Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[NH:22]1[CH:26]=[C:25]([CH2:27][C:28](O)=[O:29])[N:24]=[N:23]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([NH:1][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:6][CH2:5]2)=[O:29])[N:24]=[N:23]1
Reactant: O=C(O)Cc1c[nH]nn1
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1c[nH]nn1)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (Example 3, step 1) (100 mg, 0.302 mmol), 2-(1H-1,2,3-triazol-4-yl)acetic acid (57.6 mg, 0.453 mmol), 1-propanephosphonic anhydride solution (0.353 mL, 0.604 mmol) and Huenig's Base (0.105 mL, 0.604 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and the solvent concentrated under pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: ClC(Cl)C(O)=O.[C:7]([O:10][C@@H:11]1[C@@H:15]([CH3:16])[O:14][C@@H:13]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:12]1)(=[O:9])[CH3:8].C1(N=C=NC2CCCCC2)CCCCC1.[C:42]([CH:47]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:44][CH2:45][CH3:46])=[O:43]>CS(C)=O.N1C=CC=CC=1>[C:7]([O:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:47]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])[O:14][C@@H:13]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:12]1)(=[O:9])[CH3:8]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](C)O2)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/[C@H]1O[C@@H](n2cc(CC)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
1.9 g of dichloroacetic acid were added to a mixture of 8.95 g of 3'-O-acetyl-2',5'-dideoxy-5-ethyluridine and 18.6 g of dicyclohexylcarbodiimide in 75 ml of dimethyl sulfoxide. The mixture was stirred at room temperature for 24 hours. 1.2 ml of pyridine and 10.5 g of carbethoxymethylenetriphenylphosphorane were added and the mixture was stirred at room temperature for an additional 24 hours. The solvent was removed in vacuo and the residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 300 ml of water, dried over anhydrous sodium sulfate and evaporated to give a yellow oil. This oil was subjected to flash chromatography on a column of silica gel using 5% methanol/dichloromethane for the elution. The product was recrystallized from ethanol to give 7.3 g of trans-3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethylene)-5-ethyluridine in the form of a white solid of melting point 132°-133° C.
Reaction SMILES: Br[C:2]1[C:3]([F:16])=[C:4]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.ClCCl.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>[CH:17]([C:2]1[C:3]([F:16])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8])=[CH2:18]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=Cc1cccc(N)c1F
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of 1,1-dimethylethyl (3-bromo-2-fluorophenyl)carbamate (500 mg, 1.72 mmol) and 2,6-ditert-4-methylphenol (3 mg, 0.02 mmol) in toluene (3 mL) was deoxygenated for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) and tributyl(vinyl)tin (708 μl, 2.43 mmol) were added to the solution, which was then stirred at refluxed for 4 hrs. The mixture was cooled to room temperature, and then filtered through a pad of celite. The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane). The product was isolated as a colorless oil, and was then diluted in dichloromethane (2 mL). To the solution was added trifluoroacetic acid (500 μl), and the solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous portion was extracted twice with dichloromethane, and the combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in-vacuo to afford 138 mg, 1.0 mmol, (58% over two steps) of 3-ethenyl-2-fluoroaniline as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.92-6.82 (m, 3H), 6.71-6.66 (m, 1H), 5.80 (d, 1H), 5.35 (d, 1H); 3.72 (br s, 2H); MS (EI) for C8H8FN: 138 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH:25][CH3:26])[CH:22]([CH3:24])[CH3:23]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:26])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-isobutyl-N-methylamine (3.02 g, 34.7 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.87 g, 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC#N.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:15]2[CH:16]=[C:11]([NH2:10])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)nc(-c2cccc(N)c2)n1
Temperature: 150 °C

Procedure:
A mixture of 2-Chloro-4,6-dimethyl-pyrimidine (92 mg, 0.645 mmol, 1 eq.), 3-aminobenzene boronic acid (100 mg, 0.645 mmol, 1 eq.), Na2CO3 (137 mg, 1.29 mmol, 2 eq.), and Pd(PPh3)2Cl2 (23 mg, 0.032 mmol. 5 mol %) in a 1:1 v/v mixture of CH3CN/H2O (2.6 mL) is purged with N2 for 5 minutes and then heated in a microwave at 150° C. for 5 minutes. After cooling to room temperature, the reaction is diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:1 hexanes/EtOAc) to give 3-(4,6-Dimethyl-pyrimidin-2-yl)-phenylamine as a yellow semisolid. [MS: (ES+) 200.1 (M+1)+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:30])([CH:27]([F:29])[F:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[N:24][NH:23][C:22]2=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.O.CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:23]2[C:22](=[O:26])[N:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]([F:11])([F:30])[CH:27]([F:28])[F:29])=[CH:20][CH:19]=3)[CH:25]=[N:24]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)cnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 4-fluoronitrobenzene (3.1 g), 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (5.8 g), potassium carbonate (13.8 g) and N,N-dimethylformamide (60 ml) was stirred at 80° C. for 2 hours. The resultant was cooled and poured into water (500 ml). The mixture was neutralized with hydrochloric acid and the precipitated crystals were collected by filtration. The crystals thus obtained were dissolved in ethyl acetate (300 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-(4-nitrophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (5.5 g, 67%) as yellow crystalline powders.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C:34]1([CH:41]=[O:42])[CH2:38][CH2:39][CH3:40])=[O:32])([CH3:29])([CH3:28])[CH3:27]>CCOCC>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C:34]1([CH:41]([OH:42])[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1)[CH2:38][CH2:39][CH3:40])=[O:32])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCC1(C(O)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a stirred solution of 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (0.587 g, 1.66 mmol) in ether (20 mL) at −78° C. and under nitrogen was added tert-butyllithium (2.30 mL of 1.51 M solution in pentanes, 3.49 mmol) dropwise. After 90 minutes, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.400 g, 1.66 mmol) in ether (1 mL) was added to the reaction mixture dropwise. After stirring for one hour, the reaction mixture was warmed to ambient temperature over 30 minutes. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) then extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (0.90 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.576 g, 1.12 mmol, 53%) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH:14]=O)[CH:6]=[CH:5][CH:4]=1.[CH3:16][C:17]([CH3:19])=[O:18].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2/[CH:14]=[CH:16]/[C:17](=[O:18])[CH3:19])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: COc1cccc(-c2ccsc2C=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2ccsc2/C=C/C(C)=O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a 500 mL recovery flask was added 3-(6-methoxypyridin-2-yl)thiophene-2-carbaldehyde (30C, 6.2 g, 28.3 mmol, 1.0 eq.), acetone (16.6 mL, 226 mmol, 8.0 eq.), and H2O (130 mL). Upon cooling to 0° C. in an ice bath, aqueous NaOH (5N, 6.2 mL, 31.1 mmol, 1.1 eq.) was added. The reaction mixture was stirred overnight while warming to room temperature. LC/MS monitoring showed the reaction to be ˜60% complete, so additional aqueous NaOH (5N, 1 mL, 5.0 mmol, 0.18 eq.) was added. After stirring for an additional 6 h the reaction was complete by LC/MS. The reaction mixture was neutralized with 3N aqueous HCl to a pH ˜8. The mixture was extracted with EtOAc (3×100 mL). The organic phases were combined and washed with saturated aqueous NaCl (100 mL). The combined aqueous phases were extracted with EtOAc (100 mL). The organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated to give a black solid. The residue was purified via flash chromatography (60% CH2Cl2/Hex to 100% CH2Cl2) to give a yellow solid 30D (4.8 g, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 3.96 (s, 3H) 6.59 (d, J=15.92 Hz, 1H) 6.84 (d, J=8.34 Hz, 1H) 7.41 (d, J=7.58 Hz, 1H) 7.60 (d, J=5.31 Hz, 1H) 7.75-7.88 (m, 2H) 8.71 (d, J=15.92 Hz, 1H). ESI-MS: m/z 260.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH2:14]([NH:18][OH:19])[CH2:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:18]([CH2:14][CH2:15][CH2:16][CH3:17])[O-:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCCCNO
Product: CCCC[N+]([O-])=Cc1ccc(OC)c(OCC)c1

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 3-ethoxy-4-methoxybenzaldehyde and N-n-butylhydroxylamine. The title compound was isolated in 41.1% yield as a solid, m.p. 117.3° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:51])[CH2:44][CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:51])[CH2:44][CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(CC1CCOCC1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 57.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: [C:1]1(=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[N:21]=3)[C:10]2=[O:32])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:1]1([NH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])(=[O:31])[N:21]=3)[C:10]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 240C (0.099 g, 0.22 mmol) in tetrahydrofuran (4.0 mL) (0.099 g, 0.22 mmol) in tetrahydrofuran (4.0 mL) and methanol (0.020 mL, 0.49 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.16 mL, 0.32 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43 (m, 11 H) 1.87 (m, 1 H) 3.25 (m, 1 H) 5.53 (d, J=3.68 Hz, 1 H) 7.04 (m, 1 H) 7.28 (m, 2 H) 7.51 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.73 (d, J=8.46 Hz, 1 H) 8.05 (dd, J=7.72, 1.47 Hz, 1 H) 16.30 (s, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([C:14]2[S:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=O)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:21][NH2:22]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:21][NH:22][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(C)s2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccc(C)s3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(5-methylthiophene-2-carbonyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C@H:26]([N:33]([C:41](=[O:43])[CH3:42])[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:25][C@@H:24]3[CH3:44])=[O:22])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1)=[O:5])C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:41]([N:33]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C@H:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:4]([OH:5])=[O:3])=[CH:16][CH:17]=2)=[O:22])[C@@H:24]([CH3:44])[CH2:25]1)(=[O:43])[CH3:42]
Reactant: CCOC(=O)c1nccn1CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3ccnc3C(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,4R)-1-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-1H-imidazole-2-carboxylic acid was prepared from (2S,4R)-1-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-1H-imidazole-2-carboxylic acid ethyl ester. The ester (0.100 g, 0.16 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-1-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-1H-imidazole-2-carboxylic acid in 65% yield.
Reaction SMILES: C([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([N:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([N:34]1[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:13]=2)C1C=CC=CC=1.C(=NC1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].CN(C=O)C>O>[CH:45]1[C:46]2[N:34]([C:12]3[CH:11]=[CH:10][C:9]4[NH:8][C:20]5[C:15]([C:14]=4[CH:13]=3)=[CH:16][C:17]([N:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][CH:19]=5)[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc(Cn2c3ccc(-n4c5ccccc5c5ccccc54)cc3c3cc(-n4c5ccccc5c5ccccc54)ccc32)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc2[nH]c3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
Under a nitrogen atmosphere, a suspension of N-benzyl-3,6-di(N-carbazolyl)carbazole (2.06 g, 3.5 mmol), benzylideneaniline (1.27 g, 7.0 mmol) and t-BuOK (5.06 g, 50 mmol) in a dried DMF (30 mL) was stirred at 75° C. for 4 hours. Water (about 150 mL) was added and black tar precipitated was filtrated. The tar-like material was dissolved in hot chloroform, to which anhydrous magnesium sulfate and activated carbon were added to be stirred for 30 minutes with heating. The mixture was filtrated, the filtrated liquid was concentrated, and then the residuum was recrystallized with chloroform/ethanol to give the compound in the title, (3,6-di(N-carbazolyl)carbazole) as beige powder. The yield was 29%. The melting point was 185 to 187° C. NMR data are shown in FIG. 17 (1H NMR) and FIG. 18 (13C NMR).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH3:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)CCC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCC(=O)N1CCCCC1

Procedure:
4-Methylvaleric acid (238 g) and DMF (833 mL) were mixed. After an addition of piperidine (233 mL), HOBt.H2O (361 g) and WSC.HCl (452 g) to the mixture at ice temperature, the resulting mixture was stirred at RT overnight. To the reaction was added water (1000 mL) at ice temperature and the resulting mixture was extracted with toluene (500 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (500 mL+300 mL) and water (500 mL×2). The organic layer was concentrated in vacuo to give the title compound (414.29 g) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[OH:37])[CH:30]=[CH:29][N:28]=[CH:27]1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:37][C@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]2[N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: O[C@H]1CCCC[C@H]1n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(O[C@H]2CCCC[C@H]2n2ccnc2)cc1F
Yield: 64.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (WO 2010/079443; 390 mg, 0.949 mmol), (1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexanol (Heterocycles, 31(3), 537-48, 1990; 160 mg, 0.963 mmol), sodium hydride (63%; 75.0 mg, 1.97 mmol) and DMF (4.0 mL), to yield the title compound (340 mg, 64%) as a colorless oil.
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[C:15](#[N:17])[CH3:16].S(=O)(=O)(O)O.[Na]>C(O)(=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:4]([CH2:3][C:2]([CH3:14])([CH3:13])[N:17]=[C:15]2[CH3:16])=[CH:9][C:8]=1[OH:10]
Reactant: COc1ccc(CC(C)(C)O)cc1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)CC(C)(C)N=C2C
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a flask (ice cooled) containing acetic acid (1.2 ml) was added 5-(2-hydroxy-2-methylpropyl)-2-methoxyphenol (500 mg, 2.5 mmol) and acetonitrile (0.27 ml, 5.1 mmol). To this was added sulfuric acid (1.2 ml) slowly with stirring. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was poured onto ice-water and the aqueous solution neutralised with sodium C(Ar)bonate, then extracted with diethyl ether (2×) and ethyl acetate (2×) after saturation with sodium chloride. Purification (flashmaster: 20 g, 100% DCM to 100% EtOAc, then 30% MeOH/70% EtOAc) afforded the title compound (324 mg, 56%) as a pale brown solid. mp=160° C. dec. 1H NMR (270 MHz; CDCl3) 1.18 (6H, s, 2×CH3), 2.28 (3H, s, CH3), 2.59 (2H, s, CH2), 3.91 (3H, s, OCH3), 6.60 (1H, s, CH), 7.07 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 23.21 (CH3), 28.02 (2×CH3), 38.81 (CH2), 53.78 (C(CH3)2), 55.98 (CH3), 110.47 (CH), 112.35 (CH)<121.96 (C), 128.86 (C), 144.35 (C), 148.88 (C), 161.39 (C N). LC/MS (ES+) tr=1.2 min, m/z 219.95 (M++H).