Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.Cl.[CH3:16][NH:17][CH3:18].C(N(CC)CC)C>ClCCl>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([N:17]([CH3:18])[CH3:16])=[O:10]
Reactant: CNC
Reactant: O=C(O)c1ccccc1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of 156 g (1.13 mol) of salicylic acid and 471 g (3.96 mol) of thionyl chloride was stirred for 4 hr at 50° C.-60° C. Excess thionyl chloride was distilled off under vacuum, and the residue was additionally dried in vacuum. A solution of this product in 300 mL of dichloromethane was added dropwise with vigorous stirring to a mixture of 270 g (3.31 mol) of dimethylamine hydrochloride and 702 g (6.95 mol) of triethylamine in 1200 mL of dichloromethane for 1 hr at 0° C. The resulting mixture was slowly warmed to room temperature, stirred for 1 hr, and then filtered through glass frit. The precipitate was additionally washed with 300 mL of dichloromethane. The combined filtrate was washed by 5% hydrochloric acid, water, dried over K2CO3, and then evaporated to dryness. The residue was washed with 200 mL of diethyl ether to yield 112 g (60%) of white solid.
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.Cl[CH2:21][CH:22]=O.CCOC(C)=O.CO.CO>C([O-])(=O)C.[Na+]>[C@@H:2]1([N:10]2[CH:11]=[N:12][C:13]3[C:14]4=[N:15][CH:21]=[CH:22][N:16]4[CH:17]=[N:18][C:19]2=3)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1
Reactant: O=CCCl
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c2ncn2ccnc32)C[C@@H]1O
Temperature: 45 °C
Reaction time: 70 h

Procedure:
2′-Deoxyadenosine monohydrate (1) (5.0 g, 20 mmol) was dissolved in 1M aq. sodium acetate buffer (pH 4.5-5.0, 110 mL) by warming to 40-50° C. To the solution chloroacetaldehyde (50% aq. soln, 7.7 mol/L, 25 mL) was added, and the reaction mixture was stirred for 70 h at room temperature. The yellow solution was evaporated to dryness, and the residue was dissolved in MeOH and filtered to remove inorganic salt. After washing with MeOH the combined filtrate and washings were concentrated in vacuo at 40-50° C. The residue was applied to FC (silica gel 60H, column: 20×6 cm). Elution with CH2Cl2-MeOH (85:15) gave a main fraction from which upon evaporation of the solvent and subsequent crystallization from MeOH-EtOAc compd. 5 (3.86 g, 70%) was isolated as colorless crystals. M.p. 138-141° C. TLC (silica gel, EtOAc-MeOH, 3:1): Rf 0.4. UV (MeOH): λmax 275 (7300), 265 (7600), 258 (6600), 229 nm (35700). 1H-NMR ([D6]DMSO) δ 2.39 (m, 1H, Hα—C(2′)); 2.70 (m, 1H, Hβ—C(2′)); 3.57 (m, 1H, Ha—C(5′)); 3.67 (m, 1H, Hb—C(5′)); 3.88 (m, 1H, H—C(4′); 4.43 (m, 1H, H—C(3′)); 4.99 (t, 1H, 3J(H,H)=5.2 Hz, 5′-OH); 5.38 (d, 1H, 3J(H,H)=3.8 Hz, 3′-OH); 6.47 (pt, 1H, 3J(H,H)=6.2 Hz, H—C(1′)); 7.55 (s, 1H, H—C(11); 8.07 (s, 1H, H—C(10); 8.53 (s, 1H, H—C(2)); 9.29 (s, 1H, H—C(8)).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:11]1[C:7]2([CH2:12][CH2:13][CH2:14][C:5]([CH2:3][OH:2])=[CH:6]2)[CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C1=CC2(CCCC2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC1=CC2(CCCC2)CCC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (3.50 g) obtained in Step 5 in tetrahydrofuran (70 mL) was added dropwise a 1M toluene solution of diisobutylaluminum hydride (54.6 mL) under argon atmosphere at −70° C. over 15 minutes, followed by stirring the reaction mixture at −70° C. for 2 hours. After raising the temperature up to −15° C., to the reaction mixture were added successively 2N aqueous hydrochloric acid solution (60 mL) and ethyl acetate (100 mL), followed by separation of the organic layer. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=3:97 to 15:85) to give spiro[4.5]dec-6-ene-7-methanol (2.375 g).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]#[N:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1C=CC=CC=1>[NH2:6][C:5]1[S:21][CH:1]=[N:3][C:4]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)[C@H](C#N)NC=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ncsc1N

Procedure:
Ethyl N-formyl-3-nitriloalaninate (11.22 g, 71.86 mmol) is dissolved in anhydrous benzene (220 mL). Following the addition of Lawesson's reagent (14.53 g, 35.93 mmol), the suspension is refluxed for 24 h. Most of the solvent is removed in vacuo, and the viscous red residue is absorbed on silica gel and loaded to a silica gel column (elution solvent: EtOAc:hexanes=50:50). The title compound is obtained as yellow solids. 1H NMR (400 MHz, CDCl3) 7.87 (1H, s), 7.26 (1H, s), 6.01 (2H, broad s), 4.38 (2H, q), 1.41 (3H, t).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1cscn1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and thiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[Cl:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]3)[CH:22]=2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 99 %

Procedure:
Following general procedure D, tert-butyl 4-(4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (54 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (60 mg, 99%) as a yellow-brown solid. ESI MS m/z 606 [C32H33ClFN5O4+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:25][C:21]1[N:20]=[C:19]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(Br)n1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cccc(Nc2ncc(-c3cccnc3)c3cccnc23)n1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
5-Pyridin-3-yl-[1,7]naphthyridin-8-ylamine (0.1 g, 0.45 mmol) and 2-bromo-6-methylpyridine (0.14 g, 0.8 mmol) were dissolved in 4 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg, 0.09 mmol), cesium carbonate (0.23 g, 0.72 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (47 mg, 0.045 mmol) were added and the reaction mixture was stirred for 20 hrs at 130° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1->0:100 gradient). The desired product was obtained as a light yellow solid (66 mg, 47%), MS: m/e=314.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)#[N:22]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]#[N:22])[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4C#N)CC3)nc2c1
Yield: 94 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl) piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 94%). 1H NMR (200 MHz, CDCl3): δ 3.30 (s, 4H), 3.88-3.90 (m, 6H), 4.07-4.20 (m, 4H), 6.94-7.07 (m, 3H), 7.27-7.34 (m, 2H), 7.53-7.63 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:34][C@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: C[C@@H]1CN(CCO)CCN1C
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 33 %

Procedure:
7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 1, Step A), 0.300 g, 0.678 mmol), (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.536 g, 3.39 mmol), and potassium t-butoxide (0.456 g, 4.07 mmol) were combined in t-butanol in a pressure tube. The tube was sealed and warmed to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) of the crude material followed by trituration with ether gave 136 mg (33%) of the title compound. MS (APCI), positive scan, m/z=581.1 (M+H). [α]D=−5.3° (c=1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[OH-].[NH4+:28]>O1CCOCC1>[NH2:28][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([CH:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][CH:5]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(F)c1)c1ncc(Cl)nc1Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(F)c1)c1ncc(N)nc1Cl
Temperature: 90 °C

Procedure:
In a high pressure reaction vessel, a suspension of 59B (300 mg, 0.742 mmol) in dioxane (2 mL) was treated with ammonium hydroxide (28%) (3 mL) and heated at 90° C. overnight. Solvents were removed and the crude was purified by flash chromatography to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, 1H), 7.33-6.97 (m, 2H), 6.84-6.31 (m, 4H), 5.25 (m, 1H), 4.65 (s, 1H), 3.42 (d, 2H), 3.27-2.96 (m, 6H), 2.47 (m, 2H), 1.38 (m, 1H), 1.05 (m, 1H). MS (m/z) 385 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][NH2:18]>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2cc(C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-tert-Butyl-1-indanone (13.41 g, 71.23 mmol) and methoxyamine hydrochloride (6.68 g, 80 mmol) were disolved in pyridine (75 ml) and stirred at ambient temperature for 16 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between water and diethyl ether (×2). The combined organic layers were washed with 1N aqueous hydrochloric acid, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound which was used without further purification in the next step.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]([NH:44][C:45]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][N:18]=2)=[CH:28][CH:29]=1)=[S:46])=[O:43]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 73%).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[N:13]([C:29](=[O:31])[NH2:30])[CH:12]=2)=[C:6]([O:32][CH3:33])[CH:5]=1.O1CCCC1.O.[OH-].[Li+]>O>[C:29]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([NH:20][C:21]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:16][CH:15]=2)[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][C:6]=2[O:32][CH3:33])=[CH:12]1)(=[O:31])[NH2:30]
Reactant: COC(=O)c1ccc(Cc2cn(C(N)=O)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(N)=O)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 46 h
Yield: 93.3 %

Procedure:
To a solution of 4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.15 grams, 2.47 mmol) in a 6:1 ratio tetrahydrofuran:water (70 mL) was added lithium hydroxide monohydrate (0.21 grams, 4.94 mmol) and the resulting solution was stirred, at room temperature, for 46 hours. The reaction mixture was concentrated in vacuo to a volume of 15 mL, then diluted with water (300 mL). The aqueous solution was acidified by addition of 1 M hydrochloric acid (aq), and the resulting precipitate was collected via filtration to give 4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (1.04 grams, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:21]/[OH:22])/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18]
Reactant: COc1ccc(C(=O)c2ccccc2F)c(O)c1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1C
Temperature: 200 °C

Procedure:
2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone (30.0 g) is refluxed 18 hours in 350 ml of pyridine containing 32.0 g of hydroxylamine hydrochloride. The solvent is removed in vacuo and the residue is distributed between ether and 5% HCl. Drying and concentration of the ether gives a crude product that is heated as a melt at 200° C. for 30 minutes in a nitrogen atmosphere. The melt is allowed to cool and the solid mass is triturated well with hexane to give E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime, mp 167°-169° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:44]=[CH:43][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=[CH:6][CH:5]=1>C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=[CH:43][CH:44]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1

Procedure:
27 ml of a 4N ethyl acetate solution of hydrogen chloride were added to a solution of 5.2 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-t-butoxycarbonylpiperazin-1-ylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 27 ml of ethyl acetate, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was concentrated to dryness by evaporation under reduced pressure, and the resulting concentrate was triturated with diethyl ether. The powder thus obtained was collected by filtration and dried to give 4.2 g of the title compound.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:17]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:18].Cl>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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[S:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH:19]([C:17]#[N:18])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:7]=2[CH:8]=[CH:9]1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: Brc1cccc2sccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C#N)c1cccc2sccc12
Yield: 67.6 %

Procedure:
To 1,2-dimethoxyethane (3 mL) solution of 0.30 g of 4-bromobenzothiophene were added 0.33 g of potassium tert-butoxide, 0.21 g of tert-butyl cyanoacetate, 0.01 g of dichlorobis(triphenylphosphine)palladium(II) and 0.01 g of triphenylphosphine, which was then refluxed for 40 minutes. Thereto were added 0.33 g of potassium tert-butoxide, 0.01 g of dichlorobis(triphenylphosphine)palladium(II) and 0.01 g of triphenylphosphine, which was then refluxed for 30 minutes. The reaction mixture was added to a mixed solution of water and ethyl acetate, and the pH was adjusted to 1 with 6 mol/L hydrochloric acid. The organic layer was separated, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to provide 0.26 g of tert-butyl 2-(1-benzothiophen-4-yl)-2-cyanoacetate as pale brown oily form.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13][O:14]C1C=C(C=CC=1)C(OC)=O>>[CH3:13][O:14][C:8]1[CH:7]=[C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: COC(=O)c1cccc(OC)c1
Product: COc1cccc(C(C)(C)N)c1
Yield: 31 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 3-methoxybenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 31%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O:14][C:15](=O)/[CH:16]=[C:17](/[O:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH2:29][CH3:30])[C:22]=1[F:31])\[CH2:18]Br)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:18][C:17]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH2:29][CH3:30])[C:22]=2[F:31])=[CH:16][C:15]1=[O:14])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1c(F)ccc(OCC)c1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OC)C2)c1F
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a solution of (L)-leucine methyl ester hydrochloride (6.00 g, 0.033 mol) dissolved in acetonitrile (50 mL) was added (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (6.05 g) in acetonitrile (10 mL) and N,N-diisopropylethylamine (7.27 g, 0.056 mol) and the resulting mixture refluxed for 14 h. The reaction mixture was cooled to room temperature and then poured into ethyl acetate. The mixture was filtered to remove salts and the filtrate washed successively with saturated ammonium chloride, water, and brine. The solution was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in tetrahydrofuran (10 mL) and then transferred to an Emry Optimizer microwave reaction vessel and heated at 160° C., for 4 h. The crude product obtained after aqueous work-up, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 100 g, 5% to 60% ethyl acetate/hexanes) to afford (S)-2-[4-(3ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.80 g, 28%) as an oil.