Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[N:19][C:18]=3[C:17]([O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[N:19][C:18]=3[C:17]([O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a solution of 0.13 g (0.274 mMol) of 4-{4-Methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 6.0 ml of methanol and 6.0 ml of tetrahydrofuran 80.0 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 8 h, then filtered and evaporated to dryness. The residue was subjected to column chromatography on silica gel (ethyl acetate) to yield 0.048 g (37%) 4-{4-Methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester as a colorless foam. ES-MS m/e (%): 477 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[N:17]([CH3:16])[NH2:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of crude carbamoyl chloride 1 (9.35 g) in dry THF (40 ml) was added to an ice-cold solution of methylhydrazine (3.46 g; 4.00 ml; 0.075 mol) and triethylamine (6.33 g; 8.73 ml; 0.063 mol) in dry THF (40 ml). Stirring was continued at room temperature for 18 hours. The reaction mixture was filtered and evaporated, giving a light yellow solid. Recrystallization from hexane - chloroform gave 2 (6.62 g; 0.0272 mol; 68%) as a white solid, mp 89°-92°, TLC (silica gel; CH2CL2 --CH3OH, 10:1) Rf=0.45. MS m/e 243 (M+) Analysis: Calculated for C11H21N3O3 ; C,54.30; H, 8.70; N, 17.27. Found: C, 54.45; H, 8.96; N, 17.29, NMR (CDCl3): δ1.42 (9H,S); 1.7-2.3(4H.S); 3.00 (3H,S); 3.4-3.8(2H,m); 3.8(2H.bs); 4.4(1H.m) 1R(CHCl3): 35-3300, 1730, 1630 cm-1 [α]D =-55.7°±0.5°.
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.O[N:11]=[C:12]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.[OH2:36]>CN(C=O)C>[O:36]=[C:12]1[CH2:13][C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:18][CH2:19]2)[C:30]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:11]1
Reactant: O
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=NO)c1ccccc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
2,4,6-trichloro-[1,3,5]-triazine (1.32 g, 7.16 mmol) was added to DMF (9.6 mL) maintained at 25° C. The reaction was monitored by TLC until TCT was consumed. Then benzyl 3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (1.6 g, 4.77 mmol) in DMF (17 mL) was added. After the addition, the mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. Na2CO3, followed by 1N HCl and brine, dried over Na2SO4 and concentrated. The residue was purified by prep HPLC to obtain benzyl 2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1-carboxylate (260 mg, yield 16%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(Cl)nn2)cc1
Yield: 86.1 %

Procedure:
3,6-Dichloropyridazine (3.00 g, 20.1 mmol), 4-hydroxybenzaldehyde (2.46 g, 20.1 mmol), potassium carbonate (2.78 g, 20.1 mmol) and 60 mL of N,N-dimethylformamide were mixed and the mixture was refluxed for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted solution was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 4.06 g (86%) of the title compound as colorless crystalline powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:15]1([P:14]([CH2:4][CH2:3][Si:2]([CH2:5][CH2:6][P:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:7])[CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=C[Si](C)(C)C=C
Reactant: c1ccc(Pc2ccccc2)cc1
Product: C[Si](C)(CCP(c1ccccc1)c1ccccc1)CCP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 9.0 g (0.8 mole) dimethyl divinyl silane and 32.7 g (0.176) diphenyl phosphine (10% excess over equivalent amounts) was reacted for 22 hours in the manner described in Example 1. The reaction mixture was fractionated in vacuo to obtain minor amounts of the clear, colorless, slightly viscous liquid monoadduct, and major amounts of the clear, colorless, highly viscous liquid diadduct, i.e. the desired bis-(diphenylphosphinoethyl)dimethyl silane. The distillation yield of desired product was 84%. The bis-diphenylphosphinoethyl)dimethyl silane product had a boiling point of 238°-239° at 0.20 mm.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>COCCOC>[CH:20]([O:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:22])[CH3:21]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)OCCC=CCCl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(=O)c1ccc(OCC=CCCOC(C)C)cc1
Reaction time: 24 h

Procedure:
3.4 g (0.06 mol) of pulverised potassium hydroxide are added to a solution of 8.2 g (0.06 mol) of p-hydroxy-acetophenone and 14.6 g (0.09 mol) of 1-chloro-5-isopropoxy-2-pentene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 60° during the course of 24 hours and is subsequently filterd. The filtrate is evaporated at reduced pressure, the residue is taken up in ether, and the ether solution is washed with saturated salt solution. The organic phase is dried with sodium sulphate and evaporated. The residue is chromatographed with hexane/ethyl acetate 4 : 1 on silica gel and then the 4'-(5-isopropoxy-2pentenyloxy)-acetophenone is obtained as colourless oil. nD20 = 1.5240.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([C:20]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a 0C solution of benzotriazole (5.05 g, 42.39 mmol) in CH2Cl2 (100 mL) was added dropwise triethylamine (9.0 ml, 64.57 mmol) followed by cyclopropyl carbonyl chloride (4.2 ml, 46.28 mmol). The mixture was stirred at rt for 1 h and then quenched with a solution of 2N aqueous HCl (75 ml). The organic phase was washed with 2 N HCl (2×75 mL) and water (100 ml), dried with MgSO4 and concentrated in vacuo. The solid residue was washed with hexenes, filtered and dried to yield 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole as a white solid (5.92 g, 75%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1>CC(O)C.CS(C)=O>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:6][CH:5]=1)[CH2:3][N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: O=C(O)CC1CNCCO1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C(O)CC1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CCO1
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (25 mg, 0.063 mmol) in 2-propanol (2 mL) and DMSO (1 mL) was added 2-(morpholin-2-yl)acetic acid (18.18 mg, 0.125 mmol). The reaction mixture was hated at 80° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the desired product was 12.8 mg, and its purity was 99%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.28 Hz), 7.38-7.86 (7H, m), 5.03 (1H, ddd, J=9.03, 4.39, 4.14 Hz), 3.97-4.11 (1H, m), 3.90 (1H, t, J=9.66 Hz), 3.69-3.84 (1H, m), 2.97-3.21 (2H, m), 2.69-2.93 (2H, m), 2.18-2.63 (4H, m). MS (m+1)=545.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C1C=[C:17]2[N:19]=NN(O)[C:16]2=[CH:15]C=1.O.CCN=C=NCCCN(C)C.Cl.N1CCC1>C(Cl)Cl>[N:19]1([C:10](=[O:12])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[CH2:17][CH2:16][CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccc(O)cc1F
Agent: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccc(O)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-fluoro-4-hydroxyphenyl)acetic acid (1 g, 5.88 mmol), HOBT monohydrate (2.7 g, 17.6 mmol), and EDC.HCl (3.38 g, 17.6 mmol) were dissolved in 25 mL of DCM and stirred at rt for 30 min. Azetidine (1 g, 17.6 mmol) was added to this mixture and the reaction aged at rt for 3 hrs. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (KP-Sil 50 g SNAP column, Biotage system) eluting with 100% EtOAc over 14 CV to give the desired product. LC/MS (m/z): 210 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[Br:1][C:2]1[C:3]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OCCCCCO
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(O)c1cnc(OCCCCCO)c(Br)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31a, using 5-bromo-6-chloro-nicotinic acid and 1,5-pentanediol as starting materials to give the product as brownish oil, MS (ISP): 302.3 (M−H+).
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.C[Si](Cl)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:39]1[O:51][C@H:50]([CH2:52][O:53]C(=O)C)[C@@H:45]([O:46]C(=O)C)[C@H:40]1[O:41]C(=O)C)(=O)C>C(#N)C>[C@@H:39]1([N:1]2[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:51][C@H:50]([CH2:52][OH:53])[C@@H:45]([OH:46])[C@H:40]1[OH:41]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc[nH]c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
A mixture of 5-azacytosine, HMDS, and TMSCl in acetonitrile is heated to reflux for 20 hours under an inert atmosphere. TMS-triflate and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose are then added directly to the silylated 5-azacytosine in acetonitrile. The addition is performed at ambient temperature and under an inert atmosphere. The reaction mixture is maintained under stirring for 20 hours, then the acetonitrile is removed under vacuum. The solids are then dissolved in dichloromethane, and the mixture is poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10%). The resulting mixture is extracted with dichloromethane. The combined organic extract is washed with cooled (0-5° C.) 10% sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam is dissolved in methanol and treated with a solution of 25% sodium methoxide in methanol. The suspension is stirred at ambient temperature for 15 hours, then the solid is filtered off, washed with methanol and anhydrous ether, then dried in vacuum. The crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1.[CH3:27][Sn:28](Cl)([CH3:30])[CH3:29]>CCOCC>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:15]([Sn:28]([CH3:30])([CH3:29])[CH3:27])[CH:14]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(NC(=O)OC(C)(C)C)c([Sn](C)(C)C)c1
Temperature: -20 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
A solution of t-butyllithium in pentane (1.70M, 148 mL, 251 mmol, 2.50 equiv) was added via cannula to a solution of tert-butyl 4-methoxycarbanilate (22.4 g, 100 mmol, 1 equiv) in ether (500 mL) at -20° C., producing a cloudy yellow solution. After stirring at -20° C. for 5 h, the reaction mixture was cooled to -78° C. and a solution of trimethyltin chloride (50.0 g, 251 mmol, 2.50 equiv) in ether (50 mL) was added via cannula. After the addition, the reaction mixture was warmed to -20° C. and was stirred at that temperature for 30 min, then was stirred in an ice bath for 30 min. The product solution was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 600 mL) and ether (400 mL). The aqueous layer was separated and further extracted with ether (2×400 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (15% ethyl acetate-hexanes) to afford tert-butyl 4-methoxy-2-(trimethylstannyl)carbanilate (7) as a yellow oil (33.3 g, 85%).
Reaction SMILES: CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].CCOCC.[OH2:24]>>[CH3:14][Si:15]([O:24][Si:15]([CH3:17])([CH3:16])[CH3:14])([CH3:17])[CH3:16]
Reactant: O
Reactant: C[Si](C)(C)Cl
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCOCC
Product: C[Si](C)(C)O[Si](C)(C)C

Procedure:
N-Methylglucamine (10 g, 0.05 mol) was suspended (partly dissolved) in dry freshly-distilled pyridine and cooled in an ice-bath. Trimethyl silylchloride (30 g, 0.28 mol) was added in portions so that the temperature did not rise above 20°- 25°. After 1 hour the reaction slurry was poured into ether (200 ml) and water (200 ml) and shaken; the ether layer was washed several times with water, dried and evaporated at 50°-60° to leave the oily per-trimethylsilyl ether containing a trace of pyridine. Yield: ca. 20 g (50%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]#[N:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-:24].[K+]>O.CC(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([C:20]([NH2:21])=[O:24])=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(N)=O

Procedure:
A solution of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (727 mg, 2.28 mmol) and KOH (767 mg, 13.7 mmol) in H2O (7.70 mL) and i-PrOH (11.55 mL) was subjected to microwave irradiation (300 W 130° C., 4 h) in a sealed tube. The reaction mixture was concentrated in vacuo to remove the i-PrOH. The aqueous slurry obtained was diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried (Na2SO4) and concentrated in vacuo to afford 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J=8.1, 1H), 3.68 (s, 3H), 2.84 (septet, J=6.7 Hz, 1H), 1.19 (d, J=6.7 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:30])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.CO.C(=O)([O-])[OH:34].[Na+]>Cl.O1CCOCC1>[OH:1][CH2:2][C:3]1([CH3:30])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:29]=[CH:28][C:25]([C:26]([NH2:27])=[O:34])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(N)=O)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of the compound (9.14 g, 17.2 mmol) obtained in Example 60-5) in 2 N hydrochloric acid-1,4-dioxane (200 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature, methanol (40 mL) was added to the reaction mixture, and insoluble substances were dissolved by sonication. Saturated aqueous sodium hydrogencarbonate (400 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane and purified by silica gel column chromatography (ethyl acetate:methanol=3:2) to obtain the title compound (2.74 g, 38%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[O:20][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(O)c3cccc(Cl)c3)ccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(OS(C)(=O)=O)c3cccc(Cl)c3)ccc21
Yield: 99.9 %

Procedure:
5-Amino-indazole-1-carboxylic acid tert-butyl ester was prepared following the procedure outlined by S. J. Brickner, WO9002744. 5-Amino-indazole-1-carboxylic acid tert-butyl ester was then coupled with 2-(3-chlorophenyl)-2-hydroxyacetic acid following the procedure as described in Example 1 to afford 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester. To a solution of 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (7.47 mmol) in dry THF (20 mL) at 0° C. was added pyridine (37.33 mmol, 5 equivalents) followed by methanesulfonyl chloride (22.40 mmol, 3 equivalents) added in a dropwise fashion. The resultant solution was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (3.58 g, qunatitative yield), which was used without further purification.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35]C(N)=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].CI.[CH3:45][N:46]([CH:48]=O)[CH3:47]>>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:48]([N:46]([CH3:45])[CH3:47])=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: CN(C)C=O
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
To a solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (100 mg, 0.192 mmol) in DMF (4 mL) was added NaH (15 mg, 0.575 mmol) followed by methyl iodide (24 μL, 0.383 mmol). The reaction was stirred at room temperature for 20 h and quenched with water. Methanol (3 mL) and acetic acid (1 mL) were added to the reaction mixture and heated at 80° C. for 2 h. The mixture was poured into water (10 mL) and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 3%-7% MeOH/DCM as eluent) to afford the desired product as a gel (32 mg, 0.104 mmol, 54%). 1H NMR: 3.02 (s, 6H), 3.16 (t, 2H, J=6.4 Hz), 4.39 (t, 2H, J=6.4 Hz), 6.99 (t, 4H, J=7.8 Hz), 7.18-7.24 (m, 2H), 7.35 (d, 2H, J=10.8 Hz), 7.69 (s, 1H), 7.70 (d, 1H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33]Cl)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][NH:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reactant: CCCCN
Product: CCCCNCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Yield: 63 %

Procedure:
From (+,-) cis 7-Benzyloxy4-[4-(2-chloroethyloxy)-phenyl]-3-phenyl-chroman (235 mg, 0.5 mmol) and butylamine (183 mg, 2.5 mmol). The evaporated product was precipitated from ether-petrolether to give 160 mg of material, which was chromatographed as described above.