Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:20]=[C:19]([CH3:21])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:7]([CH3:22])[CH:6]=1)=[O:4].C(Cl)(Cl)Cl.CO>CO>[CH:3]([C:5]1[CH:20]=[C:19]([CH3:21])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:7]([CH3:22])[CH:6]=1)=[O:4]
Reactant: CCOC(=O)CCCCOc1c(C)cc(C=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(C=O)cc(C)c1OCCCCC(=O)O
Yield: 101.9 %

Procedure:
2 N aqueous NaOH (30 mL) was added to ethyl 5-(4-formyl-2,6-dimethylphenoxy)valerate (4.0 g, mw 278.4, 14 mmol; prepared as in Example 18) dissolved in methanol (40 mL) and that the solution stirred at 25° C. for 1 hour, at which point TLC (CHCl3-methanol, 99:1) indicated the reaction was complete. Methanol was removed under reduced pressure and the reaction diluted with water (150 mL), washed with ethyl acetate (2×25 mL, discarded), acidified to pH 4 with 6 N aqueous HCl, and extracted with ethyl acetate (3×30 mL). The organic extract was washed with brine (2×75 mL), dried over Na2SO4, filtered and concentrated to yield 3.57 g (99%) of an amber oil. A portion of the oil was purified by flash chromatography on silica (CHCl3-methanol, 45:1) to provide NMR and TLC (Rf origin) pure title product:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
A mixture of 3-bromobenzenethiol (1.5 g, 7.93 mmol), 2-bromoethanol (1.19 g, 9.52 mmol) and Cs2CO3 (5.16 g, 15.8 mmol) in DMF (10 ml) was heated to 50° C. overnight. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and dried. The crude product was purified by column chromatography to afford the titled compound (1.5 g, 81%). 1HNMR (400 MHz, CDCl3): δ 3.12 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.4 Hz, 2H), 7.14 (t, J=8.0 Hz, 1H), 7.26-7.34 (m, 2H), 7.51 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:14]N1C(=O)CCC1=O.O>C1COCC1>[Br:14][C:6]1[CH:7]=[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncccc1CC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(Br)cc1CC(C)(C)C
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
To a solution of 2-methoxy-3-neopentylpyridine (4.22 g) in THF (40 mL) was added N-bromosuccinimide (6.29 g) at room temperature, and the mixture was stirred at 100° C. for 20 min. Water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, hexane) to give the title compound (4.38 g) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+].CN(C)[CH:20]=[O:21]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[N:9][C:10]([CH:20]=[O:21])=[C:4]2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccn2cncc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ncn2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 4.93 g of 7-bromoimidazo[1,5-a]pyridine in 2.2 ml of dry N,N-dimethylformamide is cooled to 0-5° C. in an ice bath. Phosphorus oxychloride (5.37 g) is added dropwise at 0-5° C. and the reaction mixture is subsequently stirred at 100° C. over 1 hour. The reaction mixture is cooled and poured onto ice-water. The quenched solution is basified with 25% ammonium hydroxide solution and extracted with dichloromethane (3×200 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc2oc(Nc3ccccc3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2cc(CC(=O)O)ccc2o1
Temperature: 25 °C
Yield: 88 %

Procedure:
Methyl 2-(2-methylphenylamino)-5-benzoxazolylacetate (2.32 g, 7.86 mmol) was dissolved in THF (40 ml). After addition of 0.25N NaOH (40 ml) under stirring at room temperature, the mixture was stirred for 15 hours. The residue, which had been obtained by distilling the reaction mixture under reduced pressure to remove the solvent, was acidified with 1N HCl. The crystals thus obtained were collected by filtration under reduced pressure, washed with water, dried under reduced pressure, whereby the title compound (894 mg) was obtained as a pale black crystalline powder. The water layer was extracted with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (1.03 g) was obtained as a colorless solid (total yield: 88%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]>C1COCC1>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TEA (8.00 mL, 57.5 mmol) followed by pivaloyl chloride (2.80 mL, 22.8 mmol) in THF (25 mL) are added to 4-chloro-3-nitrobenzylamine (5.00 g) in THF (100 mL). The reaction mixture is diluted with THF and stirred at rt for 1.5 h. The mixture is filtered and washed and the filtrate is concentrated.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH:20]2[CH2:22][CH:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=32)[N:16]=[C:15]([CH3:23])[N:14]4[CH2:24][CH2:25][CH3:26])[CH2:9]1)=O)(C)(C)C.[ClH:27].CCOC(C)=O>>[ClH:27].[CH3:23][C:15]1[N:14]([CH2:24][CH2:25][CH3:26])[C:13]2[C:17](=[CH:18][C:19]3[CH:20]4[CH2:22][CH:10]([C:11]=3[CH:12]=2)[CH2:9][NH:8][CH2:21]4)[N:16]=1
Reactant: CCCn1c(C)nc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCn1c(C)nc2cc3c(cc21)C1CNCC3C1
Temperature: 100 °C
Yield: 34 %

Procedure:
6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester (90 mg, 0.253 mmol) was dissolved in 3N HCl EtOAc (5 mL) and warmed to 100° C. for ½ hour. The mixture was cooled, concentrated, stirred in EtOAc, and filtered to provide a white solid (25 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, NH), 7.91 (s, 1H), 7.83 (br m, NH), 7.74 (s, 1H), 4.38 (m, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.10 (m, 2H), 2.87 (s, 3H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H), 1.85 (m, 2H), 0.97 (m, 3H). mp 147-150° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[CH2:10]([NH:28][C:29]([O:31][CH2:32][CH:33]([CH2:36][O:37][C:38](OC1C=CC=CC=1)=[O:39])[O:34][CH3:35])=[O:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:10]([NH:28][C:29]([O:31][CH2:32][CH:33]([CH2:36][O:37][C:38](=[O:39])[NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1)[O:34][CH3:35])=[O:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)Oc1ccccc1)OC
Reactant: CCN1CCCC(N)C1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)NC1CCCN(CC)C1)OC
Temperature: 60 °C

Procedure:
3-Amino-1-ethylpiperidine (1 ml) was added to 1.3 g of 1-octadecylcarbamoyl-2-methyl-3-phenoxycarbonylglycerol, and the reaction solution was heated at 60° C. for 1 hour and purified by silica gel chromatography [ethyl acetate-methanol (10:1)] to give 1.13 g of the objective compound as a milk-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:25][C:26]1[O:30][C:29]([CH:31]([NH:33][OH:34])[CH3:32])=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[OH:34][N:33]([CH:31]([C:29]1[O:30][C:26]([CH3:25])=[CH:27][CH:28]=1)[CH3:32])[C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(C(C)NO)o1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)N(O)C(=O)c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a solution of 4-(methylsulfonyl) benzoic acid (3.1 g, 15.5 mmol) in 100 mL of methylene chloride was added dimethylformamide (1.2 mL, 15.5 mmol). The reaction vessel was cooled to 0° C. and oxalyl chloride (3.1 mL, 35 mmol) was added. The mixture stirred 1 h at 0° C. and was added to a solution of N-(1-(5-methyl-fur-2-yl)ethyl) hydroxylamine (2.6 g, 18.6 mmol) and triethylamine (3.3 mL, 23.3 mmol) in 75 mL methylene chloride at 0° C. The mixture stirred 1.5 h and was poured into 2M HCl (100 mL). The aqueous layer was extracted with methylene chloride (3×, 100 mL) and the combined organic extract was washed with saturated sodium bicarbonate solution (1×100 mL) and brine (1×100 mL). The solution was dried over MgSO4, filtered and evaporated. The material was recrystallized from ethyl acetate to yield 1.14 g of a white solid; m.p.=177° C.; 1H NMR (300 MHz, DMSO-d6) 9.85 (bs, 1H), 7.97 (d, J=8.41 Hz, 2H), 7.83 (d, J=9.01 Hz, 2H), 6.24 (d, J=3.60 Hz, 1H), 6.02 (m, 1H), 5.71 (bs, 1H), 3.26 (s, 3H), 2.24 (s, 3H), 1.47 (d, J=6.91 Hz, 3H). MS (M+H)+ =324; Analysis calc'd for C15H17NO5 : C, 55.20; H, 5.25; N, 4.29. Found: C, 55.07; H, 5.20; N, 4.23.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5](OC)([O:7]C)[CH2:4]1.Cl>>[F:1][CH:2]([F:17])[C:3]1([C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])[CH2:4][C:5](=[O:7])[CH2:6]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(F)F)C1
Agent: Cl
Product: CC(C)OC(=O)C1(C(F)F)CC(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.2 %

Procedure:
To a stirred solution of Intermediate 304B (300 mg, 1.189 mmol) was added a conc. aq. solution of HCl (0.457 mL, 5.94 mmol) and the reaction mass was stirred at RT for 48 h. The reaction was quenched with water and extracted with DCM (2×25 mL). The organic layer was washed with water, a 10% aq. solution of NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (4 g REDISEP® column, eluting with 25% ethyl acetate in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 304C as a pale yellow liquid (150 mg, 61%). 1H NMR (400 MHz, chloroform-d) δ ppm 6.40 (s, 1H), 5.15 (s, 1H), 3.33-3.51 (m, 4H), 1.23-1.33 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:24]([NH:34][CH3:35])=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CC(C)N=C=NC(C)C>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:34]([CH3:35])[C:24]2[CH:25]=[C:26]([O:32][CH3:33])[C:27]([C:28]([OH:30])=[O:29])=[CH:31][C:23]=2[N:22]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(OC)c(C(=O)O)cc1N
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(=O)O)nc(Nc1cc(CNC(=O)C3(C(F)(F)F)CC3)ccc1Cl)n2C
Temperature: 25 °C

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (1.71 g; 5.10 mmol) and 5-amino-2-methoxy-4-(methylamino)benzoic acid (1.00 g; 1.00 mmol) in DMF (20 mL) was stirred over night at rt. The mixture was thereafter heated to 60° C. and BSTFA (1.44 g; 5.61 mmol) was added and stirred for 1 h before the addition of DIC (0.772 g; 6.12 mmol). The resulting mixture was stirred at 80° C. for 3 h. Acetic acid (2 mL) was added and the mixture was concentrated and the residue poured in aqueous NaOH (2 M) and pH adjusted to −3-4. The mixture was extracted with EtOAc and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the sub-title compound. Yield: 0.570 g (22%).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N+:25]([O-])=O)=[C:10]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:11]=1)=[O:5])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:25][C:9]1[CH:8]=[CH:7][C:6]([C:4]([N:3]([CH2:1][CH3:2])[CH2:28][CH3:29])=[O:5])=[CH:11][C:10]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH3:23])=[CH:19][CH:20]=1
Reactant: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-[(Diethylamino)carbonyl]-2-nitrophenyl]4-ethoxy-benzeneacetamide (1.00 g, 2.50 mmol) was dissolved in EtOAc (50 mL) containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (35 psi) at rt overnight. The solution was filtered through celite and the solvent was concentrated. LC/MS analysis showed that the title compound was pure enough (>95%) and could directly be used for next step. Yield: 927 mg (99%); 1HNMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.25 (d, J=7.6 Hz, 2H), 7.07 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.91 (d, J=7.2 Hz, 2H), 6.66 (d, J=8.4 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 3.69 (s, 2H), 3.39 (br s, 4H), 1.42 (t, J=6.8 Hz, 3H), 1.15 (br s, 6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][C:13]([OH:15])=O.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]2[C:9]=1[O:10][CH2:11][CH2:12][C:13]2=[O:15]
Reactant: O=C(O)CCOc1cc(F)c(F)cc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCOc2c(Br)cc(F)c(F)c21
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
Oxalyl chloride (1.7 mL, 20 mmol) was added to the solution of 2.8 g (10 mmol) of 3-(2-bromo-4,5-difluorophenoxy)-propanoic acid in 40 mL of anhydrous DCM followed by a drop of DMF. After 1.5 hours, a drying tube was attached and the solution was cooled in an ice-water bath. AlCl3 (1.5 g, 11 mmol) was added and the dark red solution was allowed to slowly reach room temperature while being stirred for 16 hours. The mixture was poured into ice and the organic layer was separated. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with 0.5 N NaOH and brine, then dried over Na2SO4 and concentrated. Column chromatography of this residue with hexane and EtOAc provided 1.9 g of the title compound as an off-white solid (73%). 1H NMR (300 MHz, CDCl3): δ 7.6 (t, 1H), 4.65 (t, 2H), 2.85 (t, 2H).
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:1][C:26]2=[S:27])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=S)n1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
2.3 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate was added dropwise to a solution of 0.5 g of sodium hydride (purity: 55%) in 20 ml of dimethylformamide with stirring at 0° C. The mixed solution was stirred at room temperature for 15 minutes, then cooled to 0° C. and added with 1.7 g of 4-chlorophenyl isothiocyanate. The resulting solution was heated to room temperature and further stirred at 100° C. for one hour. Then the solvent was distilled away under reduced pressure and the residue was dissolved by adding 100 ml of water. This aqueous solution was washed twice with diethyl ether and added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid. The aqueous mixture was extracted with 100 ml of ethyl acetate, washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away to obtain 2.1 g of a crude product. This crude product was washed with heated diisopropyl ether and dried to obtain 1.0 g of the objective compound.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1N.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1F
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Product: Fc1ccc(-c2ccccc2)c(F)c1

Procedure:
To a 50 liter resin pot equipped with stirrer, thermometer, nitrogen-inlet, internal steam coil and reflux condenser is charged 31.5 liters of benzene, 1.025 liters of isoamyl nitrite and 700 g. (5.43 moles) of 2,4-difluoroaniline.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)(=[O:24])=[O:23])[CH2:17]2)[CH:15]=1)[C:4]([OH:45])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C2)c1
Temperature: 78 °C

Procedure:
To a solution of 40a, 4-Methyl-2-{4′-trifluoromethyl-5-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester (47.0 mg, 0.072 mmol) in EtOH (4.0 ml) was added 2M KOH (.36 ml, 0.72 mmol). The reaction was heated to 78° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, gave the product as a white lyophilate. (31.8 mg, 71% ) 1H NMR (300 MHz, MeOD) δ ppm 0.84 (d, J=6.41 Hz, 6 H) 1.36-1.47 (m, J=13.42, 6.97, 6.76, 6.76 Hz, 1 H) 1.50-1.64 (m, J=16.81, 7.11, 3.77, 3.58 Hz, 2 H) 1.76-1.91 (m, 3 H) 2.43 (t, J=10.93 Hz, 2 H) 2.78-2.89 (m, 1 H) 3.63 (t, J=7.72 Hz, 1 H) 3.69-3.78 (m, 2 H) 7.16 (s, 1 H) 7.38 (d, J=19.59 Hz, 2 H) 7.61-7.77 (m, 5 H) 7.88-7.99 (m, 3 H) Calcd for C31H31F6NO4S (M+H) 627.64, Found 628.0.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C(#N)C.O.C([O-])(=O)C.[K+].FC1C=CC(B(O)O)=CN=1>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:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[CH:2][N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: OB(O)c1ccc(F)nc1
Solvent: CC#N
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccncc1OCC2
Temperature: 25 °C

Procedure:
10-Chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (85.0 mg, 0.257 mmol) dissolved in Acetonitrile (2 mL, 50 mmol) and Water (2 mL, 100 mmol) with dissolved Potassium acetate (85.5 mg, 0.871 mmol). Degas by bubbling nitrogen for 5 min. 2-Fluoropyridine-5-boronic acid (47.1 mg, 0.334 mmol) was added, then Tetrakis(triphenylphosphine)palladium(0) (4.0E1 mg, 0.035 mmol). The reaction was microwaved at 145 C 35 min, cooled to RT, and extracted with ethyl acetate. Combined organics were concentrated to give fluoro intermediate, 1046-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine, which was dissolved in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol). 10% aqueous HCl (3 mL) was added. The reaction was allowed to stir and heat at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to give 306, analyzed by rHPLC. MS: (ESI+)=390.1
Reaction SMILES: C1(C)C=CC(S([NH:10][C:11]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])(=O)=O)=CC=1.ClC1C=C2C(C(CC(O)=O)=[C:35]([C:39]([C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=3)=[O:40])N2)=CC=1>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:12]2[C:11](=[CH:22][CH:21]=[C:20]([O:23][C:24]([F:25])([F:26])[F:27])[CH:19]=2)[NH:10][C:35]=1[C:39]([C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1)=[O:40]
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Reactant: COC(=O)/C=C/c1cc(OC(F)(F)F)ccc1NS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2ccc(OC(F)(F)F)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(n-butylaminocarbonylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.