Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccnc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccnc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and pyridine-3 carbaldehyde. MS (ESI) m/z 470.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.Cl>[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: Cc1ncc(Br)cc1N

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (13.8 g, 63.9 mmol) in industrial methylated spirit (330 mL) at 40° C. was added iron powder (20 g) (portionwise to avoid dumping) followed by concentrated aqueous hydrochloric acid (5 mL). The dark brown mixture was stirred vigorously at reflux for 2 hours and then cooled and filtered through Celite®(which was washed with 1 L of industrial methylated spirit). The solvent was then removed in vacuo and the residue taken up in ethyl acetate (200 mL) and washed with a saturated aqueous solution of sodium bicarbonate (200 mL), dried over magnesium sulfate and solvent removed in vacuo to give 5-bromo-2-methylpyridin-3-amine as an orange solid, (10.7 g, 57.5 mmol, 89.9%). 1HNMR (400 MHz, CDCl3): δ ppm 7.91 (s, 1H), 7.00 (s, 1H), 3.75 (br.s, 2H), 2.25 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH:6](O)[N:5]([CH3:8])[C:4](=[O:9])[N:3]1[CH3:10].S(=O)(=O)(O)O>O>[CH3:8][N:5]1[CH2:6][C:2](=[O:1])[N:3]([CH3:10])[C:4]1=[O:9]
Reactant: CN1C(=O)N(C)C(O)C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1CC(=O)N(C)C1=O
Yield: 87.9 %

Procedure:
In a 30 ml glass vessel equipped with a stirrer, thermometer and a reflux condenser were charged 1.0 g (6.8 mmol) of 4,5-dihydroxy-1,3-dimethyl-2-imidazolidinone synthesized in the same manner as in Reference example A1, 2 ml of water and 0.18 g (1.8 mmol) of 98% sulfuric acid, and the mixture were reacted at 95 to 100° C. for 6 hours. After completion of the reaction, the reaction mixture was analyzed by high-performance liquid chromatography (quantitative value by refractive index detector), then, 766 mg (Reaction yield; 87%) of 1,3-dimethylimidazolidin-2,4-dione was formed.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9](=[O:12])[CH2:10][CH3:11].N1C=CC=CC=1C(O)CCC>>[Br:8][C:4]1[N:3]=[C:2]([CH:9]([OH:12])[CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CCC=O
Reactant: Brc1cccc(Br)n1
Agent: CCCC(O)c1ccccn1
Product: CCC(O)c1cccc(Br)n1

Procedure:
The title compound was prepared from 2,6-dibromopyridine (purchased from Sigma-Aldrich, St. Louis, Mo.) and propionaldehyde following a procedure similar to the one described above for the synthesis of 1-(pyridin-2-yl)butan-1-ol (Example 231, step A). Mass Spectrum (ESI) m/z=219.9 and 217.9 (M+1).
Reaction SMILES: [CH:1]1([C:5]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:8]([CH2:9][N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][C:17]4=[O:26])[CH2:12][CH2:11]3)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:5]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:8]([CH2:9][N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]4=[O:26])[CH2:12][CH2:11]3)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1cc(C2CCC2)c(C2CC2)cc1CN1CCC(n2ccc(C(=O)OC)cc2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(C2CCC2)c(C2CC2)cc1CN1CCC(n2ccc(C(=O)O)cc2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A mixture of methyl 1-(1-(4-cyclobutyl-5-cyclopropyl-2-ethoxybenzyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (567 mg), a 1 M aqueous sodium hydroxide solution (3 mL), and ethanol (3 mL) was stirred at 70 C for 2 hours. The reaction mixture was pH-adjusted to 4 using 1 M hydrochloric acid and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and recrystallized (DMSO/ethanol) to obtain the title compound (358 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Li+].C[SiH](C)O[SiH](C)C.BrCC1C=CC(OC)=C(OC2CCCC2)C=1.[C-:42]#[N:43].[Na+]>C(#N)C.CN(C)C=O.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:42]#[N:43])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: [C-]#N
Agent: COc1ccc(CBr)cc1OC1CCCC1
Agent: C[SiH](C)O[SiH](C)C
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilychloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C., 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 10% ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p. 32°-34° C.; an additional quantity (1.3 g) of slightly impure material also was isolated.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[S:9][CH:10]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:13]([NH:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:15])[CH3:14]
Reactant: BrBr
Reactant: CC(=O)NCc1nc(C(C)=O)cs1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NCc1nc(C(=O)CBr)cs1
Temperature: 70 °C

Procedure:
Bromine (2.2 g) was added slowly to a solution of 4-acetyl-2-acetylaminomethylthiazole (2.2 g) in acetic acid (20 ml) and water (20 ml), and the mixture was heated at 70° C. for 4 hours. The solvent was removed under reduced pressure to give crude product of 2-acetylaminomethyl-4-bromoacetylthiazole. The above residue was dissolved in ethanol (50 ml). Diaminomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. The filtrate was extracted by ethyl acetate and then the solvent was removed under reduced pressure. The residue and the precipitate were chromatographed on an alumina column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (430 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:22]=[N:21][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc2ccc(CNc3ccc(F)cc3N)cc2s1
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Temperature: 100 °C
Yield: 67 %

Procedure:
A stirred mixture of 4-fluoro-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (0.93 g, 2.93 mmol) from the previous step, formic acid (0.5 mL) and triethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.64 g, 67%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.47-7.51 (m, 2H), 7.26 (m, 1H), 7.17 (m, 1H), 7.00 (dt, J=9.3, 2.4 Hz, 1H), 5.44 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].CN(C=O)C.CCN(CC)CC.FC(F)(F)S(O[Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])(=O)=O>CCOC(C)=O>[C:30]([Si:27]([CH3:29])([CH3:28])[O:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4])([CH3:33])([CH3:32])[CH3:31]
Reactant: C#CC(C)(O)CCC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(C)(CCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
An oven dried flask was charged with 3-methyl-hex-1-yn-3-ol (1.02 g, 0.009 mol) and dry DMF (9.0 mL). To this solution, cooled in an ice bath, was added Et3N (4.6 mL, 0.033 mol) followed by dropwise additon of tert-butyldimethylsilyl trifluoromethanesulfonate (2.9 g, 0.016 mol) under nitrogen atmosphere. The resulting mixture was stirred at RT for 18 h and then diluted with EtOAc (50 mL). The organic layer was washed with a saturated solution of NH4Cl (30 mL), water (4×20 mL), brine (40 mL), dried over sodium sulfate, and evaporated to afford the desired compound (2.05 g, 99.6%), as a yellow oil, used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.152 (s, 3H), 0.156 (s, 3H), 0.85-0.84 (m, 9H), 0.91 (t, J=6.69 Hz, 3H), 1.41 (s, 3H), 1.61-1.44 (m, 4H), 3.37 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][O:3]1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)c2[N+](=O)[O-])O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
Methyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoate (2.8 g, 9 mmol) was dissolved in 25 mL of methanol and 2 mL of water. To the above solution was added lithium hydroxide (1.13 g, 3 eq.). After stirring the reaction mixture at room temperature for 5 h, the volatile was removed under vacuo and the residue was partitioned between EtOAc and H2O. The aqueous layer was separated, cooled with an ice bath, and then acidified with 10% aq. HCl. The acidic aqueous layer was extracted with EtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na2SO4, and concentrated to give 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoic acid as a white solid (1.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:22]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[N:11]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:22]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[N:11]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Agent: [Pd]
Product: Nc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1

Procedure:
2-(m-Nitrophenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline (11.7 g.) is hydrogenated at atmospheric pressure and at room temperature in the presence of 3 g. of 10% Pd on charcoal. The product obtained is purified by crystallization from a 50:50 mixture of ethyl acetate and isopropyl ether. Yield 8.5 g. of the title product which melts at 118°-9° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)N3CCOCC3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=599.1 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 4-morpholine carbonyl chloride.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[CH:15]([NH:18][C:19]([NH:21][C:22]#[N:23])=[NH:20])([CH3:17])[CH3:16].[OH-].[Na+]>O>[ClH:1].[ClH:1].[CH3:2][CH:3]([NH:14][C:22]([NH:21][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[NH:20])=[NH:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=1
Reactant: CC(N)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)NC(=N)NC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(=N)NC(=N)NC(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred mixture of 15.5 g (0.0687 mole) of α-methyl-p-trifluoromethylbenzylamine hydrochloride and 9.55 g (0.0756 mole) of 1-i-propyl-3-cyanoguanidine is immersed in a 190° C oil bath for ten minutes. The melt is cooled to room temperature, dissolved in 100 ml of water, made alkaline with 40% sodium hydroxide solution and extracted twice with 200 ml of ether. The combined ether extracts are dried over potassium carbonate, filtered, and the ether solution made strongly acidic with a saturated ethereal hydrochloric acid ether solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether, and dried at 40°C/125 mm. for 5 hours. The dihydrochloride is dissolved in 50 ml of water, made strongly alkaline with 40% sodium hydroxide solution, and extracted twice with 100 ml of ether. The combined ether extracts are dried over potassium carbonate, filtered, and the ether solution made strongly acidic with a saturated ethereal hydrochloric acid solution. The precipitate is collected on a filter, washed twice with 50 ml of anhydrous ether, and dried at 40° C/125 mm. to obtain 1-(α-methyl-p-trifluoromethylbenzyl)-5-i-propylbiguanide dihydrochloride.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([O:43]C)=[O:42])=[CH:37][C:36]=4[CH3:45])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O1CCOCC1>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=4)[O:14][C:13]3=[O:26])[C:8]([C:27]3[CH:28]=[C:29]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([OH:43])=[O:42])=[CH:37][C:36]=4[CH3:45])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(Cl)cc(Cl)c2)[C@@H]1C
Temperature: 60 °C
Yield: 90.9 %

Procedure:
To methyl 3′-[2-(azetidin-1-yl)-4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (78 mg, 0.121 mmol) in dioxane (2.4 mL) was added LiOH (0.5 M, 1.2 mL, 0.605 mmol). The reaction was heated to 60° C. for 1 hour before cooling and acidifying with TFA. The volatiles were removed and the crude material was purified by reverse phase HPLC to yield 3′-[2-(azetidin-1-yl)-4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (70 mg, 0.110 mmol). LCMS calc.=633.2. found=−633.3. 1H NMR (CDCl3, 500 MHz) 8.19 (s, 1H), 7.98 (m, 2H), 7.33 (m, 3H), 7.15 (m, 3H), 7.04 (d, J=8.6 Hz, 1H), 5.42 (br s, 1H), 4.75 (br s, 1H), 4.23 (m, 5H), 4.01 (br s, 1H), 3.87 (s, 3H), 2.43 (m, 2H), 2.36 (s, 3H), 0.73 (s, 3H). RTA=4.43 nM
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][S:7][C:8]1[N:13]=[C:12](O)[C:11]([CH2:15][C:16]([O:18]CC)=O)=[CH:10][N:9]=1.C(O)C.[CH3:24][NH2:25]>CO>[CH3:6][S:7][C:8]1[N:9]=[CH:10][C:11]2[CH2:15][C:16](=[O:18])[N:25]([CH3:24])[C:12]=2[N:13]=1
Reactant: CCOC(=O)Cc1cnc(SC)nc1O
Reactant: CN
Solvent: CCO
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1ncc2c(n1)N(C)C(=O)C2
Yield: 36 %

Procedure:
Phosphorus oxychloride (59.0 g) was added to 4.84 g (21.2 mmoles) of ethyl 2-methylthio-4-hydroxy-pyrimidine-5-acetate, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and after adding chloroform, neutralized with an aqueous solution of sodium hydrogen carbonate. The chloroform layer was concentrated under reduced pressure. To the concentrate were added 20 ml of ethanol and 3.48 g (44.9 mmoles) of a 40 methanol solution of methylamine, and the mixture was reacted at 100 ° C. for 5 hours in an autoclave. The solvent was evaporated under reduced pressure, and after adding water, the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure, treated with activated carbon in ethanol, and recrystallized to give 1.50 g (yield 36%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][Cl:9].[H][H]>CO>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: COC(=O)CC(=O)CCCCl
Reactant: [H][H]
Solvent: CO
Product: COC(=O)CC(O)CCCCl
Yield: 44 %

Procedure:
A 214.9 g portion of the above-mentioned crude 6-chloro-3-oxo-hexanoic acid methyl ester (1), Ru2Cl4-[(S)-Segphos]2(NEt)3 (60.7 mg, 0.0725×10−3 mol) and methanol (130 ml) were put into a 500 ml capacity autoclave and stirred with hydrogen (3 MPa) at 65 to 70° C. for 6 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure using an evaporator, and then the residue was distilled under a reduced pressure (75 to 85° C./0.1 ton) to obtain 6-chloro-3-hydroxy-hexanoic acid methyl ester (2); 178.2 g {GC purity; 80.1%, pure amount; 142.7 g (0.790 mol, yield 44%/4-chlorobutanoic acid chloride)}.
Reaction SMILES: [CH2:1]1[C:5]2([O:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH2:4][C@@H:3]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:29]=[C:30]([C@@H:33]6[CH2:37][CH2:36][CH2:35][N:34]6[C:38]([C@@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[CH:41]([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=5)=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[N:15]=2)[NH:2]1.[CH3:49][O:50][C:51]([NH:53][C@H:54]([C:58](O)=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:52].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:42][CH:41]([CH3:43])[C@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:38]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:30]1[NH:31][CH:32]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:18]=[CH:17][C:16]([C:14]4[N:15]=[C:11]([C@@H:3]5[CH2:4][C:5]6([O:10][CH2:9][CH2:8][CH2:7][O:6]6)[CH2:1][N:2]5[C:58](=[O:59])[C@@H:54]([NH:53][C:51]([O:50][CH3:49])=[O:52])[CH:55]([CH3:57])[CH3:56])[NH:12][CH:13]=4)=[CH:21][CH:20]=3)=[CH:23][CH:24]=2)[N:29]=1)=[O:39]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5C(=O)[C@@H](NC(=O)OC)C(C)C)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Yield: 55.8 %

Procedure:
Methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[(3S)-2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (47 mg, yield: 53%) was prepared from methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Intermediate 19) (68 mg, 0.104 mmol), N-[(methyloxy)carbonyl]-L-valine (18.2 mg, 0.104) and HATU (40 mg, 0.104 mmol), following the similar procedure outlined in Example 5. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.20-11.06 (m, 2H) 7.35-8.02 (m, 8H) 7.22 (d, J=7.78 Hz, 2H) 4.97-5.89 (m, 4H) 3.22-4.58 (m, 15H) 2.83-3.20 (m, 1H) 2.58-2.83 (m, 1H) 2.29-2.58 (m, 1H) 1.57-2.31 (m, 8H) 0.64-1.22 (m, 12H). HRMS: (M+H)+ calcd: 811.4143; found: 811.4142.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[Cl:10][C:11]1[C:12]([O:19][CH3:20])=[C:13]([NH:17][NH2:18])[CH:14]=[CH:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[C:12]([O:19][CH3:20])=[C:13]([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1c(Cl)cccc1NN
Reactant: N#CCC(=O)C(F)(F)F
Solvent: CCO
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1N
Yield: 24.1 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-3-oxobutanenitrile (1.64 g, 11.96 mmol, 1.0 eq) in ethanol (15 mL) was added (3-chloro-2-methoxyphenyl)hydrazine (2.5 g, 11.96 mmol, 1.0 eq) and the mixture was refluxed for 3 h. Ethanol was evaporated, the mixture diluted with water and extracted with ethyl acetate (300 mL×2), dried (Na2SO4), evaporated again under vacuum. The crude product was purified by CC using EtOAc/PE (1:4) as eluent to get 1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (0.84 g, 24%, yellow oil; TLC system: EtOAc/PE (2:3), Rf: 0.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:25]([O:30][CH2:31][CH3:32])(=[O:29])[C:26]#[C:27][CH3:28].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:27]([CH2:26][C:25]([O:30][CH2:31][CH3:32])=[O:29])[CH2:28][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=S)cc3c2)cn1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (2.04 g), ethyl 2-butynoate (1.8 mL), tributylphosphine (1.5 mL), tetrahydrofuran (25 mL) and toluene (30 mL) was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 70/30, volume ratio) to give the title compound (1.36 g, 52%) as a yellow amorphous solid. MS 578 (MH+).