Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)CCC1.C(N(CC)CC)C.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+]([O-])=O)=CC=1)=[O:15].[CH3:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]1[CH:44]=[C:43]([O:45][CH:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[N:42]=[CH:41][N:40]=1)[CH2:34][CH2:33]2)(=[O:29])=[O:28]>C(Cl)Cl>[CH:17]1([O:16][C:14]([N:49]2[CH2:50][CH2:51][CH:46]([O:45][C:43]3[CH:44]=[C:39]([N:35]4[C:36]5[C:32](=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:38][CH:37]=5)[CH2:33][CH2:34]4)[N:40]=[CH:41][N:42]=3)[CH2:47][CH2:48]2)=[O:15])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Agent: OC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of the cyclobutanol (0.48 mmol, 4 eq) and triethylamine (0.3 mL, 4.4 eq) in 1 mL of DCM, was added 4-nitrophenyl chloroformate (0.1 g, 4.2 eq) and the mixture was stirred at room temp for 17 h. This solution was then added to a vial containing 4b (0.12 mmol) and the reaction mixture was stirred for 5 h at room temperature. The solvent volume was reduced to 0.7 mL under a stream of nitrogen and the residue was purified by preparative HPLC to afford 5-1, LCMS 473.4 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(C3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(C3CCOCC3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 104.8 mg of (2S,4R)-1-acetyl-2-methyl-4-{[4-(tetrahydro-2H-pyran-4-yl)phenyl]amino}-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 70.5 mg (67.3%, cis:trans=9:1) of the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[C@@H:16]3[C@@H:14]([CH2:15]3)[C@@H:13]([OH:17])[C@H:12]2[OH:18])=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[CH:22]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2[C@@H]3[C@@H](C3)[C@@H](O)[C@H]2O)=C(NCC2C=CC=C(C#CCCCC3[N:67]=[N:68][N:69]([C:71]4[CH:76]=[CH:75][C:74]([F:77])=[C:73]([N+:78]([O-:80])=[O:79])[CH:72]=4)C=3)C=2)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[C@@H:16]3[C@@H:14]([CH2:15]3)[C@@H:13]([OH:17])[C@H:12]2[OH:18])=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[N:67]=[N:68][N:69]([C:71]4[CH:76]=[CH:75][C:74]([F:77])=[C:73]([N+:78]([O-:80])=[O:79])[CH:72]=4)[CH:34]=3)[CH:22]=2)[N:3]=1
Reactant: C#CCCCCC#Cc1cccc(CNc2nc(Cl)nc3c2ncn3[C@H]2[C@H](O)[C@H](O)[C@@H]3C[C@@H]32)c1
Reactant: O=[N+]([O-])c1cc(-n2cc(CCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Product: O=[N+]([O-])c1cc(-n2cc(CCCCC#Cc3cccc(CNc4nc(Cl)nc5c4ncn5[C@H]4[C@H](O)[C@H](O)[C@@H]5C[C@@H]54)c3)nn2)ccc1F
Yield: 95 %

Procedure:
Compound 215 (95%) was synthesized from compound 212 following the same procedure as for compound 214. 1H NMR (CDCl3, 400 MHz) δ 8.44-8.39 (m, 1H), 8.07-8.11 (m, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.51-7.43 (m, 2H), 7.33-7.26 (m, 3H), 6.58 (br s, 1H), 4.87 (s, 1H), 4.79 (br s, 2H), 4.15 (s, 1H), 4.02 (d, J=6.8 Hz, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H), 2.08-2.04 (m, 1H), 1.96-1.90 (m, 2H), 1.76-1.64 (m, 3H), 1.31-1.28 (m, 1H), 0.79-0.85 (m, 1H). HRMS calculated for C32H30ClFN9O4 (M+H)+: 658.2093. Found 658.2124.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[CH2:17][C:18]([CH2:20][Si](C)(C)C)=[CH2:19])(=O)C>C1COCC1.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.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:17]=[C:18]1[CH2:20][C@@H:2]([C:1]([O:11][CH3:12])=[O:10])[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:19]1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: COC(=O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine)palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a suspension of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanol (1.97 g, 7.44 mmol) in DCM (39.4 mL) at about 0° C. was added Dess-Martin periodinane (9.47 g, 22.3 mmol). The reaction mixture was stirred at ambient temperature for about 4 h then quenched by the addition of saturated aqueous Na2SO3 (125 mL). To control the resulting exothermic reaction, the reaction flask was cooled down in an ice bath during the addition. The product was extracted into DCM (3×40 mL) and the combined organic extracts were washed with aqueous NaOH (2 N, 100 mL). The organic phase was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone as an off-white solid (1.75 g, 90%); LC/MS (Table 2, Method a) Rt=2.61 min; MS m/z: 263 and 265 (M+H)+. The material was used directly in the next step without further purification.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[C:14](=O)[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][OH:30])[OH:19])[CH3:9].C([O-])(=O)C.[NH4+].C([BH3-])#[N:37].[Na+]>CO>[NH2:37][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][OH:30])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH:15]1[O:16][CH3:17]
Reactant: COC1C(=O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC1C(N)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-4oxocyclohexanol (1.07 g) and ammonium acetate (1.86 g) were dissolved in methanol (25 ml). To the solution was added sodium cyanoborohydride (304 mg), and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 40 g, developing solvent: chloroform-methanol-NH4OH=20:1:0.1) to obtain 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (629 mg; yield 58%) as a colorless oily product.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]4=[CH:20][CH:21]=[C:22]([C:23]5[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=5)[N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][S:55]([CH2:58][CH2:59][NH2:60])(=[O:57])=[O:56].Cl.Cl.CN(C)CCCN=C=NCC>>[CH3:54][S:55]([CH2:58][CH2:59][NH:60][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:22]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)=[N:15]3)=[CH:20][CH:21]=2)=[CH:24][CH:25]=1)(=[O:57])=[O:56]
Reactant: O=C(O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 30 mL vial, 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid (104 mg, 0.251 mmol), N,N-Dimethylformamide (2.08 mL, 26.9 mmol; Supplier=EMD), 1-Hydroxybenzotriazole (41 mg, 0.30 mmol), 4-Methylmorpholine (33.1 uL, 0.301 mmol), [B] 2-Methanesulfonyl-ethylamine; hydrochloride (0.0601 g, 0.376 mmol), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0577 g, 0.301 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with sat'd NaHCO3. The precipitate was filtered and washed with water to afford N-(2-Methanesulfonyl-ethyl)-4-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzamide as a yellow solid. MP 241-242° C. LCMS (E/I+) 521.00M+H). NMR 1H (DSMO-d6)-9.34 (d, 1H, J=2.00), 8.97 (s, 1H), 8.60 (d, 1H, J=8.21 Hz), 8.79 (t, 1H, J=5.72 Hz), 8.34 (d, 2H, J=8.52 Hz), 7.97 (d, 2H, J=8.52 Hz), 7.65 (d, 2H, J=9.00 Hz), 7.28 (d, 1H, J=4.80 Hz), 6.94-7.00 (m, 3H), 3.65-3.80 (m, 6H), 3.41 (t, 2H, J=6.88 Hz), 3.03-3.12 (m, 7H).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:33])[CH:5]=1)([CH3:3])[CH3:2].[C:34]1([CH2:40][O:41][C:42](=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:49])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Reactant: O=C(CCCCCO)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Product: CC(C)c1cc(OCCCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (6 g; 12.46 mmol), 6-hydroxyhexanoic acid phenylmethyl ester (4.2 g;14.96 mmol), DEAD (4.35 g; 24.9 mmol) and(Ph)3P (6.54 g; 24.93 mmol) in methylene chloride (100 ml) was combined with cooling in ice/water and then was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel; 20-80% ethyl acetate/hexane) to afford 2.5 g (29%) of 4-isopropyl-6-[5-(phenylmethyloxycarbonyl)pentyloxy]-2-(1-phenyl-3-trifluoromethyl pyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)5C(O)OCH2H) as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([OH:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:22]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC(O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Under a nitrogen atmosphere, methanol (2.0 mL) was added to (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid (No. 5444958; 20.0 mg, 0.0302 mmol) and the mixture was cooled to 0° C. While maintaining the temperature at 0° C., sodium borohydride (1.14 mg, 0.0302 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2,12-dihydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5534088; 11.9 mg, 59% yield).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.Br[CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25].O>CS(C)=O.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[CH2:22][N:17]1[C:18]2[C:13](=[N:12][CH:11]=[C:10]([F:9])[CH:19]=2)[CH2:14][CH2:15][C:16]1=[O:20]
Reactant: COC(CBr)OC
Reactant: O=C1CCc2ncc(F)cc2N1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(CN1C(=O)CCc2ncc(F)cc21)OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a suspension of 49.8 g of potassium phosphate in 90 mL dimethyl sulfoxide, 30.0 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one and 39.7 g of 2-bromo-1,1-dimethoxyethane were added, and the mixture was stirred at 100° C. for 3 hours. To the mixture, 7.7 g of potassium phosphate and 6.1 g of 2-bromo-1,1-dimethoxyethane were added, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, and 120 mL of water and 120 mL of toluene were added thereto. The mixture was adjusted to pH 8.5 with acetic acid, and 3.0 g of activated carbon was added thereto. Insoluble matter was filtered out, and the filter residue was washed using 30 mL of toluene and 30 mL of water. The filtrate and the wash liquid were combined, the organic layer was separated, and the aqueous layer was extracted with 60 mL of toluene. The organic layer and the extract were combined to evaporate the solvent under reduced pressure, 90 mL of dibutyl ether was added thereto, and the mixture was cooled to −3° C. The solid product was obtained by filtration and washed using in the order of dibutyl ether and water to give 30.8 g of 1-(2,2-dimethoxyethyl)-7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:32]2[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 4-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(N(CC)CC)C.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][S:1]([CH3:4])(=[O:3])=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Mesyl chloride (25.8 mg) and triethylamine (0.055 ml) were added to a chloroform (0.9 ml) solution of benzyl alcohol (16.2 mg), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was eluted by NH-type silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography using tetrahydrofuran as a solvent to obtain methanesulfonic acid benzyl ester. To a tetrahydrofuran (0.9 ml) solution of the methanesulfonic acid benzyl ester, 4-chloro-N-[(1R)-1-(4-ethyl-5-mercapto-4H-1,2,4-triazol-3-yl)ethyl]benzenesulfonamide (Compound 90) (17.3 mg) obtained by performing the same procedure as in Example 1 using the corresponding raw materials, and potassium t-butoxide (8.4 mg) were added, followed by stirring the mixture for 20 hours at 40° C. PSA (polymer supported amine) (0.15 ml) was added to the reaction mixture, and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was eluted with ethyl acetate and tetrahydrofuran, and the solvents were distilled off. The resulting residue was eluted by NH-type silica gel column chromatography using tetrahydrofuran as a solvent, and the eluate was purified by silica gel column chromatography to obtain Compound 5 (2.3 mg).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>C(O)C>[CH:19]1([CH2:18][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH2:21][CH2:20]1
Reactant: NC(=O)c1ccccc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1ccccc1OCC1CC1
Yield: 70.7 %

Procedure:
A stirred mixture of salicylamide (10.02 g., 0.074 mole), potassium carbonate (10.24 g., 0.074 mole) and bromomethylcyclopropane (10.0 g., 0.074 mole) in ethanol (15 ml.) was heated under reflux for 19 hours. The mixture was concentrated and the residue treated with water. The mixture was filtered and the collected solid recrystallized from benzene-Skellysolve B to give 2-cyclopropylmethoxybenzamide (10.0 g., 71.6%), m.p. 102°-105°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([CH:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH3:58])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][CH3:58])=[CH:55][CH:56]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 35 (1.03 g, 1.30 mmol) in THF/MeOH (30 mL/30 mL) was added Pd/C (10% Pd, 154 mg). The mixture was stirred at rt under hydrogen atmosphere for 15 h. The catalyst removed by filtration, and then the filtrate was concentrated in vacuo. The residue was purified by prep HPLC (reverse phase) to provide the compound E010 (0.28 g, 0.64 mmol, 49%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[O:6]=[P:7](Cl)([Cl:9])[Cl:8]>C(Cl)Cl>[P:7]([Cl:9])([Cl:8])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCO
Solvent: ClCCl
Product: CCCCOP(=O)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of butanol (0.98 mL, 10.0 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise POCl3 (3.0 mL, 32.0 mmol) at 0° C. After stirring at 0° C. for 1 h, the mixture was refluxed for 5 h and then followed by vacuum distillation to afford butyl dichlorophosphate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH2:5]2.C(O)(=O)C.N1CCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([Cl:22])=[C:4]2[C:8]([C:7]3[C:6]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:5]2)[CH2:13][CH2:14][C:15](=[O:17])[CH:16]=3)=[CH:9][C:10]=1[F:11]
Reactant: CCCCC1(CCC(C)=O)Cc2c(cc(F)c(N)c2Cl)C1=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(N)c(Cl)c1C2
Temperature: 90 °C
Yield: 82.8 %

Procedure:
The crude diketone from step 7 (approx. 10.6 mmol) was dissolved in toluene (106 mL) and treated with acetic acid (0.606 mL, 10.6 mmol) and pyrrolidine (0.883 mL, 10.6 mmol). The resulting solution was stirred and heated in an oil bath at 90° C. for 3.5 hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel and the product washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 4:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide 7-amino-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (2.7 g, 83%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:4]([C:19]([OH:21])=O)=[C:3]1[CH3:22].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[Cl:33]>>[Cl:33][C:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:19]([C:4]3[CH:5]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=4)[CH2:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]=3[CH3:22])=[O:21])[CH:25]=2)[NH:29][N:28]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 41, Step 2 and 5-amino-3-chloroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 463 [M+H]+