Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:31]2[C:26](=[C:27]([CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:26]=4[CH:25]=[N:24][N:23]5[CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][O:17]4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cnn(C3CCCCO3)c2c1
Temperature: 120 °C
Yield: 94.8 %

Procedure:
A tube was charged with 53 (350 mg, 1.47 mmol), 199 (340 mg, 1.47 mmol), and DIPEA (5 mL) in IPA (10 mL), degassed, sealed and heated at 120° C. for 48 h. The solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 600 mg (94%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)pyrimidine-2,4-diamine (200) as yellow solid: MS (ESI) m/z=431.2 [M+1]+.
Reaction SMILES: C[C@:2]1([C:34]([OH:36])=[O:35])[CH2:7][CH2:6][C@:5](O)([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:4][C:3]1([CH3:33])[CH3:32].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:51](=O)(O)[O-].[Na+]>>[CH3:32][C:3]1([CH3:33])[CH:4]=[C:5]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:6][CH2:7][CH:2]1[C:34]([O:36][CH3:51])=[O:35]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@](C)(C(=O)O)C(C)(C)C3)s2)c1
Reactant: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: COC(=O)C1CCC(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)=CC1(C)C
Temperature: 65 °C
Yield: 73 %

Procedure:
A suspension of methyl(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (200 mg, 0.38 mmol) in phosphorous pentoxide (2.2 g, 15.4 mmol) was heated at 65° C. for 3 hours. The resulting mixture was cooled to room temperature, slowly poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (ethyl acetate/hexanes) afforded methyl 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohex-3-ene-1-carboxylate (141 mg, 0.28 mmol, 73% yield) as a colorless oil. MS ESI: [M H] m/z 503.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:15]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:16]=2[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][S:2]([N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:15]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:16]=2[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N(S(C)(=O)=O)S(C)(=O)=O
Reaction time: 20 h
Yield: 78.3 %

Procedure:
Methanesulfonyl chloride (0.86 ml, 1.1 mmol) was added to a stirred solution of ethyl 3-[(2-aminophenyl)sulfanyl]-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 12 220 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.2 ml, 1.1 mmol) in dichloromethane (3 ml). The mixture was left at ambient temperature for 20 hours and then diluted with dichloromethane and washed with water. The organics were dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether, and then ethyl acetate, as eluant. The title product was crystallised from diethyl ether to give a colourless solid (232 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[C:26]([C:23]1([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:3][CH:4]=3)[CH:10]=2)=[O:28])[CH2:24][CH2:25]1)#[N:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)nc4)c3)c2)CC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (2.0 g, 5.4 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.13 g, 5.94 mmol) under ice-cooling, and the mixture was stirred with heating at 80° C. for 2 days. After the reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate and diisopropyl ether to give the title compound (2.61 g, 92%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCSCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with thiomorpholine (0.020 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(thiomorpholinomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=5)[CH:26]=[N:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: Fc1ccc(-n2ccnc2)cc1
Product: Fc1ccc(-n2cncc2-c2ccc3ncn(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (26 mg, 20%), MS (ISP) m/z=373.5 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 28 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (204 mg, 0.7 mmol) and commercially available 1-(4-fluoro-phenyl)-1H-imidazole (56.8 mg, 0.35 mmol).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]=[C:8]1[C@@H:14]([N:15](C)[C:16](=O)C(F)(F)F)[CH2:13][CH2:12][S:11][C@H:10]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:27]([O:29][CH3:30])=[O:28])[N:9]12>O.CO>[CH3:16][NH:15][C@H:14]1[CH2:13][CH2:12][S:11][C@H:10]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:27]([O:29][CH3:30])=[O:28])[N:9]2[C:8]1=[O:7]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N(C)C(=O)C(F)(F)F)C(=O)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of K2CO3 (18.8 mg, 0.136 mmol) in water (0.16 mL) was added to a solution of (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoro-N-methylacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (45.6 mg, 0.124 mmol) in MeOH (0.4 mL). The reaction mixture was stirred at rt for 2 hr. After a total of 3 hr, a stream of nitrogen gas was used to partially evaporate the MeOH. The residue was then partitioned between CHCl3 and saturated aqueous NaCl. The aqueous layer was isolated and extracted once again with CHCl3. All organic phases were combined, dried over MgSO4 and concentrated to give (4S,7S,10aS)-methyl 4-(methylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (34 mg, 0.12 mmol, 100% yield) of a yellow oil. Anal. Calcd. for C12H20N2O3S m/z 272.3. found: 273.2 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:24])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)=[O:4].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([CH:2]([CH3:24])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=[CH:8]3)=[O:4])[CH2:28][CH2:27]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C(=O)C(C)Br)ccc32)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C(=O)C(C)N4CCC(O)(c5ccccc5)CC4)ccc32)cc1
Yield: 86.8 %

Procedure:
5-(2-Bromopropionyl)-1-(p-toluenesulfonyl)indole (1.67 g, 3.37 mmol, 83% purity) was dissolved in hot ethanol (100 ml) and 4-hydroxy-4-phenylpiperidine (0.6 g, 3.39 mmol) and triethylamine (0.94 ml, 6.74 mmol) were added. The mixture was refluxed overnight. The reaction was cooled and concentrated directly onto silica gel and flash chromatographed. Elution with 1:3 ethyl acetate:hexane removed 0.1 g of non-brominated ketone. Continued elution with 1:1 ethyl acetate hexane gave 1.47 g, 87% of the title product as a glassy orange solid. NMR 8.34 (s, 1H), 8.09 (d, J=9 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.33-7.29 (m, 2H), 7.24-7.21 (m, 4H), 6.72 (d, J=3.5 Hz, 1H), 4.18 (q, J=7 Hz, 1H), 2.88-2.84 (m, 2H), 2.73-2.62 (m, 2H), 2.32 (s, 3H), 2.18-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.77-1.66 (m, 1H), 1.59-1.54 (m, 1H), 1.31 (d, J=7 Hz, 3H). IR 1679, 1605, 1375, 1289, 1260, 1169, 1126, 994. FAB HRMS calcd for C29H31N2O4S (MH+): 503.2006. Observed m/e: 503.2023.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2c(CNc3ccc(-c4ccc(Cl)cc4)cc3)cccc2C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2c(CNc3ccc(-c4ccc(Cl)cc4)cc3)cccc2C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
A 1M aqueous solution of NaOH (0.30 mL, 0.30 mmol) was added to a THF (0.6 mL) and MeOH (0.3 mL) solution of ethyl 3-(5-(2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)-6-(trifluoromethyl)phenyl)picolinamido)propanoate (57.5 mg, 0.10 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 45 min the resulting mixture was acidified with 1M HCl (0.31 mL, 0.31 mmol) and then extracted with DCM. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.O.C([O-])([O-])=O.[Na+].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[OH:11][CH:8]([C:4]1[CH:3]=[C:2]([NH:1][C:27](=[O:28])[O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:9][OH:10]
Reactant: Nc1cccc(C(O)CO)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(C(O)CO)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
1-(3-Aminophenyl)ethane-1,2-diol (10 g) was dissolved in DCM (80 mL). H2O (80 mL) and Na2CO3 (10.98 g) were added and the mixture cooled to 0° C. Benzylchloroformate (22 g) was added drop-wise over 20 minutes and the reaction mixture stirred at room temperature overnight. The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (8 g, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(COc2ccc3c(c2)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-ditert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.021 ml) and pyridine (0.025 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (100 mg).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:11][C:10](=[O:12])[CH2:9][C:6]1[C:5]2[CH:13]=[CH:14][C:2]([OH:1])=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2cc(O)ccc12
Yield: 70 %

Procedure:
(6-Hydroxy-1-benzofuran-3-yl)acetic acid (9.85 g, 51.3 mmol) was suspended in methanol (45 mL), concentrated sulfuric acid (5 mL) was added, and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The extract was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50.), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (7.38 g, yield 70%) as pale-yellow prisms.
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:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1F)[C:35]([O:37][CH3:38])=[O:36].[H-].[Na+].O>CS(C)=O>[F:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1[O:1][C:2]1[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]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 17.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (485 mg, 1.127 mmol) synthesized in Example (38d) and commercially available methyl 3,4-difluorobenzoate (540 mg, 3.137 mmol) were dissolved in dimethyl sulfoxide (10 mL), and sodium hydride (60%, 180 mg, 4.50 mmol) was added, followed by stirring at 100° C. for 2.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, and extraction was carried out with diethyl ether (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium 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=10%-30%) to afford the desired compound (97 mg, yield 18%) as a white solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:23][CH:22]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of the product of Example 9 (4.0 g, 8.0 mmol) stirring in 1,2-dichloroethane (50 mL) at 0° C. was added boron trichloride (10 mL, 117.0 mmol). The resulting dark purple solution was stirred at room temperature overnight in a sealed tube then cooled to 0° C. Methanol (50 mL) was carefully added dropwise over a 30 minute period (caution: gas evolution). The resulting solution was concentrated and dissolved in ethyl acetate. The organic extract was washed with saturated aqueous, sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated. The resulting brown foam was purified by flash chromatography (silica gel, methanol/chloroform gradient) to give 2.7 g (63%) of desired product as a white foam: 1H-NMR (300 MHz, DMSO) δ9.72 (br s, 1H), 7.62-7.80 (m, 2H), 7.22-7.50 (m, 6H), 7.10-7.22 (m, 2H), 7.00 (m, 1H), 6.80-6.90 (m, 2H), 6.78 (m, 1H), 4.23 (s, 2H), 3.85-4.10 (m, 2H), 2.50-2.75 (m, 2H), 2.25-2.50 (m, 4H), 1.25-1.56 (m, 6H); Anal. Calc'd. for: C, 82.35; H, 7.14; N, 3.20. Found: C, 82.17; H, 7.11; N, 3.35; MS (FD) m/e 437 (M+); IR (KBr) 2935.07, 2855.01, 1621.38, 1597.26 cm−1.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) is added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution is stirred 15 minutes at 0° C. and then treated with a 1.6 M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting solution is stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-(4-fluorophenyl)cinnamaldehyde (82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution is stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12 N hydrochloric acid (ca. 20 ml). The reaction mixture is diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts are combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate is evaporated in vacuo leaving the title compound as an oil.
Reaction SMILES: Cl.[F:2][C:3]([F:33])([F:32])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:25]=[CH:24][C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:17]=4[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C=O)C>[F:33][C:3]([F:2])([F:32])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:25]=[CH:24][C:18]4[CH2:19][CH2:20][N:21]([CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:22][CH2:23][C:17]=4[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)ccc1-c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
7-{5-[2-(Trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 20) (200 mg, 0.424 mmol), DIPEA (0.281 ml, 1.608 mmol) and ethyl 4-bromobutanoate (0.131 ml, 0.919 mmol) were stirred at RT in DMF (10 ml) for 5 hours. The reaction mixture was then heated to 60° C. for 5 hrs, and then allowed to stand overnight at room temperature. Further ethyl 4-bromobutanoate (0.066 ml, 0.459 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (277 mg, 0.454 mmol) as an orange solid. MS (ES): C31H30F3N3O3 requires 549; found 550 [M+H]+.