Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:28]([CH2:30][NH2:31])[OH:29]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:31][CH2:30][CH2:28][OH:29])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: NCCO
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCO)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (1900 mg; 4.57 mmol; 1 eq), is dissolved in anhydrous DCM (180 ml). The reaction is put under nitrogen. Triethylamine (3.2 ml; 22.9 mmol; 5 eq) and ethanolamine (1.1 ml; 18.3 mmol; 4 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat, brine and dried over MgSO4, affording the title compound (1760 mg; 88%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:27][NH2:28]>O1CCOCC1>[NH:27]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:28]
Reactant: NN
Reactant: COc1cc(C(=O)N2CCc3nnc(Cl)cc3C2)cc(OC)c1OC
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCc3nnc(NN)cc3C2)cc(OC)c1OC

Procedure:
12.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl)pyrido[4,3-c]pyridazine and 40 cc of hydrazine hydrate in 40 cc of dioxane are stirred at a bath temperature of 100° for 41/2 hours. The title compound has a M.P. of 194°-197° (decomp., from absolute ethanol/methanol 2:1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:22][CH3:23])[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[N:9][C:10]=1[Cl:11])=[O:5])C.C1COCC1.[OH-].[Li+]>O>[Cl:11][C:10]1[N:9]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:22][CH3:23])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)nc(-c2cccc3ccccc23)n1CC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(-c2cccc3ccccc23)nc(Cl)c1C(=O)O
Temperature: 50 °C

Procedure:
5-Chloro-3-ethyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester (62 g, 35 mmol) is dissolved in. THF (10 ml), and aqueous lithium hydroxide solution (2.0 N, 6.35 ml, 2.0 eq.) is added. The mixture is heated at 50° C. overnight. THF is stripped off under reduced pressure, and the residue is diluted with water (10 ml) and basified to pH=4=5. The solid precipitate is collected, washed with water and ether, and dried under high vacuum to give the title compound. LCMS 301 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:12](=[O:13])[O:8][C:6](=[O:7])[C:5]2=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a mixture of 10.0 g (58.0 mmol) of 4-chloroanthranilic acid in 100 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 8.78 g (76.2%) of the 4-chloroisatoic anhydride as a light brown solid. MS (Cl mode) m/z 198 (M+H, 100%), Cl pattern 200, 35%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[C:11]([F:39])[CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>ClCCCl>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=4[F:39])[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)cc(F)c32)C1c1cccc(Cl)c1F
Yield: 30.6 %

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 71 (0.95 g, 1.6 mmol), was reacted with diisopropylethylamine (0.82 g, 6.4 mmol), diphenylphosphinic chloride (0.75 g, 3.2 mmol) in 1,2-dichloroethane at room temperature, then reacted with 4-amino-3-methoxy benzonitrile prepared in Example 57 (0.71 g, 4.8 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield 0.3 g, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7](B(O)O)[CH:8]=1)#[N:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:22]1[C:23]([N:42]2[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]2)=[N:24][CH:25]=[C:26]([CH:41]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([Cl:40])([F:39])[F:38])=[CH:32][CH:31]=1)=[O:28]>O1CCOCC1>[Cl:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:41]=[C:22]([C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[F:12])[C:23]([N:42]3[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]3)=[N:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(F)c(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c1
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
5-Cyano-2-fluorophenylboronic acid (53.5 mg, 0.324 mmol), K3PO4 (138 mg, 0.648 mmol) and PdCl2(dppf)-(CH2Cl2) (17.65 mg, 0.022 mmol) were added to (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1,) in dioxane (1.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2.5 h. The RM was diluted with EtOAc (60 mL), washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 18% to 23% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=6.31 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=503.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-2.01 (m, 2H) 2.93 (br. s, 1H) 3.19 (dd, J=11.14, 4.11 Hz, 1H) 3.23-3.43 (m, 2H) 4.21 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.99 Hz, 3H) 7.57 (br. s, 1H) 7.80-7.91 (m, 3H) 7.94-8.24 (m, 4H) 8.79 (d, J=1.96 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=2)=[O:20])=[CH:7][CH:6]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])/[CH:18]=[CH:17]/[C:12]2[CH:13]=[N:14][N:15]([CH3:16])[C:11]=2[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)=[CH:23][CH:24]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
A mixture of dimethylamine (2M tetrahydrofuran solution, 1.7 mL), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-N-{4-[2-(dimethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.36 g, yield 49%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-diisopropyl ether gave colorless prism crystals. melting point: 209-210° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([Mg]Cl)[CH:14]=[CH2:15].O>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]([OH:12])[CH2:11][CH2:15][CH:14]=[CH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
To a stirred solution of benzyl-(S)-glycidyl ether (5.0 g, 30.5 mmol) in THF (100 ml) was added allylmagnesium chloride (1.0 M in Et2O, 30.5 ml, 30.5 mmol) at −78° C., and the resulting mixture was gradually warmed up to rt with stirring. The mixture was poured into water and concentrated in vacuo, then extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyloxy-2-(R)-hydroxy-5-hexene (2.18 g, 35%) as a colorless oil: 1H-NMR (CDCl3) δ1.52-1.60 (m, 2 H), 2.11-2.25 (m, 2 H), 2.34 (d, J=3.2 Hz, 1 H), 3.35 (dd, J=9.6, 8.0 Hz, 1 H), 3.52 (dd, J=9.6, 3.2 Hz, 1 H), 3.84-3.86 (m, 1 H), 4.57 (s, 2 H), 4.96-5.07 (series of m, 2 H), 5.78-5.88 (m, 1 H), 7.29-7.38 (m, 5 H); MS (ESI) m/z, 224 (M++NH4+).
Reaction SMILES: C([O:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:9]1)(=O)CCC.C[O-].[Na+].CO.C(Cl)(Cl)Cl.Cl>CO>[F:20][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@H:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1

Procedure:
A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl butyrate (PREPARTION 12, 2.789 g, 9.91 mmol) in methanol (10 ml) is treated with a 25 wt. % mixture of sodium methoxide in methanol (57 μl, 0.99 mmol) at 20-25°. After 45 min as measured by TLC (methanol/chloroform, 5/95) the starting material has been consumed. The reaction mixture is carefully quenched by the addition of hydrochloric acid (1N, 0.99 ml, 0.99 mmol) and then concentrated under reduced pressure. Chromatography of the concentrate over silica gel, eluting first with hexane/ethyl acetate (1/1), and then ethyl acetate, pooling and concentratig the appropriate fractions gives the title compound, mp 106.5-107.5°; [α]25D -66.8° (c 1.1, CH3CN); IR (mineral oil mull): 3520, 1724, 1612, 1590, 1496, 1428, 1420, 1232 and 1199 cm-1 ; NMR (CDCl3, 300 MHz) δ 7,44, 7.32, 7.23, 6.84, 4.77, 4.07-3.96, 3.76 and 2.44; MS (m/z) 211, 180, 136, 124, 95; HRMS (m/z) 211.0641 (calc'd for C10H10FNO3 : 211.0645).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]1([C@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C@@H:33]([OH:39])[CH2:32]2>O.C1(C)C=CC=CC=1.CN(C=O)C>[CH:16]1[CH:17]=[CH:18][C:13]([C@@H:19]2[N:20]([C:1]([O:39][C@@H:33]3[CH:34]4[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]4)[CH2:32]3)=[O:2])[CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2=3)=[CH:14][CH:15]=1
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4.26 g portion of 1,1′-carbonyldiimidazole was added to 5.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 25 ml of toluene and stirred at room temperature for 30 minutes. By adding 25 ml of water thereto, the water layer was separated, the organic layer was washed with 25 ml of water, and the solvent was evaporated under a reduced pressure. A 10 ml portion of toluene was added to the residue. This solution was added dropwise at room temperature to a solution prepared by adding 1.00 g of sodium hydride to a mixture of 3.65 g of (R)-quinuclidin-3-ol, 25 ml of toluene and 5 ml of DMF and heating to 100° C., and 5 ml of toluene was further added thereto. This was heated at 110° C. for 3 hours, cooled and mixed with 25 ml of water, and the water layer was separated. This was again washed with 25 ml of water, and the organic layer was extracted with a mixture of 3.25 g of concentrated hydrochloric acid and 18 ml of water. 34 ml of EtOAc, and a mixture of 5.28 g of potassium carbonate and 14 ml of water were added to the thus obtained water layer, the thus obtained organic layer was washed with 7 ml of water, and then the solvent was evaporated under a reduced pressure to obtain solifenacin.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 80 °C
Yield: 92.1 %

Procedure:
In an apparatus similar to Example 1, 15.2 g (0.083 mol) of syringaldehyde and 15.0 g (0.11 mol) of potassium carbonate were heated to 105° C. under nitrogen and 15 ml (0.12 mol) of trimethyl phosphate were added over 10 minutes. The mixture was maintained at about 80° C. for 3 hours then cooled to 45° C. and quenched with 50 ml of H2O. The tan solid which precipitated was collected, washed with 3×50 ml of water and dried to give 15 g (92%) of 3, 4, 5-trimethoxybenzaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[C:26]([F:32])=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=2[F:32])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(Cl)c1F
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-2-fluorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.03–8.00 (2H, m), 7.96–7.93 (1H, m), 7.45–7.35 (3H, m), 7.27–7.15 (2H, m), 5.43–5.35 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 463 (M+H)+, 461 (M−H)−.
Reaction SMILES: C1(O)C=CC=CC=1.[N+](=[C:10]([C:18]([O:20]C(C)(C)C)=[O:19])[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[N-]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:18]([O-:20])(=[O:19])[CH2:10][C:11]([O-:13])=[O:12].[CH3:10][CH2:11][O:13][CH2:14][CH3:15]
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: CCOCC
Product: O=C([O-])CC(=O)[O-]

Procedure:
Alkylation of phenol E-4 (from Chart E) is accomplished by a carbenoid insertion reaction with di-t-butyl diazomalonate (Synthesis 1974, 347) catalyzed by rhodium acetate (J. Med. Chem. 1995, 38:4270), affording malonate ether I-1. Removal of the t-butyl esters is accomplished with trifluroacetic acid in methylene chloride, and the benzyl ester is removed by hydrogenolysis, affording the desired triacid I-3.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:12]([CH3:14])[CH3:13])=[N:7]2.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[CH:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:22][C:20]3[CH:21]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=3[S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Product: Cc1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C(C)C)ccc23)c1

Procedure:
The product from Example 8b (0.098 g, 0.475 mmol) was reacted with the product from Example 1f (0.102 g, 0.475 mmol) for 18 h following the procedure from Example 1g to give the title compound, which was purified by HPLC with TFA. Converted to the hydrochloride salt by treatment with 4N HCl in dioxane at room temperature gave the hydrochloride salt (0.076 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.99 Hz, 6H) 2.38 (s, 3H) 3.30 (m, 1H) 6.32 (d, J=6.99 Hz, 1H) 7.24 (s, 5H) 7.34 (m, 3H) 7.86 (d, J=8.82 Hz, 1H) 8.39 (d, J=7.35 Hz, 1H) 9.08 (d, J=8.46 Hz, 1H) 11.16 (s, 1H) 14.36 (m, 1H); MS (ESI+) m/z 386.0 (M+H)+.
Reaction SMILES: ClCC([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[F:14])[NH:10][C:9](=[O:15])[CH2:8]2)=O.N1C=CC=C[CH:17]=1.[C:22](=[O:25])([O-])[O-:23].[K+].[K+].Cl.O1CCOCC1>>[F:14][C:13]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[O:15])[NH:10]2)=[CH:6][C:5]=1[C:22]([O:23][CH3:17])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: c1ccncc1
Reactant: O=C1Cc2cc(C(=O)CCl)c(F)cc2N1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(cc1F)NC(=O)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of the compound obtained in Step A (3.24 mmoles) in pyridine (99 mmol) is stirred at 90° C. for 2 hours. The reaction mixture is cooled to ambient temperature and then filtered. The solid obtained is washed with ethanol and dried in vacuo at 50° C. The compound is dissolved in MeOH (80 mL), and 0.434 mmol of potassium carbonate is added. The mixture is stirred at 80° C. for 5 hours. After cooling to ambient temperature, 4M HCl/dioxane solution is added (pH 3) and the mixture is evaporated to dryness. The residue obtained is triturated in water, filtered, washed with water and then dried in vacuo at 50° C. to yield the title product.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1CCCCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C2CC2)nn1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a stirred solution of 3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.03 mmol) and triethylamine (0.66 g, 6.53 mmol) at rt, was added phenyl chloroformate (0.94 g, 6.01 mmol). The reaction mixture was stirred at rt for 15 h. The reaction mixture was partitioned between a mixture of dichloromethane (20 mL) and water (20 mL) and the organic layer was washed thrice with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give yellow oil. Trituration with cyclohexane afforded phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.01 g, 63%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 6.71-7.55 (m, 10H), 6.18 (s, 1H), 1.92 (m, 1H), 0.91 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1.O>CN(C)C=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)c1ccc(F)cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 72 h
Yield: 36 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70.0 mg, 0.16 mmol) synthesized in Example (38d) and 5-fluoro-2-(methylsulfonyl)pyridine (35.0 mg, 0.20 mmol) synthesized in Example (65b) were dissolved in N,N-dimethylformamide (5 mL), and stirring was carried out at 90° C. for 3 days under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, followed by extraction with ethyl acetate (30 mL), and washing was carried out with saturated brine (30 ml), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-40%) to afford the desired compound (28 mg, yield 35%) as a pale yellow solid.
Reaction SMILES: C(#N)C[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([OH:19])(=[O:18])[CH2:17][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCOCCCC#N
Reactant: CC(=O)O
Agent: Cl
Product: CCCCCCCCOCCCC(=O)O
Yield: 32 %

Procedure:
A solution of 5-oxatridecanonitrile (1.90 g, 9.6 mmol) in a mixture of acetic acid (10 mL) and concentrated HCl (50 mL) was refluxed for 20 h. After evaporation of the solvent in vacuo, water (50 mL) and ethyl acetate (100 mL) were added to the residue. The organic phase was washed with water (2×50 mL), brine (1×50 mL), and then dried over Na2SO4. After distillation (Kugelrohr device, 120°-125° C./0.1 torr) and column chromatography (silica gel) using ethyl acetate:hexane (1:1) as eluent. 5-Oxatridecanoic acid (0.66 g, 32%) was isolated as a colorless oil. IR: 3550-2300, 1700 cm-1, 1H-NMR: 0.78-0.98 (t, 3H), 1.00-1.40 (m, 10H), 1.42-1.62 (p, 2H), 1.82-1.94 (p, 2H), 2.40-2.56 (t, 2H), 3.38-3.52 (m, 4H). Anal. Calcd. for C12H24O3 : C, 66.63, H, 11.18%; Found: C, 66.53, H, 11.14%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:3]=1[NH2:4].C(C1C([NH2:20])=CC=CC=1)C.ClN1C(=O)CCC1=O>C(#N)C>[Cl:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Cl:1])[CH:8]=1)[NH:4][N:20]=[C:10]2[CH3:11]
Reactant: CCc1ccccc1N
Reactant: CCc1cc(Cl)cc(Cl)c1N
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1n[nH]c2c(Cl)cc(Cl)cc12

Procedure:
5,7-Dichloro-3-methyl-1H-indazole was prepared using a procedure similar to that described in Example 109, part a and b, except starting from 2,4-dichloro-6-ethylaniline (2.9 g) that was prepared by chlorination of 6-ethylaniline (10 g) with N-chlorosuccinimide (22 g) in acetonitrile (80 mL).