Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CN(C)C=O.[C@@H:14]12[C:23](=O)[O:22][C:20](=[O:21])[C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2.[OH-].[K+]>O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:1]2[C:20](=[O:21])[C@H:15]3[C@H:14]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:23]2=[O:22])=[CH:4][CH:5]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NCc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1Cc1ccncc1
Yield: 43.8 %

Procedure:
To 17.0 g (157 mmoles) of 4-aminomethylpyridine was added 40 mL of dimethylformamide and 24.2 g (157 mmoles) of cis-1,2-cyclohexanedicarboxylic anhydride. The mixture was heated under reflux for 2 hours. The cooled solution was diluted with water, made basic with aqueous potassium hydroxide, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated to afford 16.8 g of 2-(4-pyridinylmethyl)-cis-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione, m.p. 91°-92°; NMR (CDCl3): δ8.53-8.63 (d, 2H); 7.19-7.29 (d, 2H); 4.63 (s, 2H); 2.80-3.00 (m, 2H); 1.78-2.00 (m, 2H); 1.63-1.78 (m, 2H); 1.33-1.58 (m, 4H) .
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:22][C:23]1[S:24][C:25]([CH3:30])=[C:26]([CH2:28][CH3:29])[N:27]=1>C1(C)C(C)=CC=CC=1>[CH2:28]([C:26]1[N:27]=[C:23]([NH:22][C:3]([C:5]2[NH:6][S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[S:24][C:25]=1[CH3:30])[CH3:29]
Reactant: CCc1nc(N)sc1C
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Solvent: Cc1ccccc1C
Product: CCc1nc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2)sc1C
Yield: 55 %

Procedure:
N-(4-Ethyl-5-methyl-2-thiazolyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 37 from 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 2-amino-4-ethyl-5-methyl-thiazole. Yield: 55% of theory; m.p. 268°-270° C (decomp.; from xylene).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[NH:12]C(=O)C.[N:17](OC(C)(C)C)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[C:6](=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[NH:12][N:17]=1)=[O:16]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)Cc1ccc(Cl)cc1NC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1n[nH]c2cc(Cl)ccc12
Yield: 77 %

Procedure:
To a solution of (2-Acetylamino-4-chloro-phenyl)-acetic acid methyl ester )32.0 g, 133 mmol) in acetic acid (200 mL) stirred at 90 degree Celsius was added tert-butyl nitrite (20.5 mL, 172.3 mmol) over 1 hour. The reaction was poured into water (1.4 L) and the solids were recovered by filtration. The yellow precipitate was dissolved in EtOAc, then washed with saturated NaCl. The organic was dried over MgSO4, filtered, and concentrated to a solid. The solids were triturated with hexanes and filtered to afford the desired material (21.63 g, 77%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[S:8][CH2:7][CH2:6]1)[CH3:3].[H-].[Na+].[CH:20](I)([CH3:22])[CH3:21].CCOCC>CN(C)C=O>[CH3:3][N:2]([CH2:4][CH:5]1[C:10]2[N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[S:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCSc2c1[nH]c1ccccc21
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)n1c2c(c3ccccc31)SCCC2CN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of 4-dimethylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.00 g) in dry dimethylformamide (25 ml) is mixed with 50% sodium hydride (293 mg) under stirring and the mixture is allowed to stand at 40° C. for 1 hour. Then, the reaction mixture is mixed with a solution of isopropyl iodide (1.63 g) in dimethylformamide (2 ml) and kept at 40° C. for 2 hours and further for 20 hours after addition of the reagent. The reaction mixture is mixed with ether and ice water successively at under 5° C. and the ether layer is separated. The aqueous layer is further extracted with ether. The combined ether layers are extracted with a dilute hydrochloric acid solution. The extract is made alkaline and extracted with methylene chloride. The extract is washed with water, dried and evaporated to give the title compound (910 mg) as an oil: Yield 77.8%.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH3:14])[CH:20]=[CH:19][C:18](/[C:21](/[CH3:22])=[CH:3]/[C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C(=C\C#N)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (13.2 g, 74.6 mmol) in 50 mL of THF was added sodium hydride (60% content, 2.98 g, 74.6 mmol). The mixture was stirred at room temperature for 2 hours. 1-(4-methylphenyl)ethanone (5 g, 37.3 mmol) was added and the mixture was stirred for 2 hours. After evaporation of THF, the residue was taken up in ethyl acetate (50 mL) and quenched with water (50 mL). The organic phase was washed with water (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was used in the next step without further purification. LC-MS: m/z 158 (M+H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15](C2C=NC=CN=2)[N:16]=1>>[CH2:1]([NH:9][C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[CH:15][N:16]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Clc1cc2c(NCCc3ccccc3)ncnc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-pyrazin-2-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1B(O)O.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
Diethyl 2-(3-bromophenyl)propanedioate (3.75 g), 2-chloro-4-(trifluoromethyl)phenyl boronic acid (4.0 g), dioxane (10 mL), 2M aqueous sodium carbonate solution (5 mL) and dichlorobis(triphenylphosphine)palladium(II) (422 mg) were added to a vial, and the reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was then cooled, poured into water, extracted with ethyl acetate, and the organic phase was separated and concentrated under vacuum in the presence of Celite® (diatomaceous earth) to yield a crude solid. The crude solid was purified by medium pressure liquid chromatography on silica gel eluting with a gradient of ethyl acetate in hexanes to yield 3.2 g of the title compound. 1H NMR (CDCl3) δ 7.74 (s, 1H), 7.57 (d, 1H), 7.37-7.50 (m, 5H), 4.57 (s, 1H), 4.23 (q, 4H), 1.27 (t, 6H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:4].[CH3:13][C:14]([CH3:16])=[O:15]>O>[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:13][C:14](=[O:15])[CH3:16])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C=CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 ml of 10% strength sodium hydroxide solution is added to a mixture of 111.4 (0.83 mol) of 4-ethylbenzaldehyde, 133 g of acetone and 100 ml of water, and the mixture is stirred overnight at room temperature. It is then diluted with 300 ml of ice water and extracted five times, each time with 100 ml of dichloromethane. The extracts are dried over sodium sulfate and concentrated.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:15]=[CH:14][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[ClH:1].[CH2:9]1[C:8]2[CH:14]=[CH:15][C:5]([NH2:2])=[CH:6][C:7]=2[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CCNCC2
Yield: 166.4 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-7-nitro-1H-3-benzazepine hydrochloride (1.68 g, 7.35 mmol) in ethanol (100 ml) was added 5% palladium on carbon (0.2 g) and the solution was placed on a Paar Hydrogenator Apparatus and pressurized with 45 psi of hydrogen. After the theoretical uptake of hydrogen had been achieved (2 h), the catalyst was filtered off and washed with water (25 ml). The filtrate was concentrated. Absolute ethanol was added and evaporated until all of the water had been evaporated and a solid formed. The solid was dissolved in hot ethanol (50 ml) and the product was precipitated by the addition of ether (75 ml). The solid was collected and air-dried to give the product as an off-white solid (2.43 g (94%)), m.p. 288-91° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:19][CH:20]=[C:21]([NH2:23])[CH:22]=2)=[CH:13][C:12]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:32][C:33]1[CH:34]=[C:35]([C:39](O)=[O:40])[CH:36]=[N:37][CH:38]=1>>[CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:19][CH:20]=[C:21]([NH:23][C:39]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([I:32])[CH:34]=3)=[O:40])[CH:22]=2)=[CH:13][C:12]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(I)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)c1
Product: O=C(Nc1ccc(-c2cc(NC(=O)c3cncc(I)c3)cnc2OCC(F)(F)F)cc1Cl)OCc1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using {4-[5-amino-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-chloro-phenyl}-carbamic acid benzyl ester (example 73 a) and 5-iodo-3-pyridinecarboxylic acid (CAN 15366-65-1) as starting materials; LC-MS (UV peak area/ESI) 68.6%, 683.4 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:14][C@@H:15]([OH:41])[C@@H:16]([NH:29][C:30](=[O:40])[O:31][C@@H:32]3[C@H:39]4[C@H:35]([O:36][CH2:37][CH2:38]4)[O:34][CH2:33]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27]I)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[S:46]1[CH2:50][CH2:49][NH:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:14][C@@H:15]([OH:41])[C@@H:16]([NH:29][C:30](=[O:40])[O:31][C@@H:32]3[C@H:39]4[C@H:35]([O:36][CH2:37][CH2:38]4)[O:34][CH2:33]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:48]4[CH2:49][CH2:50][S:46][CH2:47]4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCI)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: C1CSCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN2CCSC2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.3 %

Procedure:
A solution of 35 mg (0.046 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(3-iodopropoxy)benzyl]propylcarbamate, 11 μL (0.14 mmol) of thiazolidine, and 32 μL (0.18 mmol) of N,N-diisopropylethylamine in 0.5 mL of anhydrous DMF was heated to 80° C. with stirring. After 1.5 hours TLC indicated the reaction to be complete. The solution was cooled to RT and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 22 mg (67%) of the desired compound as a white foam. 1H NMR (CDCl3): 7.29 (d, 1H), 7.13 (s, 1H), 7.08 (d, 2H), 7.85 (d, 1H), 6.77 (d, 2H), 6.04 (s, 2H), 5.60 (d, 1H), 5.00 (q, 1H), 4.88 (d, 1H), 4.01 (s, 2H), 4.00-3.88 (m, 3H), 3.80 (m, 3H), 3.67 (m, 2H), 3.55 (br s, 1H), 3.19-3.01 (m, 4H), 3.00-2.65 (m, 7H), 2.52 (t, 2H), 1.93 (m, 2H), 1.79 (m, 1H), 1.70-1.42 (m, 2H), 0.89 (d, 3H), 0.83 (d, 3H). MS(ESI): 722(M+H).
Reaction SMILES: CS(O[CH2:6][C:7]([N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[N:11]1)([CH3:9])[CH3:8])(=O)=O.[I-].[Na+].[CH3:25][S:26]([O-:28])=[O:27].[Na+].O>CN(C)C=O>[C:19]([O:18][C:16](=[O:17])[NH:15][C:13]1[CH:12]=[N:11][N:10]([C:7]([CH3:9])([CH3:8])[CH2:6][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)COS(C)(=O)=O)c1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CS(C)(=O)=O)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of the crude 2-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)-2-methylpropyl methanesulfonate (1.1 g) obtained in Step B of Example 114 in N,N-dimethylformamide (10 mL) were added sodium iodide (740 mg) and sodium methanesulfinate (1.0 g), and the mixture was stirred overnight at 140° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (250 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11]3[CH2:12][CH2:13][N:14]4[CH2:19][C@H:18]5[CH2:20][C@@H:21]([O:30]C(C6C=C(OC)C(OC)=C(OC)C=6)=O)[C@H:22]([O:28][CH3:29])[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[C@H:17]5[CH2:16][C@@H:15]4[C:10]=3[NH:9][C:7]=2[CH:8]=1.C[O-].[Na+]>CO>[CH3:29][O:28][C@@H:22]1[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[C@@H:17]2[C@@H:18]([CH2:19][N:14]3[C@H:15]([CH2:16]2)[C:10]2[NH:9][C:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[C:11]=2[CH2:12][CH2:13]3)[CH2:20][C@H:21]1[OH:30]
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](O)[C@@H]1OC
Yield: 97.1 %

Procedure:
A suspension of reserpine (1.00 g, 1.64 mmol), NaOMe (0.20 g, 3.61 mmol), and MeOH (50 mL) was refluxed for 4 h (more NaOMe was added twice), cooled, and concentrated to one-third the volume. The solution was diluted with water (60 mL) and acidified to pH=1 with concentrated HCl. The water layer was washed with Et2O repeatedly and made basic with concentrated NH4OH and repeatedly extracted with CH2Cl2 (4×30 mL). The combined organic phases were dried, filtered, and concentrated to give a colorless solid (0.66 g, 97%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.82-6.74 (m, 2H), 4.41 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.73-3.68 (m, 1H), 3.59 (s, 3H), 3.58-3.45 (m, 3H), 3.18-3.15 (m, 2H), 3.01-2.91 (m, 2H), 2.68-2.43 (m, 4H), 2.26-2.18 (m, 2H), 1.98-1.75 (m, 4H), 1.27-1.18 (m, 2H); 13C NMR (CDCl3) δ 173.5, 156.2, 136.5, 130.9, 122.3, 118.6, 108.99, 108.03, 95.3, 81.6, 75.3, 66.0, 61.1, 58.4, 55.9, 53.8, 51.9, 51.5, 51.3, 49.4, 34.6, 32.9, 32.5, 24.4, 18.5, 16.9, 15.4.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH2:23][CH2:24][C:25]5[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=5)[N:27]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:35](O)(=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39]>>[C:35]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH2:23][CH2:24][C:25]5[N:26]([C:28]([C:31]([F:33])([F:34])[F:32])=[N:29][N:30]=5)[N:27]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(=O)O
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Product: CCCCC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 36 %

Procedure:
Obtained in 36% yield by an analogous method to Example 4.1, starting from 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine and pentanoic acid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[N:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[N:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4nn(C)c5ccccc45)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4nn(C)c5ccccc45)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-3-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (13.5 mg, 0.022 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30ClN4O3S: 597.2; found: 597.2. 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=5.6 Hz, 1H), 8.93 (s, 1H), 8.59 (d, J=7.6 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.75 (d, J=6.8 Hz, 1H), 7.60-7.46 (m, 6H), 5.36 (s, 1H), 4.29 (s, 3H), 2.65 (s, 3H), 1.02 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].S(Cl)(Cl)=O.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>C1(C)C=CC=CC=1>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([CH3:12])[CH:5]=3)=[O:9])[CH2:22][C:21]=12
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C#N
Reaction time: 18 h

Procedure:
A solution of 4-cyano-3-methylbenzoic acid from Example C (1.2 g, 7.5 mmol) and thionyl chloride (3.6 ml, 54 mmol) in toluene (20 ml) was heated at reflux for 2 h. The mixture was evaporated and azeotroped with toluene. The residue was dissolved in dichloromethane, 10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine (1.4 g, 7.5 mmol) was added and the mixture stirred for 18 h. The mixture was evaporated and the residue purified by flash chromatography on silica (EtOAc:pet ether, 30:70 to 80:20) to give a cream solid, yield 1.5 g, 63%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[OH:19][CH2:18][C:14]1[CH2:15][CH2:16][O:17][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:21][C:12]=2[CH:13]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(CO)CCO3)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (841 mg) and triethylamine (0.42 ml) in THF (15 ml) was added dropwise at −5° C. a solution of ethyl chloroformate (0.29 ml)/THF (2 ml). The resulting mixture was stirred at −5° C. for 30 minutes, and an insoluble material was removed by filtration. Into the filtrate was added dropwise under ice cooling a solution of sodium borohydride (284 mg)/water (6 ml). After stirring at room temperature for 1.5 hours, the reaction mixture was mixed with 1 N hydrochloric acid and was extracted with ethyl acetate. The extract was washed successively with water, a 1 N aqueous solution of sodium hydroxide, water and an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/diethyl ether/hexane to obtain 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (708 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (5.50 g, 15.5 mmol) in CH2Cl2 (100 mL) was added 2-trimethylsilyl-ethanol (3.67 g, 31.0 mmol), EDC (5.36 g, 27.9 mmol), and DMAP (3.67 g, 31.0 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (150 mL), and extracted with CH2Cl2 (100 mL). The combined organics were dried (Na2SO4) and concentrated. The residue was purified using silica gel chromatography (hexanes/EtOAc 9/1) to afford the title compound as an oil (5.90 g, 84%). 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 9H), 1.14 (t, 2H, J=8.8 Hz), 1.52 (s, 9H), 4.41 (t, 2H, J=8.8 Hz), 5.10 (s, 2H), 6.20 (d, 1H, J=15.6 Hz), 7.13 (dd, 1H, J=3.0, 8.3 Hz), 7.34-7.44 (m, 5H), 7.50 (d, 1H, J=3.0 Hz), 7.53 (d, 1H, J=8.8 Hz), 8.41 (d, 1H, J=16.1 Hz).