Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4[CH:36]=CC=C[CH:32]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)([CH3:42])([CH3:41])[CH3:40].C(=O)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([N:29]([CH2:40][CH:39]([CH3:42])[CH3:41])[CH2:30][CH:31]([CH3:36])[CH3:32])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)C=O
Agent: [Na+]
Product: CC(C)CN(CC(C)C)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 79.5 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (97.1 mg, 0.228 mmol), isobutyraldehyde (32.8 mg, 0.455 mmol) and NaBH(OAc)3 (135.1 mg, 0.638 mmol) yielded 87.4 mg (79.5%) of intermediate 9a. MS (ESI) 539.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CO>[BrH:17].[C:21]1([C:19]2[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:16][CH:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CO
Product: Br
Product: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Temperature: 70 °C
Reaction time: 22 h
Yield: 95.9 %

Procedure:
A mixture of 1 g (4.1 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 0.816 g (4.1 mmol) 2-bromo-1-phenyl-ethanone (commercially available) in 10 ml methanol was stirred at 70° C. for 22 h. After evaporation to dryness the residue was suspended in diethyl ether and filtered. The residue washed with diethyl ether and dried under vacuum to yield 1.279 g (96%) of the title compound in white crystalline form. (m/e): 245.2 (MH+(−HBr); 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH2:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:36]1[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:42]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ncccc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M216) (335 mg, 0.536 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (159 mg, 58%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Product: COC(=O)[C@@H](C)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 82 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and (R)-methyl 2-aminopropanoate hydrochloride. Yield 82%, colorless liquid. MS 324 (MH+).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:32]#[C:33][Si](C)(C)C)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl>CCO.C1COCC1>[C:32]([C:15]1[N:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=2)[N:17]([CH3:18])[C:16]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:23][CH2:22]1)=[O:20])#[CH:33]
Reactant: CCCCCCc1cccc(-c2nc(C#C[Si](C)(C)C)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: C#Cc1nc(-c2cccc(CCCCCC)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a solution of 0.52 g (1.00 mmol) of [2-(3-hexyl-phenyl)-3-methyl-5-trimethylsilanylethynyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 12) in 10 ml EtOH:THF 5:1 was added 0.277 g (2.0 mmol) of solid potassium carbonate and the reaction mixture was stirred at RT for 18 hours. It was then poured into crashed ice, acidified with HCl (25% in water) and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.27 g (60%) of the title compound as light brown solid. MS: 447.4 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(C(=O)CBr)cc1
Product: Cc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Yield: 32 %

Procedure:
2′-Nitro-4-(4-p-tolyl-thiazol-2-yl)-biphenyl-2-carboxylic acid (85 mg, 32%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-4′-methylacetophenone (available from ASDI Incorporated) using the procedure described for the preparation of Example 39. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.57 (d, J=1.9 Hz, 2H), 8.26 (dd, J=8.0, 1.9 Hz, 1H), 8.20 (s, 1H), 8.15 (dd, J=8.1, 0.9 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.77-7.82 (m, 1H), 7.63-7.69 (m, 1H), 7.42-7.48 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 2.36 (s, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1CCCO.N1CC[CH2:35][CH2:34][CH2:33]1>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:33][CH2:34][CH:35]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=1
Reactant: OCCCc1ccccn1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2cccnc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 676 mg (5.0 mmol) of 3-(2-pyridyl)-1-propanol in 20 ml of ethanol, 43 mg (0.5 mmol) of piperidine-was added, followed by refluxing for 4 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.56 g (71.1%, yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[C:20]=[O:21]>ClCCl>[C:15]([O:14][C:12]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH:11][C:20]([NH:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)=[O:21])=[CH:7][CH:6]=2)[C:2]([NH2:1])=[N:3]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cccc(CN=C=O)c1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Solvent: ClCCl
Product: COc1cccc(CNC(=O)Nc2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)c1
Yield: 69.2 %

Procedure:
1.1 3.3 g of tert-butyl 3,5-diaminoindazole-1-carboxylate (13.3 mmol) and 2.0 g of 1-isocyanatomethyl-3-methoxybenzene (12.3 mmol) are stirred at RT for 24 hours in 40 ml of dichloromethane. The reaction mixture is washed with water, the organic phase is separated off, dried and evaporated. Purification of the residue by column chromatography (eluent ethyl acetate) gives 3.5 g of tert-butyl-3-amino-5-[3-(3-methoxybenzyl)ureido]indazole-1-carboxylate (64%); MS-FAB (M+H+)=412.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc([N+](=O)[O-])cc1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5 (b) by reaction of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloro-propane with N-methyl-N-[2-(4-nitro-phenyl)-ethyl]-amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH3:22])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:23])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CC#N.C(Cl)Cl>[CH3:22][C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:23])[N:10]([C@H:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:9])[CH2:15][CH2:14]1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](c1cccc(O)c1)N1CCC(C)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1cccc([C@H](C)N2CCC(C)(c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.2 %

Procedure:
A mixture of (R/S)-3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (0.0955 g, 0.31 mmol, 1.0 equiv), Cs2CO3 (0.3307 g, 1.01 mmol, 3.3 equiv), and ethyl bromoacetate (0.1468 g, 0.88 mmol, 2.8 equiv) in CH3CN (1.5 mL) was stirred at rt for 3 d. The mixture was diluted with CH2Cl2, treated with H2O (2 mL), dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.1025 g (84%) of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate. LC-MS Method 1, tR=1.75 min, m/z=398 (M+1). 1H NMR (CDCl3) 7.40-7.23 (m, 6H), 6.95-6.93 (m, 1H), 6.88 (m, 1H), 6.81-6.78 (m, 1H), 5.76 (q, J=7.1 Hz, 1H), 4.61 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.68-2.65 (m, 2H), 2.28-2.23 (m, 1H), 2.06-1.98 (m, 1H), 1.63 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.26 (d, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19]>CN(C=O)C>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:6][CH:7]=1)#[N:19]
Reactant: OCCCc1ccc(O)cc1
Reactant: N#CCCCCCBr
Solvent: CN(C)C=O
Product: N#CCCCCCOCCCc1ccc(OCCCCCC#N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 3-(4hydroxyphenyl)-1-propanol (2.0 g, 13.1 mmole) in DMF (5 mL) was added to a solution of DMF (35 mL) containing Nail (1.31 g, 60% in mineral oil) at 0° C. under nitrogen atmosphere. The reaction mixture was slowly warmed to 80° C. After stirring for 1 h at 80° C., the reaction mixture was cooled to 0° C., and 6-bromohexanenitrile (5.78 g,.32.83 mmole) was added. The final mixture was re-heated to 80° C., and stirred for 24 h. The reaction mixture was quenched with saturated NaCl solution (200 mL), and the product was extracted with EtOAc (300 mL). The organic layer was washed with brine solution, dried with Na2SO4, and evaporated to dryness, yielding a pale yellow solid. Purification of the crude product by flash silica column chromatography: 4/1 to 1/1 hexane/EtOAc provided 6-{3-[4-(5-cyanopentyloxy)phenyl]propoxy}hexanenitrile in 30% yield (1.33 g). Rf=0.63 in 1/1 EtOAc/hexane. 1H-NMR (CDC3, 299.96 MHz): δ (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:16])([O-:11])=[O:10]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)c1cccc([N+](=O)[O-])c1
Yield: 76.1 %

Procedure:
Using 4-fluoroaniline (1.1 ml, 10.9 mmol) and 3-nitrobenzoic acid (1.76 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.98 g (76.0%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:17][C:18]1([CH3:51])[O:22][C@H:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:31]3[C:36]([F:37])=[CH:35][C:34]([N:38]4[CH2:42][C@H:41]([CH2:43]OS(C)(=O)=O)[O:40][C:39]4=[O:49])=[CH:33][C:32]=3[F:50])=[CH:27][CH2:26]2)=[O:24])[CH2:20][O:19]1.O>CN(C)C=O>[CH3:51][C:18]1([CH3:17])[O:22][C@H:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:31]3[C:36]([F:37])=[CH:35][C:34]([N:38]4[CH2:42][C@H:41]([CH2:43][N:10]([C:11]5[O:15][N:14]=[C:13]([CH3:16])[CH:12]=5)[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[O:40][C:39]4=[O:49])=[CH:33][C:32]=3[F:50])=[CH:27][CH2:26]2)=[O:24])[CH2:20][O:19]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)on1
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)CC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)C(=O)OC(C)(C)C)on1
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Sodium hydride (60% in oil, 72 mg, 1.8 mM) was suspended in dry N,N-dimethylformamide (3 ml), cooled to 0° under nitrogen, and a solution of 5-(t-butoxycarbonylamino)-3-methylisoxazole (356 mg, 1.8 mM) in N,N-dimethylformamide (3 ml) added. After stirring for 10 minutes, a solution of 3-(4(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one (516 mg, 1.5 mM) in N,N-dimethylformamide (3 ml) was added, and the mixture heated to 40° for 5 hours. After cooling, the mixture was poured into water (50 ml), extracted with dichloromethane (4×20 ml). The organic phase was dried (magnesium sulfate), evaporated and crude product purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 50% to 75% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (420 mg).
Reaction SMILES: IC.[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([OH:29])=[O:28])[N:21]([CH3:30])[C:20]=4[CH:31]=3)[C:12](=[O:32])[CH:11]=2)=[CH:6][CH:5]=1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([O:29][CH3:35])=[O:28])[N:21]([CH3:30])[C:20]=4[CH:31]=3)[C:12](=[O:32])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Iodomethane (0.111 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (400 mg) and potassium carbonate (246 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (205 mg) as a pink solid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[OH:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19](C)C.C(N(CC)CC)C.C1(CC(Cl)=O)C=CC=CC=1>ClCCl>[C:15]1([CH2:14][C:13]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])=[O:12])[CH:16]=[CH:17][CH:18]=[CH:19][CH:22]=1
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of geraniol and nerol (approximately 70:30 by weight) in the amount of 51.02 g (0.324 mol) and triethylamine in the amount of 33.13 g (0.324 mol) are combined with 275 mL of dichloromethane. The reaction mixture is treated with a solution of phenylacetyl chloride in the amount 51.14 g (0.324 mol) dissolved in 100 ml of dichloromethane over 1 h. After heating to reflux for 1 h, the product mixture is cooled to room temperature, washed with 100 mL of brine twice, 100 mL of saturated NaHCO3 solution twice, 100 mL of water, and dried over MgSO4. The filtrate is concentrated by rotary evaporation followed by Kugelrohr distallation. Purification of the product by column chromatography provides a colorless oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 13C and 1H NMR.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C.O>C(Cl)Cl>[C:26]([CH2:25][O:24][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1)[CH3:17])#[N:27]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: N#CCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
17.2 g (0.05 mole) of 4-(4'-trifluoromethylphenoxy)-α-phenoxypropionyl chloride are added dropwise at 10° C. to a mixture of 3.13 g (0.055 mole) of 100% hydroxyacetonitrile (cyanomethanol) and 5.5 g (0.54 mole) of triethylamine in 50 ml of methylene chloride. The reaction mixture is then stirred for 1 hour at room temperature. Then 100 ml of water are added and the organic phase is separated, filtered over a small column of silica gel and concentrated. The residual solid is triturated with petroleum ether, collected by filtration and dried, affording 13.2 g (72.5% of theory) of 4-(4'-trifluoromethylphenoxy)-α-phenoxy-propionic acid cyanomethyl ester with a melting point of 53°-56° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1F.CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH2:16][CH3:17]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 96.4 mmol) was dissolved in DMF (200 μL). NaH (2776 μg, 115.7 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (22.6 μL, 192.8 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC (10-40%, 60 min, BDS) to yield the title compound as a mono-TFA salt oil (24.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NO2, 304.08; found 304.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][C@@H:30]([C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccccc1
Yield: 142 %

Procedure:
Preparation of example 117 from the the title compound of Example 7 (hydrochloride) (44 mg, 0.141 mmol), (R)-tert-butoxycarbonylamino-phenyl-acetic acid (42 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (102 mg) as a yellow powder contaminated with an unknown impurity. The compound was an intermediate and carried on without further purification to Example 91.