyde (659 mg, 21.9 mmol) followed by acetic acid (1.26 ml, 21.9 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (4.65 g, 21.9 mmol). The reaction was stirred for 16 h at room temperature after which time additional paraformaldehyde (325 mg, 10.8 mmol) and sodium triacetoxyborohydride (2.40 g, 11.3 mmol) was added and the reaction was stirred for a further 18 h whereupon distilled water (30 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7 and the phases were separated, the aqueous phase was washed with EtOAc (3×50 ml), the combined organics were then washed with brine (50 ml), dried using Na2SO4, filtered and evaporated. The crude residue was purified using FCC over silica eluting with 0-10% EtOAc in heptane to afford the title compound as a colourless oil (728 mg, 52%). LC-MS 87%, m/z=341.9/343.9, 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J=2.0 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 3.92 (d, J=11.1 Hz, 2H), 3.82 (s, 3H), 3.27 (td, J=11.5, 2.0 Hz, 2H), 2.94-2.79 (m, 1H), 2.57 (s, 3H), 2.36 (s, 3H), 1.74-1.52 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26](=[O:28])[NH2:27])=S)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26](=[O:28])[N:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=S)Nc2ccccc2CC(N)=O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNC2=NC(=O)Cc3ccccc3N2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After dissolving 4-{[({[2-(carbamoylmethyl)phenyl]amino}thioxomethyl)amino]methyl}piperidine carboxylic acid tert-butyl ester (410 mg, 1.01 mmol) in tetrahydrofuran (15 mL), N,N′-dicyclohexylcarbodiimide (208 mg, 1.01 mmol) was added and the mixture was stirred at room temperature for 6 hours. The filtrate obtained by filtering the insoluble portion was concentrated under reduced pressure, and the concentrate was suspended in a solution of n-hexane:ethyl acetate=1:2 (3 mL). The insoluble portion was refiltered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/3→1/2) to obtain the title compound. Yield: 193 mg (51%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([NH2:6])[CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19](O)=[O:20])[C:15]=2[CH3:22])=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]([NH:6][C@H:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[O:20])[C:15]=2[CH3:22])=[CH:12][CH:13]=1
Reactant: N[C@H]1CCOC1
Reactant: Cc1c(C(=O)O)noc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)N[C@H]2CCOC2)noc1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
(S)-Tetrahydrofuran-3-amine (13 μL, 0.13 mmol) was added to a mixture of 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylic acid (23 mg, 0.10 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (22 mg, 0.12 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.8 mL) and N,N-dimethylformamide (0.1 mL). After stirring overnight, the volatiles were removed in vacuo and the compound was purified by silica gel chromatography eluting with 2% methanol in dichloromethane to afford the title compound: (21.6 mg, 0.07 mmol). MS (ESI) m/z (M+H+): 307.0.
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(Cc1ccccc1)C(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
In a 500-ml four-necked flask were placed 25.2 g (0.11 mole) of 1,3-diphenylpropanedione, 25.3 g (0.11 mole) of p-bromophenylhydrazine hydrochloride, and 234.7 g of toluene. The mixture was stirred at room temperature and 6.0 g (0.11 mole) of sodium methoxide was added in drops at room temperature. After the addition, the mixture was heated under reflux with stirring for three hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and a solid was recovered by filtration. The filtrate was concentrated under reduced pressure to dryness. To the residue was added 350 ml of methanol and the mixture was heated with stirring for one hour. Thereafter, the mixture was cooled to room temperature and a solid was recovered by filtration. The solid was washed with methanol and dried under reduced pressure to give 28.4 g of 1-(p-bromophenyl)-3,5-diphenylpyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][N:15]=[C:14]2[N:23]([CH3:27])[N:24]=[C:25]([CH3:26])[C:13]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=[C:14]2[N:23]([CH3:27])[N:24]=[C:25]([CH3:26])[C:13]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1NCCNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nn(C)c2ncc(C(=O)O)c(NCCNC(=O)OC(C)(C)C)c12
Yield: 826.9 %

Procedure:
To a solution of ethyl 4-[2-(tert-butoxycarbonylamino)ethylamino]-1,3-dimethyl-pyrazolo[3,4-b]pyridine-5-carboxylate (303 mg, 0.803 mmol) in methanol (30 ml) was added sodium hydroxide (4.02 g, 101 mmol) in water (10 ml) and the resulting mixture was heated at reflux for 1.5 hours. The mixture was allowed to cool to −50° C. after which ammonium chloride (6.07 g, 113 mmol) was added. The mixture was stirred at reflux for 15 minutes after which the solids were filtered off. The solids were washed with ethanol (150 ml) and the combined filtrates were concentrated under reduced pressure to yield 2.32 g of a white solid that was purified by filtration over a pad of silicagel in a glassfilter using 10% (1% AcOH in MeOH) in DCM. The filtrate was concentrated under reduced pressure to yield 240 mg (0.687 mmol, 86%). MS (ESI) m/z=350.2 [M+1]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)n2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 262.9 %

Procedure:
To the above prepared N-tert-butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide (0.110 g, 0.19 mmol) was added TFA (6 mL) and the reaction mixture was stirred at 50° C. for 2 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.235 g, 100%). MS (ISP) 471.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[N:10][CH:9]=2)[C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1ncc(-c2nc(N)ncc2Cl)n1C
Temperature: 65 °C
Yield: 233 %

Procedure:
2-Amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 26; 378 mg, 2 mmol) and N-chlorosuccimide (267 mg, 2 mmol) were dissolved in glacial acetic acid (7 ml) under an atmosphere of nitrogen. The reaction mixture was heated at 65° C. for 18 hours when further N-chlorosuccinimide (89 mg, 0.66 mmol) was added and the reaction heated at 65° C. for an additional 2 hours. The volatiles were removed by evaporation and the residue dissolved in water (10 ml). The solution was adjusted to pH 11-12 by addition of 40% aqueous sodium hydroxide solution. The precipitated solid was collected by filtration and washed sparingly with water, dried under vacuum at 60° C. to give the title compound (344 mg, 77%) as a yellow solid. NMR 2.35 (s, 3H, 3.75 (s, 3H), 4.83 (s, 2H), 7.53 (s, 1H), 8.27 (s, 1H); m/z 224.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)=[O:7])C.O.Cl>C1COCC1.CO.O>[C:13]1([C:10]2[NH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
LiOH (27.5 mg, 0.65 mmol) was added to a stirred solution of 5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (67 mg, 0.31 mmol) in THF:MeOH:H2O (3:1:1, 3 mL), and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl, filtered the solid precipitated to afford 37 mg (63.79% yield) of 5-Phenyl-1H-pyrrole-2-carboxylic acid. LCMS Purity: 92.24%.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CS(C1C=CC=C(N)C=1)(=O)=O)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)CS(=O)(=O)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-benzenesulfonyl)-acetic acid ethyl ester (prepared in one step from (3-amino-phenylsulfanyl)-acetic acid ethyl ester) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 13.08 (1H, br s), 10.26 (1H, s), 8.16 (1H, s), 7.77-7.45 (5H, m), 7.26-7.15 (2H, m), 4.80 (2H, m), 4.39 (2H, s), 4.38 (1H, d), 3.98 (1H, d), 2.86 (1H, m), 1.65-1.34 (6H, m), 1.25-1.13 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 53.55; H, 6.90; N, 8.48%; C30H36N4O7S.C7H17NO592.0H2O requires: C, 53.67; H, 6.94; N, 8.46%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=[C:2]2[C:22]1[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(Br)c2ccc(C)c(F)c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(C)c(F)c2n1
Temperature: 100 °C
Yield: 73.7 %

Procedure:
After degassing with N2, a mixture of methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 650 mg, 2.18 mmol.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (544 mg, 2.62 mmol) Pd(dppf)Cl2—CH2Cl2 adduct (89 mg, 0.11 mmol), and K3PO4 (1388 mg, 6.54 mmol) in 1,4-dioxane (12.9 mL) and H2O (1.6 mL) was heated at 100° C. for 20 min under microwave condition. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0-100%) to afford methyl 8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate (7-17, 481 mg, 74%). LRMS m/z (M+H)+ 300.3 found, 300.1 require.
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:3]=1[C:21]#[N:22].[H-].[Na+].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[CH2:45][N:44]([C:47]1[S:48][C:49]([CH2:57][CH2:58][CH2:59]I)=[C:50]([C:52]([O:54]CC)=[O:53])[N:51]=1)[CH2:43][CH2:42]2)=[O:36]>CN(C=O)C.Cl.CS(C)=O.CO>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:59][CH2:58][CH2:57][C:49]3[S:48][C:47]([N:44]4[CH2:43][CH2:42][C:41]5[C:46](=[C:37]([C:35](=[O:36])[NH:34][C:26]6[S:25][C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=7[N:27]=6)[CH:38]=[CH:39][CH:40]=5)[CH2:45]4)=[N:51][C:50]=3[C:52]([OH:54])=[O:53])=[CH:18][CH:19]=2)[C:3]=1[C:21]#[N:22]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)n[nH]c1N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To compound 31F (0.132 g, 0.44 mmol) in DMF (4 mL) was added 60% sodium hydride (0.048 g, 1.2 mmol) at 0° C. The solution was stirred for 10 minutes. To this solution was added compound 2C. The solution was stirred at rt for 2 hours. The solution was diluted with conc. HCl (0.5 mL), and heated at 60° C. for 30 minutes. The mixture was diluted with DMSO (5 mL) and MeOH (9 mL). The solid was filtered off. The filtrate was then purified by Prep HPLC to provide 12 mg of the desired product: 1H NMR (DMSO-d6): δ 8.03 (d, J=7.98 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.67-7.71 (m, 4H), 7.33-7.49 (m, 5H), 7.00 (d, J=8.59 Hz, 2H), 4.84 (s, 2H), 4.03 (t, J=5.98 Hz, 2H), 3.71-3.74 (m, 2H), 3.17-3.20 (m, 2H), 3.01-3.05 (m, 2H), 2.02 (m, 2H). MS (ESI(+)): 677 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH2:8][C:9]([CH:13]=[O:14])=[CH:10][NH:11][CH:12]=1.[S]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1C1=CNC=C(C=O)C1
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cncc(C=O)c1
Yield: 83.6 %

Procedure:
A solution of (S)-5-(1-methylpyrrolidin-2-yl)-1,4-dihydropyridine-3-carbaldehyde IV (0.011 g, 0.044 mmol) and elemental sulfur (0.0015 g, 0.044 mmol) in 2 mL of toluene was refluxed for 1 day. After filtration through a pad of Celite, and evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (silica gel, 5% EtOAc/hexanes then EtOAc) to afford 0.007 g (83%) of 5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde V as a clear oil. IR (thin film, neat, NaCl): 2950, 1586, 1370, 1120 cm−1. 1H NMR (CDCl3, 300 MHz) δ 10.13–10.12 (m, 1 H), 8.97–8.96 (m, 1 H), 8.79 (s, 1 H), 8.18 (s, 1 H), 3.30–3.20 (m, 2 H), 2.38–1.67 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 191.26, 154.81, 150.91, 135.13, 131.69, 68.53, 57.19, 40.64, 40.64, 35.66, 23.02. HRMS Calcd for C11H14N2O: 191.1184 [M+H]+. Found: 191.1182 [M+H]+. [α]23D−92 (c=0.2, CH2CI2).
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([C:14]([O-:16])=[O:15])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:23](O)[CH3:24]>ClCCl>[OH:4][C:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([C:14]([O:16][CH2:23][CH3:24])=[O:15])[CH:6]=1
Reactant: CC(=O)Oc1cc(C(=O)[O-])cc2sccc12
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2ccsc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
4-(Acetyloxy)-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (14 g, 0.1 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 2:1 as eluent to give 6.5 g (29 mmol, 37%) of ethyl 4-hydroxy-1-benzothiophene-6-carboxylate as a cream-colored solid.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]([O:7][C:8]([NH:10][C@@H:11]([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([O:16]C)=[O:15])=[O:9])([CH3:6])[CH3:5].O>C1COCC1.CO>[CH3:6][C:4]([O:7][C:8]([NH:10][C@@H:11]([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[O:9])([CH3:3])[CH3:5]
Reactant: CC[C@@H](/C=C/C(=O)OC)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
LiOH (2.95 g, 123 mmol) was added to a solution of methyl (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hexenoate (6 g, 24.66 mmol) in THF (50 mL), MeOH (10.00 mL), and water (50.0 mL). The reaction was stirred overnight at RT. After 18.5 h, the reaction mixture was concentrated under reduced pressure to remove the THF and MeOH. Water (40 mL) was added, and aqueous mixture was adjusted to pH=3 with 6 M aq. HCl, as measured by pH paper. EtOAc (80 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and dried under high vacuum, giving 6.09 g of the title compound. LC-MS m/z 230 (M+H)+, 0.77 min (ret time).