Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([C:60]2[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=2)[CH2:56][CH2:55]1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:54]3[CH2:59][CH2:58][CH:57]([C:60]4[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=4)[CH2:56][CH2:55]3)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Yield: 163.8 %

Procedure:
A solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 219.9, 40 mg, 0.13 mmol), DIEA (0.07 ml, 0.39 mmol), HOBT (34 mg, 0.19 mmol, with 20% water), EDCI (38 mg, 0.19 mmol), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 36 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel prep-TLC plate and developed using ethyl acetate/hexanes (1:1) to yield 0.1 g (68%) of the title compound as a white solid. m/z (ES+) 470 (M+H)+.
Reaction SMILES: [OH-].[Na+].Cl[P:4]1(=[O:22])[O:9][CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1.Cl.CC[O:26]CC>O>[OH:26][P:4]1(=[O:22])[O:9][CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1
Reactant: CCOCC
Reactant: CC1(C)COP(=O)(Cl)OC1c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)COP(=O)(O)OC1c1cccc2ccccc12
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 57.6 %

Procedure:
Sodium hydroxide (29.4 g, 0.735 mol) was dissolved in water (300 ml). To the solution was added 2-chloro-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide (76.1 g, 0.245 mol) little by little, with stirring and heating at 100° C. The addition was completed for 35 min, and the solution was further stirred for 20 min. The reaction solution was cooled to 55° C., which resulted in precipitation of a large amount of crystals. Under stirring, concentrated hydrochloric acid (73 ml) was added to the mixture to adjust the mixture to acidic, and the mixture solidified and turned into powder by leaving it for about 1 hr. To the powder was added ether (100 ml), and the mixture was stirred and filtered. The obtained crystals were washed alternately with water and ether and dried to give the title compound as pale ocher crystals having the melting point of 216 to 217° C. (41.23 g, yield 57.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:16][CH:17]1[C:21](=O)[CH2:20][CH2:19][O:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:9][CH2:10][N:11]([C@H:21]3[CH2:20][CH2:19][O:18][C@H:17]3[CH3:16])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCNCC1
Reactant: CC1OCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1OCC[C@@H]1N1CCC(C#N)(c2ccc(Br)cn2)CC1
Yield: 69.4 %

Procedure:
To a solution of 4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (1.15 g) in toluene (14.4 ml), was added 2-methyltetrahydrofuran-3-one (526 mg), and then, sodium triacetoxyborohydride (1.37 g), and the mixture was stirred at room temperature for five hours. Water and 1N aqueous solution of sodium hydroxide were added to the reaction solution at 0° C., and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with NH silica gel chromatography (n-hexane/ethyl acetate) to give cis-4-(5-bromopyridin-2-yl)-1-(2-methyltetrahydrofuran-3-yl)piperidine-4-carbonitrile (1.05 g) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].C(OC(=O)[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](N)=[CH:32][CH:31]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH2:28])=[CH:31][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(CN)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (6 ml), (4-aminobenzyl)carbamic acid tert-butyl ester (Gallo-Rodriguez, C et al J. Med. Chem. 1994, 37(5), 636-46) (1.16 mg, 0.52 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 1 h. The precipitate thus formed was collected by filtration and washed with diethylether. Then it was solved in dichloromethane (1 mL) and trifluoroacetic acid (0.23 mL, 3.03 mmol) was added dropwise. The final mixture was stirred at room temperature for 20 minutes. Some more dichloromethane was added and this solution was washed with saturated K2CO3 solution until pH 6. The organic layer was dried and solvent removed to yield 70 mg (54% yield) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(Nc1ccccc1-c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c2c(c(=O)n1-c1ccccc1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
Triethylamine (1.7 mL, 12.2 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 1.25 g, 5.82 mmol) in 1,2-dichloroethane (10 mL) over 1 min. A solution of N′-biphenyl-2-yl-N-methyl-hydrazinecarboxylic acid tert-butyl ester (1.09 g, 3.65 mmol) in 1,2-dichloroethane (15 mL) was added over 2 min. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 1 h. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 20 mL, 80 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1.5 h. The reaction mixture was allowed to cool. Dichloromethane (200 mL) was added and the mixture was washed with 1:1 water/brine (50 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 120 g column, eluting with 5-10% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, and then co-evaporated successively with methanol, diethyl ether and then petroleum ether. The residue was treated with petroleum ether and the mixture was stirred for 20 min. The solid was filtered off and dried under high vacuum at 90° C. for 1 h to give (4S,7R)-2-biphenyl-2-yl-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (612 mg, 47%) as a light yellow solid. APCI(+)-MS (M+H) 359.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]([C:15]1[N:16]=[C:17](Br)[S:18][CH:19]=1)=[O:14])(=[O:11])=[O:10].[CH3:21][O-:22].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]([C:15]1[N:16]=[C:17]([O:22][CH3:21])[S:18][CH:19]=1)=[O:14])(=[O:11])=[O:10]
Reactant: O=C(NS(=O)(=O)c1c(Cl)cccc1Cl)c1csc(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)cs1
Yield: 88.7 %

Procedure:
2.3 g of N-(2,6-dichlorophenylsulfonyl)-2-bromothiazole-4-carboxamide and 1.6 g of sodium methanolate in 45 ml of methanol are refluxed for 12 h. After cooling, the precipitate is filtered off with suction, washed with methanol and then dried under reduced pressure. 1.8 g of N-(2,6-dichlorophenylsulfonyl)-2-methoxythiazole-4-carboxamide with a melting point of 162°-165° C. are obtained. (Active ingredient Example No. 34).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12](C3C=CC(C(C)(C)C)=CC=3)[CH:13]=1)[C:10](=O)[CH:9](C)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:11]([CH3:10])=[C:12]([CH:12]2[C:13]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:11]2)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1Cc2cc(C(C)(C)C)cc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1ccc(C(C)(C)C)cc1C1C=Cc2cccc(C(C)(C)C)c21
Reaction time: 1 h

Procedure:
5-tert-Butyl-7-(4-tert-butylphenyl)-2-methyl-1-indanone (10.37 g, 31mmol) in Et2O (150 ml) was added dropwise at 0° C. to LiAlH4 (0.6 g, 16 mmol) in Et2O (100 ml). After 1 h of stirring, 5% HCl (50 ml) was added, the organic phase was separated, the water layer was extracted in Et2O (2×50 ml). The combined organic phase was washed with aq. Na2CO3, dried over MgSO4 and evaporated. The residue was dissolved in benzene (500 ml), p-TSA (1 g) was added, the resulting mixture was refluxed for 10 min, cooled, washed with water, dried over MgSO4, evaporated and dried in vacuo. The yield was 9.9 g (near quantitative); yellow viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([NH:14]C(OCC2C=CC=CC=2)=O)[CH2:11][C@H:10]([C:25]([O:27][CH3:28])=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([NH2:14])[CH2:11][C@H:10]([C:25]([O:27][CH3:28])=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](NC(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5-(benzyloxycarbonyl)amino piperidine (2.55 g, 6.51 mmol) was dissolved in EtOAc (75 mL), treated with Pd/C (510 mg) and shaken on a Parr apparatus at 45 psi overnight. The reaction mixture was filtered through celite, concentrated, and chromatographed (silica gel, 2% MeOH/CH2Cl2 with NH4OH) to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(OCCCOC3C=CCCC3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(OCCCOC3CCCCC3)cc2)CC1
Yield: 75.7 %

Procedure:
A mixture of crude 1-acetyl-4-[4-[3-(2-cyclohexen-1-yloxy)propyloxy]phenyl]piperazine (1.55 g) in ethanol (16 ml) was hydrogenated at atmospheric pressure with 10% palladium-carbon (0.16 g) for 5 hours. After removal of catalyst by filtration, the filtrate was concentrated in vacuo to give crude 1-acetyl-4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazine (1.18 g), that was used in the next reaction directly, as a brown oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]([OH:8])[C@H:5]([OH:7])[CH3:6].Cl[C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.Cl>C1(C)C=CC=CC=1.COCCOC.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([O:7][C@H:5]([CH3:6])[C@H:4]([OH:8])[CH3:3])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)O)c23)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
Add 2.4 ml of a 12.5 N sodium hydroxide solution to a solution of 1.34 g (14.8 mmol) (2R,3R)-butane-2,3-diol in 20 ml toluene, 7 ml 1,2-dimethoxyethane and 7 ml water at 70° C. After adding 101 mg (0.30 mmol) tetra-n-butylammonium hydrogensulphate and 1.00 g (2.97 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, stir the reaction mixture for 17 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract three times with 50 ml dichloromethane each time. Wash the combined organic extracts with satd. sodium chloride solution, dry over sodium sulphate, filter and concentrate by vacuum evaporation. Mix the raw product with methanol, filter, and purify the filtrate by preparative RP-HPLC (gradient: water/acetonitrile). 0.60 g (50% of theor.) of the desired product is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[CH:15]=[C:14]([O:24][CH3:25])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=3)[N:3]=2)[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[CH3:23])[CH:15]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(Nc2nc(Cl)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2nc(Nc3cc(OC)cc(N4CCC[C@@H]4C)c3)c3ncsc3n2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
The mixture of (S)-5-chloro-N-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.53 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (153 mg, 0.585 mmol), Pd2(dba)3 (61 mg, 0.11 mmol), X-Phos (102 mg, 0.21 mmol) and Na2CO3 (169 mg, 1.6 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford (S)-methyl 4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (121 mg, 48%) as yellow oil. LC-MS: 476 [M+H]+, tR=1.999 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCN1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1CCNC1=O
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 1-(2-hydroxyethyl)imidazolidin-2-one (100 mg; 0.77 mmol) and Et3N (81 mg; 0.80 mmol) in dry DCM (10 mL) was added MsCl (137 mg; 1.20 mmol) under nitrogen. The reaction mixture was stirred overnight, diluted with DCM (20 mL), washed with saturated aqueous Na2CO3, dried over anhydrous Na2SO4, concentrated to afford 72 mg (44%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20].C(O)CO.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.[Cu]I>[F:22][C:13]([F:12])([F:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Ic1cnc2ccccc2c1
Reactant: FC(F)(F)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: FC(F)(F)c1ccccc1Sc1cnc2ccccc2c1
Yield: 112.9 %

Procedure:
A mixture of 3-iodoquinoline (6 g, 23.5 mmol), 2-trifluoromethyl benzenethiol (5 g, 28 mmol), CuI (225 mg, 3.89 mmol), ethylene glycol (3.5 g, 56.4 mmol), K2CO3 (8 g, 58 mmol) in isopropanol (20 mL) was refluxed under N2 for 12 h. The reaction mixture was filtered through a short pad of silica gel and the filtrate was concentrated in vacuo to dryness. The product was purified by flash column chromatography on silica gel to give the product 3-(2-trifluoromethyl-phenylsulfanyl)-quinoline (8.1 g, 95%)
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10])(=[O:5])=[O:4]>CO>[CH3:15][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:3](=[O:5])(=[O:4])[NH2:1]
Reactant: N
Reactant: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ammonia in methanol (40 mL, 2 M) is added to the crude 3-chlorosulfonyl-4-methyl-benzoic acid and the solution stirred at room temperature for 16 hours. The volume is reduced by 50% by heating under reduced pressure, the solution is filtered to remove the precipitate and the precipitate washed with additional methanol. The sulphonamide precipitate is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21]CC)=[O:20])=[CH:8][N:9]2[C@@H:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][OH:14])=[CH:4][C:3]=1I.[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:26]([NH:28][C:29](=[O:49])[NH:30][C:31]1[N:36]=[CH:35][C:34]([C:3]2[CH:4]=[C:5]3[C:10](=[N:11][C:2]=2[F:1])[N:9]([C@@H:12]([C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:13][OH:14])[CH:8]=[C:7]([C:19]([OH:21])=[O:20])[C:6]3=[O:24])=[C:33]([C:40]2[S:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH:32]=1)[CH3:27]
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)(C)C)c2nc(F)c(I)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H](CO)C(C)(C)C)c3nc2F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of palladium (II) acetate (0.163 g, 0.72 mmol, 0.1 equiv.) and 1,1′-bis(di-tert-butylphosphino)ferrocene (0.344 g, 0.72 mmol, 0.1 equiv.) in acetonitrile (27 mL) was added (S)-ethyl 7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-6-iodo-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate Intermediate 78 (3.35 g, 7.25 mmol, 1 equiv.) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid Intermediate 9 (2.64 g, 7.32 mmol, 1.01 equiv.) and a solution of potassium carbonate (1.5 g, 10.87 mmol, 1.5 equiv.) in water (9 mL). This was stirred at 80° C. for 2 h. The reaction was cooled to room temperature and diluted with water. The precipitate was washed with water and dried. The compound was purified via silica gel chromatography and concentrated to afford (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Intermediate 76 (1.2 g, 25%). Calcd for C29H30F4N6O5S [M+H]+: 651.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C@H:8]([CH:11]([CH3:13])[CH3:12])[CH2:9]O)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21].P(Br)(Br)([Br:24])=O.O.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C@H:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][Br:24])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: O=P(Br)(Br)Br
Reactant: COCCCOc1cc(C[C@@H](CO)C(C)C)ccc1OC
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](CBr)C(C)C)ccc1OC
Temperature: 25 °C
Yield: 79.6 %

Procedure:
Dissolve (R)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl butanol (14.82 g, 50 mmol) in N,N-dimethyl formamide (234 ml), add phosphorus oxybromide (14.33 g, 50 mmol) in droplets slowly and control the temperature at 20° C. in that process, and then let them to react at 20° C. for 8 hours. Cool down to room temperature, and pour the reactant liquid into water (702 ml) slowly, extract with normal hexane for three cycles, combine the normal hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 17 g of oily matter. Add 51 ml of methanol, control the product to crystallize at −10° C., filter, and then treat the filter cake by vacuum drying at room temperature, so as to obtain 14.3 g of white solid matter; the yield is 79.6%, mp: 51-53° C., chiral purity: ≧99.9%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:18]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:19]2[CH:18]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[CH:22]=[CH:21][N:20]=2)[CH2:24]1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(c2cc(Cl)ccn2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1occc1-c1ccnc(N2C[C@@H](C)O[C@@H](C)C2)c1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (0.918 g, 4.41 mmol) was added to a solution of cis-4-(4-chloro-2-pyridinyl)-2,6-dimethylmorpholine (1 g, 4.41 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (0.935 g, 8.82 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (0.510 g, 0.441 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 4 hours. Crude LC/MS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (336 mg, 1.172 mmol, 26.6% yield). LC/MS [M+H]+=273.