Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[N:73]#[C:74][NH2:75]>CN(C=O)C>[C:74]([NH:75][C:37](=[O:38])[CH2:36][C:35]([CH3:41])([CH3:40])[CH2:34][CH2:33][C:20]1[C:21]([CH3:32])([CH3:31])[C@H:22]2[C@:17]([CH3:42])([CH2:18][CH:19]=1)[C@@H:16]1[C@:25]([CH3:30])([C@@:26]3([CH3:29])[C@H:13]([CH2:14][CH2:15]1)[C@H:12]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:11]1([NH:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][S:2](=[O:49])(=[O:1])[CH2:7][CH2:6]1)[CH2:28][CH2:27]3)[CH2:24][CH2:23]2)#[N:73]
Reactant: N#CN
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NC#N)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (30 mg, 0.043 mmol) in DMF (1 mL) was treated with EDC (11.7 mg, 0.061 mmol) and HOBT (8.2 mg, 0.053 mmol). The reaction mixture was stirred at rt for 1 h. N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) was added to the reaction mixture and after stirring 10 min, cyanamide (1.0 mg, 0.024 mmol) was then added. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 12) to afford N-cyano-5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanamide (4.9 mg, 28% yield). LC/MS m/e 723.5 (M+H)+, 2.29 min (method 3). 1H NMR (500 MHz, DMSO-d6) δ 5.19 (d, J=5.9 Hz, 1H), 4.71 (s, 1H), 4.58 (s, 1H), 3.49 (t, J=4.8 Hz, 1H), 3.42 (t, J=5.5 Hz, 1H), 3.14-3.03 (m, 4H), 3.01-2.92 (m, 4H), 2.72-2.58 (m, 3H), 1.96-0.76 (m, 28H), 1.66 (s, 3H), 1.04 (s, 3H), 0.95 (s, 6H), 0.92 (s, 6H), 0.87 (s, 3H), 0.79 (s, 3H)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])P(=O)(OCC)OCC)[CH3:5].[Cl:23][C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1>C1COCC1>[CH2:20]([O:19][P:15]([C:6]([N:4]([CH3:3])[CH3:5])=[CH:29][C:27]1[S:28][C:24]([Cl:23])=[CH:25][CH:26]=1)(=[O:22])[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCOP(=O)(OCC)C(N(C)C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(=Cc1ccc(Cl)s1)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.25 g, 6.25 mmol, 60% mineral oil dispersion) in 10 mL of THF is added slowly a solution of tetraethyl dimethylaminomethylenediphosphonate (2.03 g, 6.14 mmol, prepared according to the procedure described in Psaume, Montury, and Cosmetic Comm. 1982, 12, 415) in 10 mL of THF. After stirring 1 h, a solution of 5-chloro-2-thiophene carboxaldehyde (0.90 g, 6.14 mmol) in 10 mL of THF is added. The resulting mixture is heated at reflux for 1 h, then cooled to room temperature. The reaction mixture is partitioned between Et2O and water. The organic layer is washed sequentially with 1N HCl, water and saturated NaCl, then dried over MgSO4, filtered and concentrated. The crude product is purified via flash column chromatography eluting with a gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound (1.52 g, 4.69 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7.20 (d, 1H), 6.95 (d, 1H), 6.82 (d, 1H), 4.15 (m, 4H), 2.62 (s, 6H), 1.60 (t, 6H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)CC)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(=O)CC)c2)s1
Agent: CCC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CCC(=O)Nc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-propionylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-propionamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [I:1]I.[OH-].[K+].[CH:5]1([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1.OS([O-])=O.[Na+]>CN(C=O)C>[CH:5]1([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[C:17]4[I:1])[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: c1cc2[nH]ncc2cc1-c1cncc(C2CC2)n1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Yield: 100 %

Procedure:
I2 (269 mg, 1.06 mmol) followed by powdered KOH (111 mg, 1.98 mmol) was added to a solution of 5-(6-cyclopropylpyrazin-2-yl)-1H-indazole (125 mg, 0.53 mmol) in 1 mL of DMF at RT overnight. The mixture was added to 5 mL of 10% NaHSO3 (aq.). The mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indazole (192 mg, 0.53 mmol, 100% yield) as an orange solid. MS (ESI, pos. ion) m/z: 362.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br>CC(N(C)C)=O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][O:27][CH2:34][CH2:33][O:32][CH3:31])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COCCBr
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one (0.25 g, 0.00055 mol) in dimethyl acetamide at 0° C., was added NaH (0.016 g, 0.00067 mol) and stirred for 15 min. 2-Methoxyethyl bromide (0.09 g, 0.00-65 mol) was then added, and the mixture was stirred at room temperature for 6 h. Dimethylacetamide was distilled in vacuo and the product was purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z=510) were combined and freeze dried to afford the title compound (0.32 g, 80%) as a white powder:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S(C(F)(F)[F:39])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([F:39])=[C:17]([C:31](=[O:33])[NH2:32])[N:18]3[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(C(N)=O)n3Cc2ccc(F)cc2)CC1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2c(F)c(C(N)=O)n3Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
4-[2-Carbamoyl-1-(4-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.0155 gm, 0.034 mmol) was dissolved in dichloromethane and 1-fluoro-2,4,6-trimethylpyridinium triflate (85%, 0.012 gm, 0.035 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was transferred onto two preparative thin layer chromatography plates and eluted with 1/1 ethyl acetate/hexane, then further purified on two analytical thin layer chromatography plates (1/1 ethyl acetate/hexane), and then additionally purified on two more analytical plates (35/65 ethyl acetate/hexane) to give 4-[2-carbamoyl-3-fluoro-1-(4-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.009 gm, 56% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:17][NH2:18])=[O:14]
Reactant: COC(=O)c1cccc2c(Br)cccc12
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc2c(Br)cccc12
Yield: 65.6 %

Procedure:
Methyl 5-bromo-1-naphthoate (D1) (5.32 g, 20 mmol) and hydrazine hydrate (5.7 ml, 100 mmol) were stirred at reflux in methanol (50 ml) for 48 h. After cooling, the solid was filtered off, washed with cold methanol, and dried in vacuo at 60° C., yielding the title compound (3.48 g, 65%) as a grey-brown crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH:9][CH2:10][C:11]#[CH:12])[N:5]=[C:4]([N:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:15]=[N:14]2)[N:3]=1.NC1C(Br)=C(Cl)N=C(N2C=C(C(OCC)=O)C=N2)N=1.C(N)C#C.[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH:9][CH2:10][C:11]#[CH:12])[N:5]=[C:4]([N:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14]2)[N:3]=1
Reactant: C#CCNc1nc(-n2cc(C(=O)OCC)cn2)nc(N)c1Br
Agent: C#CCN
Agent: CCOC(=O)c1cnn(-c2nc(N)c(Br)c(Cl)n2)c1
Agent: [Na+]
Product: C#CCNc1nc(-n2cc(C(=O)O)cn2)nc(N)c1Br

Procedure:
The ethyl 1-[4-amino-5-bromo-6-(prop-2-ynylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate was obtained using the procedure described for example 1, but starting from ethyl 1-(4-amino-5-bromo-6-chloropyrimidin-2-yl)-1H-pyrazole-4-carboxylate (intermediate 18) and propargylamine. The ester was hydrolyzed with 1 M sodium hydroxide (10 eq.). The resulting sodium salt solution was extracted three times with 10 ml of DCM to remove organic impurities. The aqueous phase was acidified with 4 M HCl, the precipitate was filtered, washed several times with cold water and dried.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)cc(F)c1
Product: CN1c2cc(OCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluorophenyl)methanol.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:7]=1)(=[O:4])=[O:3].C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[CH3:1][S:2]([O:5][C:6]1[N:7]=[C:8]2[N:13]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:25]([OH:26])=[N:12][C:9]2=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(N)c(NC2CCCCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc2nc(O)n(C3CCCCC3)c2n1
Temperature: 70 °C
Yield: 61.1 %

Procedure:
5-Amino-6-(cyclohexylamino)pyridin-2-yl methanesulfonate (1.44 g, 5.05 mmol) was dissolved in THF (30 mL) and CDI (2.455 g, 15.14 mmol) was added. The mixture was heated at 70° C. for 3 h. THF was removed and the residue was dissolved in EtOAc. The resulting solution was washed with water followed by 1 M HCl, dried over MgSO4 and concentrated under reduced pressure to give the title compound (0.96 g) without further purification. LCMS m/z=312.50 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][C@@H:30]([CH3:34])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[C@@H:30]([CH3:34])[CH2:29]1)[CH3:27]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CCN1CCN[C@@H](C)C1
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)[C@@H](C)C1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-3-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.20 Hz, 3H) 1.38 (d, J=7.07 Hz, 3H) 2.33 (d, J=2.27 Hz, 3H) 2.68-5.32 (m, 9H) 7.63 (d, J=7.33 Hz, 1H) 7.70-7.80 (m, 1H) 7.94-8.73 (m, 4H) 8.97-10.49 (m, 1H). ESI-MS m/z [M+H]+449.3.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=2)=[C:23]([CH3:36])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[NH2:38][OH:39].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[OH:39][NH:38][C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[C:8]([CH3:20])[CH:7]=3)[CH2:1][CH3:2])=[CH:22][C:23]=2[CH3:36])=[CH:32][CH:31]=1)=[O:35]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reactant: NO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)NO)cc2)c(C)c1
Reaction time: 0.5 h
Yield: 4.5 %

Procedure:
4′-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-carboxylic acid (Example 170-(3); 25.7 mg, 0.053 mmol), hydroxylamine hydrochloride (7.4 mg, 0.106 mmol) and dichloromethane (0.5 mL) were placed in a reaction vessel. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.2 mg, 0.069 mmol) was added at 0° C., and then the mixture was stirred for 30 minutes. Subsequently, diisopropylethylamine (0.0184 mL, 0.106 mmol) and 4-dimethylaminopyridine (1.94 mg, 0.016 mmol) were added and the mixture was stirred at room temperature overnight. 1 N hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=10:1) to give the title compound (1.2 mg, 5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[C:45]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:45])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.17 mmol) in dichloromethane (20 mL), add methanol (5.85 mmol) and triphenylphosphine (3.51 mmol). To this solution, add diethyl azodicarboxylate (3.51 mmol) dropwise at room temperature. After stirring for 12 h, remove the solvent under vacuum and chromatograph the intermediate over silica gel eluting with ethyl acetate/hexane (2-35%) to afford (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester as a colorless oil. To this intermediate in dichloromethane (5 mL), add TFA (2 mL). After stirring for 2 h, quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (10 mL). Separate the organic portion, dry over sodium sulfate, filter, and remove the solvent under vacuum. This provides the title compound as a crude oil that is further used without purification.
Reaction SMILES: B.CSC.[CH2:5]([O:9][S:10]([CH:13]1[CH2:16][C:15](=[C:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH2:14]1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH3:8].C(OCC)(=O)C>C1COCC1>[OH:19][CH2:18][CH:17]([CH:15]1[CH2:14][CH:13]([S:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])=[O:11])[CH2:16]1)[CH2:23][OH:24]
Reactant: CCCCOS(=O)(=O)C1CC(=C(C(=O)OCC)C(=O)OCC)C1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCOC(C)=O
Product: CCCCOS(=O)(=O)C1CC(C(CO)CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Borane-DMS (0.2 mL, 2.3 mmol) was added to a solution of diethyl 2-(3-(butoxysulfonyl)cyclobutylidene)malonate (0.2 g, 0.575 mmol) in THF (5 mL) and the resulting reaction mass was stirred at room temperature overnight. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with 1N HCl and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography on silica gel (70% ethyl acetate in hexane) afforded 0.13 g of the product (74% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]([OH:36])[CH2:15][N:16]([CH2:24][C@H:25]3[CH2:34][CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([I:35])[CH:31]=4)[O:26]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39].N1C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:41]([O:36][C@H:14]([C:11]1[CH:12]=[N:13][C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])=[CH:9][CH:10]=1)[CH2:15][N:16]([CH2:24][C@H:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([I:35])[CH:31]=2)[O:26]1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: Cc1ccc(C)n1-c1ccc([C@@H](O)CN(C[C@H]2CCc3cc(I)ccc3O2)C(=O)OC(C)(C)C)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1ccc([C@H](CN(C[C@H]2CCc3cc(I)ccc3O2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A mixture of tert-butyl (2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 357, 7.5 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol), and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 24 hours. The reaction mixture was then poured into a saturated NaHCO3 solution (50 mL). The mixture was extracted with ether (100 mL×2). The ether layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a near white syrup which was purified by column chromatography (silica gel, hexanes/ethyl acetate (5/1, v/v)) and gave the desired compound as a colorless oil (6.5 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:13]=[C:12]([Br:11])[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cccc(Br)c2)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 6.9 grams (0.044 mole) of 4-chlorophenylboronic acid (commercially available), 25.0 grams (0.100 mole) of 1,3-dibromobenzene, 0.2 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), 75 mL of aqueous 2M sodium carbonate, and 75 mL of toluene, yielding 3-(4-chlorophenyl)phenyl bromide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:10]([I:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)c(I)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Cl)c(I)c1Cl

Procedure:
10.0 g of 2,4-dichloro-5-fluoro-3-iodo-benzoic acid and 9.5 ml of thionyl chloride are boiled until gas is no longer produced. The remaining thionyl chloride is then stripped off in vacuo. 10.2 g of crude acyl chloride, which can be employed without further purification, remain.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([CH:37]=O)[NH:28][C:27]=1[CH3:39])=[O:25]>>[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([CH:37]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:28][C:27]=1[CH3:39])=[O:25]
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN(C)C)c1-c1ccccc1
Yield: 44.2 %

Procedure:
6—(2-Methoxyphenyl)-1,3-dihydroindol-2-one (53 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 0.05 g (44%) of the title compound as an orange gum.