Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22]C=C)[CH2:6][C:5]=2[CH:4]=1.[F:25][C:26]([F:49])([C:45]([F:48])([F:47])[F:46])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[C:33]([O:35]CC)=[O:34]>>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:49])[C:45]([F:46])([F:47])[F:48])[C:33]([OH:35])=[O:34])[CH2:6][C:5]=2[CH:4]=1
Reactant: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol prepared in Example 13 and ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[CH:30]=[CH:29][C:28]=2[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:25])[C:6]1=[O:45])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[CH:29][C:28]=2[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:25])[C:6]1=[O:45])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(COC3CCCCO3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(CO)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-[(tetrahydro-2H-pyran-2-yl)-oxymethyl]phenyl]urea (34.05 g, 55.6 mmol) in methanol (340 ml) is added p-toluenesulfonic acid (10.57 g, 55.6 mmol), and the mixture is stirred at room temperature for two hours. Methanol is evaporated under reduced pressure, and to the resultant is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, an aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (ethyl acetate:hexane=1:1→ethyl acetate:hexane=3:1) to give the title compound (21.6 g, 40.8 mmol). Some of the title compound (2.03 g) is dissolved in ethyl acetate (2 ml), and thereto is added hexane. The mixture is stirred at room temperature for 3 hours, and stirred under ice-cooling for one hour. The precipitated crystals are collected by filtration to give the title compound (1.70 g) as colorless crystals.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][NH:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:44]3[CH2:45][CH2:46][CH2:47][CH2:48][O:43]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1CCONC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)N4CCCCO4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and [1,2]oxazinane
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:13]3[CH:12]=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:14]=3[N:15]=[CH:16][C:17]=2[N+:20]([O-:22])=[O:21])[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCN(Cc2ccccc2)C1
Yield: 88 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2 g, 5.9 mmol), (R)-1-Benzyl-pyrrolidin-3-ylamine (2.4 g, 15.3 mmol), and diisopropylethylamine (6 mL, 35.4 mmol) in propan-2-ol (50 mL) was heated to reflux for 4 hours. Volatile components were removed under vacuum and the residue was purified by column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane), gave 2.48 g (88%) of (R)—N-(1-benzylpyrrolidin-3-yl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine. LCMS (Method J, ESI): RT=0.98 min, M+H+=478.1; 1H NMR (400 MHz, CDCl3) δ: 9.29-9.27 (s, 1H), 9.10 (s, 1H), 8.20-8.17 (m, 2H), 7.63-7.57 (m, 2H), 7.53-7.49 (m, 2H), 7.36-7.25 (m, 6H), 6.77-6.76 (d, J=4.4, 1H), 4.55-4.54 (m, 1H), 3.73-3.63 (m, 1H), 2.94-2.91 (m, 1H), 2.78-2.77 (m, 2H), 2.49-2.41 (m, 4H), 1.90-1.88 (m, 1H).
Reaction SMILES: OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12.C([O:40][C:41]1[CH:42]2[C:57](=[O:58])[N:56]([CH:59]([CH3:61])[CH3:60])[CH2:55][CH2:54][N:43]2[C:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[N:45][C:46]=1[OH:47])C1C=CC=CC=1>>[OH:40][C:41]1[C:46](=[O:47])[N:45]=[C:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[N:43]2[CH2:54][CH2:55][N:56]([CH:59]([CH3:61])[CH3:60])[C:57](=[O:58])[C:42]=12
Reactant: CC(C)N1CCN2C(c3ccccn3)=NC(O)=C(OCc3ccccc3)C2C1=O
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(-c3ccccn3)nc(=O)c(O)c2C1=O

Procedure:
The title compound was prepared in analogy to (168) from 9-benzyloxy-8-hydroxy-2-isopropyl-6-(2-pyridyl)-4,9a-dihydro-3H-pyrazino[1,2-c]pyrimidin-1-one (195) as an off-white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CN(C=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([C:27]3[N:31]([CH3:32])[C:30]([C:33](N(OC)C)=[O:34])=[CH:29][C:28]=3[CH3:39])[CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])C>C1COCC1>[CH3:32][N:31]1[C:30]([C:33](=[O:34])[CH2:1][CH3:2])=[CH:29][C:28]([CH3:39])=[C:27]1[C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([NH2:9])(=[O:11])=[O:12])=[CH:14][CH:15]=2)[CH:20]=1
Reactant: COc1ccc(-c2c(C)cc(C(=O)N(C)OC)n2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)n1C
Temperature: 25 °C

Procedure:
Ethyl magnesium bromide (0.53 g, 3.96 ml, 3.98 mmol) was added drop wise to a solution of 5-(4′-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[1,1′-biphenyl]-3-yl)-N-methoxy-N,1,4-trimethyl-1H-pyrrole-2-carboxamide (Step 5, 0.4 g, 0.80 mmol) in anhydrous THF (10 ml) under stirring at 25° C. The reaction mixture was heated at 70-75° C. for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 0° C. and was quenched by addition of saturated solution of ammonium chloride (10 ml). The resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography using mixture of ethyl acetate and hexane as an eluent to obtain the title compound 10 (0.04 g, 12.12%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]2([CH3:33])[CH3:32])=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:32])([CH3:33])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3ccc(OC(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.44 g, 1.0 mmol) in ethanol (5 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (2 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.40 g, 91%) as a white solid which was used for next step without further purification: MS (ESI) M+1=416.1.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH:29][C:13]([C:9]1[CH:10]=[C:11]([OH:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:15])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1

Procedure:
To a solution of 12.1 g 1-phenyl-3-carboxy-5-pyrazolone, 15 g (S)-2-amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester and 22.5 g HATU in 200 ml DCM were added 34 ml triethylamine. After 2 h the mixture was extracted with water and the crude product obtained after evaporation of the solvent reacted without further purification.
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[N:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:18][C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([Cl:13])[N:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
—400 ml of acetone cooled to 0° C. are added, under nitrogen stream, with 92.3 g of 2,4,6-trichloro-1,3,5-triazine, then with 38 g of tert-butylamine, always keeping the temperature at about 0° C. After keeping the resulting mixture at this temperature for 30 minutes, 66.7 g of a 30% NaOH aqueous solution, then 400 ml of water are dropped therein, and the resulting mixture is stirred for 1 hour at 0° C. After filtration and washing with water to neutral pH, the resulting precipitate is dried to obtain 108 g of 2-tert-butylamino-4,6-dichloro-1,3,5-triazine. M.p. 129-30° C.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]=2[Br:24])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Br:24])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OCC)cc2Br)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1O
Yield: 75.1 %

Procedure:
A mixture of ethyl 4-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3-bromobenzoate (1.50 g), ethanol (15 ml) and 1N sodium hydroxide (10 ml) was refluxed for 0.5 hour, then concentrated, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate, the solvent was distilled off, and the residue was chromatographed on a column of silica gel (50 g), and eluted with a solution of chloroform-acetone-formic acid (9:1:0.1). Recrystallization from ethyl acetate gave 4-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3-bromobenzoic acid as colorless needles (1.06 g). Melting point 180°-182° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[CH2:20][N:19]([CH3:25])[CH2:18][CH:17]2[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[CH2:20][N:19]([CH3:25])[CH2:18][CH:17]2[C:26]1[CH:27]=[C:28]([S:32]([NH:2][CH:3]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CC(N)C(=O)OC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC(NS(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of dimethyl 2-aminosuccinate hydrochloride (107 mg, 0.54 mmol, 1.00 equiv) in pyridine (5 mL). This was followed by the addition of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.69 mmol, 1.27 equiv, 90%) in several batches. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (50:1). This resulted in 200 mg (72%) of the title compound as a colorless oil
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17]([O:20][CH2:21][CH:22]([CH3:24])O)[CH:18]=[CH2:19].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=NC=CC=1)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][CH:22]([CH3:24])[CH2:21][O:20][CH2:17][CH:18]=[CH2:19])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)COc1ccc(Cl)c2cccnc12
Reactant: C=CCOCC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1cccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOCC(C)OC(=O)COc1ccc(Cl)c2cccnc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
5.0 g (0.021 mol) of 5-chloroquinolin-8-oxyacetic acid and 2.44 g (0.021 mol) of 2-allyloxy-1-methylethanol are suspended in a mixture of 40 ml of methylene chloride and 40 ml of dimethylformamide and the suspension is cooled to 0° C. 4.78 g (0.023 mol) of dicyclohexylcarbodiimide, dissolved in 10 ml of methylene chloride, are added dropwise at this temperature, and 200 mg of 3-(N,N-dimethylamino)-pyridine are then added. The mixture is stirred at room temperature for 15 hours and the precipitate which has separated out is filtered off with suction and rinsed with 50 ml of methylene chloride. The filtrate is washed with 100 ml of 0.5 N HCl, with 100 ml of potassium bicarbonate solution and with 3 portions of in each case 50 ml of water. The organic phase is dried over magnesium sulfate and the solvent is stripped off in vacuo. The residue is recrystallized from n-heptane. 5.1 g (72.4% of theory) of 2-allyloxy-1-methylethyl 5-chloroquinolin-8-oxyacetate of melting point 59° C. are obtained in this manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:22]=[CH:23]/[CH2:24][OH:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][CH:15]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:14][CH:15]=1)[CH:22]=[CH:23][CH:24]=[O:25]
Reactant: COc1cc(/C=C/CO)ccc1OCc1coc(-c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC=O)ccc1OCc1coc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Activated manganese dioxide (28.0 g) was added to a solution of (E)-3-[3-methoxy-4-(2-phenyl-4-oxazolyl-methoxy)phenyl]-2-propen-1-ol (13.6 g) in chloroform (250 ml). The mixture was stirred for 8 hours at room temperature, which was subjected to filtration through a celite layer. The filtrate was concentrated to yield 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (11.8 g, 88%), which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.144-145° C.
Reaction SMILES: [OH:1][C@H:2]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:22]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:21]=2)=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[OH:1][C@H:2]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:3][NH:4][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:22]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CC(C)CCc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CCc1cc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl](2-[3′-(3-methylbutyl)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate (380 mg) in ethyl acetate (2.0 ml) was added 4N hydrogen chloride in ethyl acetate (2.0 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(3-methylbutyl)-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (80 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20](O)=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH2:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:31]([F:32])=[C:24]([Cl:23])[CH:25]=2)=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCn2cc(C(=O)O)c(OCc3ccccc3)c2C1=O
Reactant: NCc1ccc(F)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCn2cc(C(=O)NCc3ccc(F)c(Cl)c3)c(OCc3ccccc3)c2C1=O

Procedure:
To a mixture of 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylic acid (200 mg, 0.67 mmol), 3-chloro-4-fluorobenzylamine (0.16 g, 1.00 mol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophophate (BOP, 0.35 g, 0.79 mmol) in anhydrous dichloromethane (10 mL), diisopropylethylamine (0.17 g, 1.33 mmol) was added. The resultant solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue partitioned between dichloromethane and aq HCl. The organic extract was washed with aq sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the titled amide.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:21]([F:24])([F:23])[F:22])=[N:13]2)=[CH:8][CH:7]=1)([O-])=[O:4]>[Zn].C(O)C>[OH:4][NH:3][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][C:14]([C:21]([F:24])([F:22])[F:23])=[N:13]2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: ONc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
Zinc powder and ammonium chloride were added to an aqueous ethanol solution of 1-(4-nitrophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole under ice-cooling, followed by stirring at 20° C. or below for 30 minutes. The insoluble matter in the reaction solution was removed by celite filtration, and then the filtrate was treated in the usual way to give 1-(4-hydroxyaminophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole as a colorless solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9]=[C:8]([C:10]3[N:14]=[CH:13][S:12][CH:11]=3)[NH:7][C:5]=2[CH:6]=1.[OH-].[Na+].[CH2:17](OS(OCC)(=O)=O)[CH3:18]>O1CCCC1>[CH2:17]([N:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=[C:8]1[C:10]1[N:14]=[CH:13][S:12][CH:11]=1)[CH3:18]
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1c(-c2cscn2)nc2ccccc21
Yield: 64.9 %

Procedure:
5.0 g Thiabendazole and 1.31 g sodium hydroxide were added to 40 ml of tetrahydrofuran. The white slurry was stirred under nitrogen and 4.6 g of diethylsulfate was added dropwise. The mixture was stirred at 50 C for 16 hours. The mixture was quenched with 75 ml of water and then extracted with 75 ml or ethyl acetate. The organic layer was washed with 15 ml of water. Following solvent removal, an off-white solid crystallized. The solid was recrystallized from 30 ml (2:1, v/v) ethanol/water. The solid was dried under vacuum for 3 hrs at 50 C. 3.7 g of a white solid was obtained.
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH3:16])[C:6]=2[C:7]=1[CH3:8].P(Br)(Br)[Br:18]>ClCCl.N1C=CC=CC=1>[Br:18][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH3:16])[C:6]=2[C:7]=1[CH3:8]
Reactant: COc1c(C#N)ccc2oc(CO)c(C)c12
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C#N)ccc2oc(CBr)c(C)c12
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A solution of 2-hydroxymethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.17 g; 0.76 mmol) in dichloromethane (5 mL) was cooled to 0° C. To this solution was added, successively, neat phosphorus tribromide (0.11 mL; 0.32 g; 1.2 mmol; 1.5 eq) and pyridine (2 drops). The ice bath was removed and the reaction was allowed to come to room temperature overnight with stirring. After quenching with ice, the crude product was isolated by ethyl acetate extraction. The organic layer was washed with saturated sodium bicarbonate, then dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-bromomethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.20 g; 95% yield).