Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([C:14]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1Br.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:4][C:5]([C:14]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Yield: 69.1 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd(PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:26]1[C:27]2[C:23](=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]1)=[O:18]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Cc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 25.3 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 339 mg of 4-methylindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 240 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 93 mg of 3-methyl-2-[2-(4-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:39]([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH3:40][Si:39]([CH3:42])([CH3:41])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:2]=1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC=C4)CCCCC3)c1C2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC([Si](C)(C)C)=C4)CCCCC3)c1C2
Yield: 45.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.86 g (2.02 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(3,6-di-tert-butylfluorenyl)cyclohexane was placed at room temperature. Then, 12 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (colorless transparent solution). To the solution, 1.4 ml (2.28 mmol, 1.13 eq) of n-BuLi (hexane solution) was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 19 hours. The solution was cooled with an ice bath, and to the solution, 1.6 ml (12.6 mmol, 6.24 eq) of chlorotrimethylsilane was dropwise added by a syringe. The ice bath was removed, and the solution was stirred at room temperature for 4 hours. The resulting yellow solution was poured into 50 ml of a diluted hydrochloric acid solution-to perform quenching. After the soluble component was extracted with 70 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellow amorphous product. The amorphous product was purified by silica gel column chromatography (developing solution: hexane) to obtain 0.46 g a white amorphous product (yield: 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:5]=[CH:6][CH:7]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:15]([OH:16])=[CH:10][CH:9]=[N:8]2)=[CH:6][CH:7]=1.[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:15]([OH:16])=[CH:10][CH:9]=[N:8]2
Reactant: CC1(C)OC(=O)C(=CNc2cccc(Br)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2cc(Br)ccc12
Product: Oc1ccnc2cccc(Br)c12
Temperature: 25 °C

Procedure:
5-[(3-Bromophenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (32.6 g, 0.100 mol) was heated at 250° C. in DOWTHERM A heat transfer fluid for one hour, and then the reaction was allowed to cool to ambient temperature. A precipitate formed upon cooling and was isolated by filtration and washed with diethyl ether to provide 7-bromoquinolin-4-ol and 5-bromoquinolin-4-ol in a 2:1 ratio.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:33]=[CH:34][C:35]([N:38]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:36][CH:37]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.45 g of 4-nitrobenzenesulfonyl chloride in 20 ml of methylene chloride are added dropwise to a solution of 2.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine in 50 ml of methylene chloride and 1.0 ml of triethylamine. The solution is stirred overnight at RT, extracted with water, and the organic phase is dried and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 3:2. After concentration of the corresponding eluate fractions, the title compound of m.p. 234.5° C. is obtained.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34])[CH3:24].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19])[CH3:24]
Reactant: CCOc1ccccc1CCN
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCOc1ccccc1CCNC(=O)C(C)(C)Oc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2-ethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO6 [M+H]+: 430.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1.O>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]([OH:13])[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)CC(O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
165.3 g of 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-one are suspended in 6 litres of dioxane and treated with a solution of 63 g of sodium borohydride in 300 ml of dioxane and 300 ml of water. The mixture is stirred overnight at room temperature, then diluted with water, made neutral with sulphuric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. The 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-ol obtained is recrystallised from ethyl acetate; melting point 144°-146° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19]S[CH2:21][C@H:9]23)=[CH:4][CH:3]=1.O[O:23][S:24]([O-:26])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S:24](=[O:26])(=[O:23])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3CSC[C@@H]32)cc1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 75.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (10 mg, 0.033 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at 50° C. for 2 hours. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ6-thia-cyclopenta[a]naphthalen-8-ol 14 (8.5 mg, 0.025 mmol, 77%). 1H NMR (δ, 400 MHz, MeOD) 7.47 (d, 2H, J=8.3 Hz), 6.87-6.74 (m, 4H), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 5.25 (s, 1H), 4.12-4.01 (m, 2H), 3.00 (m, 1H), 2.72 (dt, 1H, J=6.8, 12.8 Hz), 2.63-2.53 (m, 1H), 2.52-2.42 (m, 1H). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.68 min).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([O:31][C:32]1[C:33]([CH2:38]Cl)=[N:34][CH:35]=[CH:36][CH:37]=1)[CH:29]=[CH2:30].O>CN(C)C=O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:38][C:33]3[C:32]([O:31][CH2:28][CH:29]=[CH2:30])=[CH:37][CH:36]=[CH:35][N:34]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: C=CCOc1cccnc1CCl
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 40 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
((S)-7-Cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (25 g, 88.2 mmol) is dissolved in dimethylformamide (150 mL) under nitrogen. Cesium carbonate (57.5 g, 176.5 mmol) and 3-allyloxy-2-chloromethyl-pyridine (16.2 g, 88.2 mmol) are added sequentially. The reaction mixture is stirred at 40° C. for 16 h. The reaction is cooled to room temperature and added to water (1250 mL). After one hour of stirring a pale cream solid is filtered. The crude material is purified by recrystallization from i-PrOH and then dried under vacuum to constant weight to afford the title compound (32 g; 84%). LC-ES/MS m/z: 431.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][NH2:15].O>CCCCO>[F:11][C:10]([F:12])([F:13])[C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:15][N:14]=[C:4]2[NH2:5]
Reactant: NN
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
2-Fluoro-5-trifluoromethyl-benzonitrile (2.66 g) was dissolved in n-BuOH (51 ml) prior to the addition of NH2NH2.H2O (1.02 ml). The solution was heated to reflux for 30 min. After cooling to rt, the solution was concentrated and CH2Cl2 was added. The organic layer was washed with H2O, brine, dried, filtered, and concentrated in high vacuum to give 5-trifluoromethyl-1H-indazol-3-ylamine (2.25 g): 1H NMR (DMSO, δppm, 300 mHz) 5.70 (s, br, 2H), 7.40 (dd, 2H), 8.20 (s, 1H), 11.90 (s, br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20](=[O:31])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH:29]=O)[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:15]([O:19][C:20](=[O:31])[NH:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([CH2:28][CH2:29][N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:26][CH2:27]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorophenoxy)piperidine (0.150 g, 0.485 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.117 g, 0.48 mmol), in 1, 2 dichloroethane (3 mL) and methanol (0.500 mL) was stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (0.175 g, 0.829 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/CH3OH (1-9:1). The product fractions were concentrated to give 0.176 g (0.45 mmol, 92.5% yield) of a light yellow solid. MS (m/e): 393.4 (M+H+).
Reaction SMILES: Cl.[NH2:2]O.[C:4](=[O:7])([O-])O.[Na+].[C:9]([C@@H:11]1[CH2:16][C@H:15]([N:17]([C:22]([C:24]2[N:28]([CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:27]3[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=3[N:25]=2)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:12]1)#[N:10]>CS(C)=O.O>[CH3:34][O:33][CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[N:25]=[C:24]1[C:22]([N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C@H:15]1[CH2:16][C@@H:11]([C:9]2[N:2]=[CH:4][O:7][N:10]=2)[CH2:12][N:13]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:14]1)=[O:23]
Reactant: NO
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3ncon3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Hydroxylamine hydrochloride (383 mg) was dissolved in dimethyl sulfoxide (10 ml), and the mixture was stirred at 40° C. for 30 min. Sodium hydrogen carbonate (463 mg) was added, and the mixture was stirred at 50° C. for 1 hr. A solution of tert-butyl (3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate (282 mg) in dimethyl sulfoxide (10 ml) was further added, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in trimethyl orthoformate (5 ml) and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (230 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4](CC([O-])=O)[CH:5]=[C:6](CC([O-])=O)[CH:7]=1.[OH-:19].[Li+].Cl.C[OH:23]>>[CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([OH:23])[CH:5]=[C:6]([OH:19])[CH:7]=1
Reactant: Cc1cc(CC(=O)[O-])cc(CC(=O)[O-])c1[N+](=O)[O-]
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: Cc1cc(O)cc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.15 g (3.63 mmol) 5-methyl-4-nitro-1,3-phenylenediacetate and 10.0 mL (10.0 mmol) 1M aqueous lithium hydroxide solution in 10.0 mL methanol was stirred overnight at RT. The reaction mixture was acidified with 4M hydrochloric acid and extracted with dichloromethane. The organic phase was separated off, dried and evaporated down i.vac. The residue was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)OC(C)(C)C=C2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl 7-(7-ethoxy-2,2,4-trimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-nona-2E,4E,6E-trienoate (Compound 119, 103 mg, 0.24 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.C([O:13][C:14](=[O:16])[CH3:15])(=O)C.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>[O-2].[O-2].[O-2].[Cr+6]>[C:22]([O:25][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[O:13][C:14](=[O:16])[CH3:15])(=[O:24])[CH3:23]
Reactant: Cc1ccc(Br)cc1F
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CC(=O)OC(OC(C)=O)c1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorotoluene (ex Fluorochem) in glacial acetic acid (88 ml) and acetic anhydride (89.7 g) was cooled to -10°. Sulphuric acid (11.7 g) was added dropwise keeping the reaction temperature lower than -5°. Chromium trioxide (14.7 g) was added portionwise at 0°, the mixture was poured onto ice (300 g) and worked up as usual to give diacetoxymethyl-2-fluoro-4-bromobenzene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(=O)O[CH2:10][CH2:9][O:8]1>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:9][OH:8])[CH:6]=1
Reactant: O=C1OCCO1
Reactant: Ic1cn[nH]c1
Solvent: CN(C)C=O
Product: OCCn1cc(I)cn1
Yield: 53.2 %

Procedure:
A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83 g, 77.6 mmol) in DMF (50 mL) was stirred at 125° C. for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC, using 30-70% EtOAc in DCM, to give the title compound (9.36 g, 53%). LCMS (Method 1): Rt 2.24 min, m/z 239 [MH+].
Reaction SMILES: [F:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.O.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2cc1F
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc2cc1F

Procedure:
The procedure used in stage 4 of Example 216 is followed. In a 30 ml round-bottomed flask under an argon atmosphere, dissolve 140 mg of equimolecular mixture of 4-(5-fluoro-6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 0.7 ml of ethanol, 0.7 ml of water and 0.7 ml of acetic acid. At room temperature, add 100 mg of zinc, in three stages, and, between each addition, stir for approximately one hour to two hours. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 by volume), in this way we obtain 127 mg of 4-(5-fluoro-6-methoxy-1H -benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige resin which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=1.[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl>[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([NH:22][C:23]2[CH:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:15])[CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(-c2ccccc2)c1
Reaction time: 0.33 h
Yield: 6.6 %

Procedure:
4.0 mL of methylene chloride, 0.015 mL of N-dimethylformamide and 0.050 mL of oxalyl chloride were added to 99 mg of 3-biphenylcarboxylic acid at room temperature sequentially and stirred at the same temperature for 20 minutes. 0.16 mL of triethylamine and 0.13 g of tert-butyl 2-amino-4-phenoxybenzoate were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 10 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform] to obtain 14 mg of tert-butyl 2-(biphenyl-3-carboxamido)-4-phenoxybenzoate as white solid.