Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O-:17])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:18]([Mg]Br)=[CH2:19].[Cl-].[NH4+].[CH2:24]1COCC1>>[NH:1]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]3[CH2:9][CH2:10][N:11]([C:15]([O:17][CH3:24])=[O:16])[CH2:12][CH2:13][C:14]3=2)[CH:19]=[CH:18]1
Reactant: O=C([O-])N1CCc2cccc([N+](=O)[O-])c2CC1
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)N1CCc2ccc3cc[nH]c3c2CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Under N2, a flame-dried, 100-mL, two-necked flask was charged with 6-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.85 g, 3.4 mmol) and THF (20 mL) and cooled to −40° C. Vinyl magnesium bromide (11.2 mL, 11.2 mmol) was added and the solution was stirred for 30 min allowing to warm to −20° C. Ammonium chloride was added and the mixture partitioned between EtOAc and water. The organic layer was concentrated to give 0.88 g of a brown oil. Column chromatography (elution with 10–30% EtOAc/heptane) afforded 0.28 g (34%) of the title compound as a solid. Crystallization from EtOAc/hexane affords 0.192 g of a white solid: mp 169–171° C.; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8 Hz, 1 H), 7.19–7.17 (m, 1 H), 6.90 (d, J=8 Hz, 1 H), 6.53–6.52 (m, 1 H), 3.76 (s, 3 H), 3.72–3.63 (m, 4 H), 3.19–3.10 (m, 1 H), 3.00–3.10 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ 156.6, 135.5, 134.1, 133.6, 126.6, 124.3, 122.7, 118.3, 102.9, 52.7, 47.4, 46.0, 37.3, 30.4; IR (diffuse reflectance) 3313, 1673, 1476, 1446, 1414, 1275, 1260, 1237, 1217, 1115, 947, 805, 764, 745, 731 cm31 1; MS (EI) m/z 244 (M+); Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.78; H, 6.58; N, 11.43.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:13][CH3:14])=[CH:11][N:12]=1)[C:8]#N)([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Na+].[OH:17]S(O)(=O)=O>OP([O-])(O)=O.[K+]>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:13][CH3:14])=[CH:11][N:12]=1)[C:8]([OH:17])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: COc1cnc(C(C)(C)C)cc1C#N
Reactant: [OH-]
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Product: COc1cnc(C(C)(C)C)cc1C(=O)O
Temperature: 120 °C
Yield: 92 %

Procedure:
The above nitrile (1.10 g, 5.68 mmol) was dissolved in H2SO4 (9.0 M, 6.0 mL) and heated to 120° C. for 8 h. The solution was cooled to rt and NaOH (˜2.0 g) was added slowly to neutralize the solution. The mixture was then diluted with an equal volume of saturate KH2PO4 and extracted several times with 25% 2-propanol in chloroform. The extracts were combined, dried over Na2SO4, filtered, and concentrated to provide 2-tert-butyl-5-methoxy-isonicotinic acid (1.09 g, 92%) as a pale brown solid which was utilized without further purification.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[NH:15][C:14]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[S:19][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCCCCC>[CH3:5][N:15]1[C:16]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:14]1=2
Reactant: COS(=O)(=O)OC
Reactant: c1ccc2c(c1)[nH]c1c3ccccc3sc21
Solvent: ClCCl
Solvent: CCCCCC
Product: Cn1c2ccccc2c2sc3ccccc3c21
Yield: 91.9 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, 10H-[1]benzothieno[3,2-b]indole (prepared by the method of K. E. Chippendale and B. Iddon, JCS Perkin Trans. I, 2023 (1972)) gave a 91.9% yield of 10-methyl-10H-[1]benzothieno[3,2-b]indole, mp 175°-176°, (CH2Cl2 /hexane), (C,H,N,S).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[O:2]1.[I:14]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[I:14][C:10]1[C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][C:3]2[O:2][CH2:1][O:13][C:12]=2[CH:11]=1
Reactant: ClI
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1I)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a stirred solution of 3′,4′-methylenedioxyacetanilide (7.7 g, 43.0 mmol) in DCM (100 mL) and AcOH (6.5 mL) was added a solution of iodine monochloride (6.3 g, 38.8 mmol) in DCM (50 mL). The reaction mixture was stirred at r.t. for 16 h. Aqueous sat. Na2S2O3 (500 mL) was added. The organic fraction was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (7.5 g, 57%) as a brown solid. LCMS (ES+) 306.0 (M+H)+, RT 2.75 minutes (Method 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:15]=[C:16]([F:23])[CH:17]=[C:18]([NH2:20])[CH:19]=2)[CH2:10][CH:9]1[CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COCC1CC(Oc2cc(N)cc(F)c2)CN1C(=O)OC(C)(C)C

Procedure:
A mixture of 23 g of 4-(3-fluoro-5-nitro-phenoxy)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7), 100 mL MeOH and 2 g of Pd(OH)2/C was stirred for 2 hours under a 50 psi hydrogen atmosphere. The mixture was filtered off through a pad of diatomaceous earth and concentrated to give a quantitative yield of 4-(3-amino-5-fluoro-phenoxy)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (8).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH2:18][N:19]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[C:48]([N:38]1[CH2:39][CH2:40][CH:35]([CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[CH:16][CH:15]=2)[CH2:18][N:19]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:36][CH2:37]1)(=[O:50])[CH3:49]
Reactant: CCOC(=O)C(=O)N(CCc1ccccc1)CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(CCc1ccccc1)CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCN(C(C)=O)CC1
Reaction time: 1 h

Procedure:
A room temperature solution of Example 47A (50.0 mg, 0.094 mmol) in dichloromethane (2 mL) was treated with triethylamine (26.2 μL, 0.19 mmol) and acetyl chloride (10.0 μL, 0.14 mmol), stirred for 1 hour, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:10]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:10][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: NCCCO
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCNCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
3-Aminopropanol (1.5 g, 20 mmol) was dissolved in dry DMF and treated with 3,4-dichlorobenzyl chloride (2.62 ml, 19 mmol) followed by anhydrous potassium carbonate (1.38 g, 10 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between 1M HCl and dichloromethane, the layers separated and the aqueous phase washed with dichloromethane. The aqueous phase was adjusted to pH 12 with 1M NaOH, and extracted with dichloromethane. The organic extract was dried (MgSO4) and evaporated to afford the title compound as a colourless oil (0.96 g 22%); δH (CDCl3) 1.68-1.77 (2H, m), 2.87 (2H, t, J=5.7 Hz), 3.75 (2H, s), 3.80 (2H, t, J=5.3 Hz), 7.12-7.41 (3H, m); MS (ES+) 234 (5%, MH+), 159 (100).
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]([N:7]([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[Si:12]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25](=O)[CH2:24][CH2:23]2)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[Si:12]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:25][CH:24]=[C:23]2[C:3]1[CH:11]=[CH:10][C:6]([N:7]([CH3:9])[CH3:8])=[CH:5][CH:4]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(=O)CC2
Reactant: CN(C)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)c1ccc(C2=CCc3cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)cc32)cc1
Temperature: 60 °C

Procedure:
Magnesium (124 mg, 5.1 mmol) is covered with 1 ml of distilled THF and heated at 60° C. with stirring. A solution of 4-bromo-N,N-dimethylaniline (1.02 g, 5.1 mmol) in 5 ml of distilled THF is added dropwise over the course of 20 min. The reaction mixture is heated at reflux of the THF for 1 h. A solution of 5,6-di(tert-butyldimethylsilyloxy)indan-1-one (2 g, 5.1 mmol) in 10 ml of distilled THF is added dropwise at room temperature over the course of 5 min to this yellow-green solution. The mixture is brought to reflux for 20 h. The reaction mixture, which is violet in colour, is hydrolyzed by saturated aqueous ammonium chloride solution, then extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaCl solution, then dried over MgSO4. The solvent is evaporated under reduced pressure. The desired product is purified by chromatography with an eluent: 9:1 hexane/ethyl acetate, and is obtained in the form of an oil (0.9 g; 36%)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH2:28][CH2:29][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:31][CH:32]=5)=[C:23]([C:37]([F:40])([F:39])[F:38])[CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CS(C1C=C(C2N3C(C=N[C:57]([OH:60])=N3)=CC=2)C=CC=1)(=O)=O.NC1C=CC(C2CCN(CC(N)=O)CC=2)=C([C:78]([F:81])([F:80])[F:79])C=1>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH2:28][CH2:29][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:31][CH:32]=5)=[C:23]([C:37]([F:39])([F:38])[F:40])[CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4].[C:57]([OH:60])([C:78]([F:81])([F:80])[F:79])=[O:3]
Reactant: NC(=O)CN1CC=C(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5=CCN(CC(N)=O)CC5)c(C(F)(F)F)c4)nn23)c1
Solvent: CS(C)=O
Product: O=C(O)C(F)(F)F
Yield: 72 %

Procedure:
2-(4-{4-[7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-trifluoromethyl-phenyl}-3,6-dihydro-2H pyridin-1-yl) acetamide. 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (46.1 mg, 0.159 mmol) and 2-[4-(4-Amino-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide (0.0596 g, 0.199 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. Concentrated reaction mixture, took up in DMSO, and purified by Gilson RP-HPLC. The fractions containing desired product were lyophilized to afford title compound as a TFA salt (65 mg, 72%). LCMS=570.9 (M+H), HPLC rt=2.435, purity=95% , 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.14 (bs, 1H), 9.60 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 8.49 (d J=7.8 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.01 (s, 2H), 7.95 (d, J=7.9 Hz, 1H) 7.80-7.73 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=4.7 Hz, 1H), 5.60 (s, 1H), 4.02 (s, 2H), 4.01-3.95 (m, 1H), 3.90-3.80 (m, 1H), 3.65-3.55 (m, 1H), 3.44-3.34 (m, 1H), 3.20 (s, 3H), 2.82-2.70 (m, 1H), 2.45-2.38 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]1=[O:28].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20]([N:19]=[CH:18][C:17](=[O:28])[N:16]2[CH2:15][CH2:14][CH2:13][CH:12]=[O:11])=[CH:21][CH:22]=1
Reactant: COc1ccc2ncc(=O)n(CCCCO)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CCCC=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
A solution of oxalyl chloride (0.171 ml, 1.99 mmol) in dichloromethane (5 ml) was cooled to −78° C., a solution of dimethyl sulfoxide (0.283 ml, 3.99 mmol) in dichloromethane (5 ml) was added dropwise under a stream of argon and the reaction mixture was stirred at the same temperature for 15 minutes. A solution of 1-(4-hydroxybutyl)-7-methoxyquinoxalin-2(1H)-one (198 mg, 0.797 mmol) in dichloromethane (5 ml) was added dropwise and the reaction mixture was further stirred at the same temperature for 1 hour. Triethylamine (0.833 ml, 5.98 mmol) was added thereto, the temperature was raised to room temperature and a saturated ammonium chloride aqueous solution and dichloromethane were added. After stirring, the organic layer was separated, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 114 mg (58%) of the title compound in the form of a yellow solid.
Reaction SMILES: C(S([N:7]=[CH:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=O)(C)(C)C.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I)[CH3:16].NC(C1C(OC)=CC=CC=1OC)CCC(OC)=O.COC1C=CC=C(OC)C=1C1NC(=O)CC1>>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:8]1[NH:7][C:11](=[O:13])[CH2:10][CH2:9]1)[CH3:16]
Reactant: COC(=O)CCC=NS(=O)C(C)(C)C
Reactant: CCOc1ccccc1I
Agent: COC(=O)CCC(N)c1c(OC)cccc1OC
Agent: COc1cccc(OC)c1C1CCC(=O)N1
Product: CCOc1ccccc1C1CCC(=O)N1

Procedure:
Synthesized from methyl 4-((tert-butylsulfinyl)imino)butanoate and commercially available 1-ethoxy-2-iodobenzene according to the procedures described for the preparations of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate and 5-(2,6-dimethoxyphenyl)pyrrolidin-2-one. The target product 5-(2-ethoxyphenyl)pyrrolidin-2-one was obtained as a colorless solid after purification by FC (heptane/AcOEt=7/3 to 3/7). LC-MS (conditions D): tR=0.81 min.; [M+H]+: 205.99 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[C:2]([F:1])[CH:3]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
3-Fluoro4-(2-methyl-imidazol-1-yl)nitrobenzene (40 g, 0.181 M) was dissolved in a mixture of MeOH (200 ml) and tetrahydrofuran (800 ml), cooled to 0° under nitrogen, and treated with ammonium formate (57 g, 0.905 M) followed by palladium on charcoal (10%, 2 g). The mixture was stirred at ambient temperature for 18 hours, filtered through celite, celite washed with MeOH (100 ml), and filtrate evaporated to dryness. The residue was partitioned between EtOAc (800 ml) and 10% aqueous sodium bicarbonate (250 ml). The organic layer was separated, washed with brine (250 ml), dried (magnesium sulfate) and evaporated to give title compound (34.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:27])(=[O:26])[NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[CH:15][CH:14]=3)[N:9]([CH2:28][C:29]([OH:31])=O)[N:8]=2)=[CH:4][CH:3]=1.C[N:35](C)C=O.C(Cl)Cl.C(Cl)(=O)C(Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19](=[O:27])(=[O:26])[NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[CH:17][CH:18]=3)[N:9]([CH2:28][C:29]([NH2:35])=[O:31])[N:8]=2)=[CH:32][CH:33]=1
Reactant: O=C(O)Cn1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)Cn1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 1 h

Procedure:
2-(3-(4-Chlorobenzyl)-5-(4-(N-thiazol-2-ylsulfamoyl)phenylamino)-1H-pyrazol-1-yl)acetic acid (30 mg, 0.00006 mol) was dissolved in N,N-Dimethylformamide (0.4 uL, 0.000005 mol) and methylene chloride (0.2 mL, 0.003 mol). Oxalyl chloride (7.6 uL, 0.000089 mol) was added and the reaction stirred 1 hour. The reaction was quenched by pouring it into 1.0 mL satd. ammonium hydroxide solution, neutralized with 1.0 N HCl, and extracted 2× with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to give the desired product, which was lyophilized from acetonitrile-water to provide a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.C([Mg]Cl)(C)C.CON(C)[C:34]([C:36]1[N:40]([CH3:41])[N:39]=[N:38][CH:37]=1)=[O:35].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:34]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][CH:37]=3)=[O:35])[CH:10]=2)[N:5]=[C:4]([O:13][CH3:14])[C:3]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CON(C)C(=O)c1cnnn1C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-chloro-6-iodo-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (41.39 g, 86.6 mL, Intermediate 62: step c) in THF (800 mL) was cooled to 4° C., and isopropylmagnesium chloride (44.2 mL, 88.4 mmol, 2 M in THF) was added over 10 min. The mixture was stirred for 20 min and then N-methoxy-N,1-dimethyl-1H-1,2,3-triazole-5-carboxamide (14.74 g, 86.6 mmol, Intermediate 61) in THF (150 mL) was added. After warming to room temperature and stirring for 15 h, a solution of aqueous ammonium chloride (900 mL, 13 wt %) was added. The resulting biphasic mixture was stirred for 15 min. The layers were then separated, and the organic layer was washed with brine (450 mL). The organic layer was diluted with heptane (500 mL) and stirred for 1 h. The resulting suspension was filtered, washed with heptane (100 mL), and dried in a 60° C. vacuum oven to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[S:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=[O:12])=O.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:2]([C:3]1[O:12][C:11](=[O:13])[CH:10]=[C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[S:6][C:5]=12)([CH3:21])([CH3:20])[CH3:1]
Reactant: COc1ccc2sc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2sc3c(C(C)(C)C)oc(=O)cc3c2c1
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 0.460 g [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]acetic acid from the Step C above, 0.345 g HOBt hydrate, and 0.504 g EDC HCl salt. This mixture was dissolved in 15 mL anhydrous DMF and 0.582 g DIEA was added. The mixture turned bright yellow. After standing at room temperature overnight, the mixture was poured into water and extracted with ether several times. The combined ether extract was washed with water (4×), 5% NaHCO3, and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the title compound as a bright yellow solid. 1H NMR (CDCl3, 500 MHz) 7.49 (d, 8.7 Hz, 1H), 7.35 (d, 2.5 Hz, 1H), 7.20 (dd, 2.5 & 8.9 Hz, 1H), 6.65 (s, 1H), 3.92 (s, 3H), 1.51 (s, 9H). LC-MS: 3.77 min. (m/Z=289.3).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17]C(OCC(Cl)(Cl)Cl)=O)[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.C(O)(=O)C>CO.O1CCCC1.[Zn]>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH2:17])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(NC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: NC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To 20 g (36 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 154) in 50 ml of methanol and 50 ml of tetrahydrofuran was added 4.69 g (72 mmole) of zinc dust and 16 g (267 mmole) of acetic acid. After stirring for 1 hour the reaction was filtered, concentrated in vacuo, partitioned between diethyl ether and water, washed with 5% aqueous sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and chromatographed on silica gel using methylene chloride and ethyl acetate to yield 6 g of the title compound, a white solid, mp 144°-146° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])(O)=O.[Na+]>COCCOC.CCO.CCOC(C)=O.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>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2cncnc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 2.4. g, 5.38 mmol) and pyrimidin-5-ylboronic acid (1.33 g, 10.76 mmol) were dissolved in a mixture of DME (15 mL) and EtOH (2.1 mL). A solution of 2 M aq. NaHCO3 (8.07 mL, 16.14 mmol) was added, the RM was flushed with argon, then Pd(PPh3)2Cl2 (0.453 g, 0.645 mmol) was added and the RM was stirred under argon at 90° C. for 2 h. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 200 g, DCM/MeOH from 2% to 5% MeOH). Treatment with Si-Thiol (1 g) in MeOH and a further purification by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH from 0 to 20% MeOH) afforded the title compound as white crystalline solid. HPLC (Condition 4) tR=4.63 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH, 0.5 mL/min, UV 210 nm) tR=31.72 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=446.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.73 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.37 (m, J=7.40 Hz, 1H) 4.19 (br. s, br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.70-8.83 (m, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.16 (s, 1H).