Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:5][CH:6]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[N:15]([CH2:17][CH:18](OC)[O:19]C)[CH3:16])=[N:10][N:9]=1)[CH3:7]>O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:5][CH:6]([C:8]1[S:12][C:11]([N:13]2[CH:18]([OH:19])[CH2:17][N:15]([CH3:16])[C:14]2=[O:23])=[N:10][N:9]=1)[CH3:7]
Reactant: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(Cl)c(Cl)c2)s1)OC
Agent: Cl
Solvent: O
Product: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N2C(=O)N(C)CC2O)s1
Yield: 109 %

Procedure:
A solution containing 4.0 grams of the 3-[5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-(2,2-dimethoxyethyl)urea (prepared above) in 200 milliliters of water and 2 milliliters of concentrated hydrochloric acid (HCl) was refluxed for 165 minutes, cooled and then extracted with chloroform CHCl3, and phase separated. The organic phase was dried over MgSO4, filtered, and topped in a roto-vac at 70° C. to yield 3.9 grams of a viscous oil. The viscous oil was dissolved in 20 milliliters of diethylether, and the solution crystallized. The crystals were removed by suction filter, and were dried in a vacuum oven at 80° C. to yield 1.9 grams of white crystals of 3-[5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-4-hydroxy-2-imidazolidinone with a (Melting point 135°-138° C.) and
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[N:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-Phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine (2.5 g, 9.9 mmol), and N,N-diisopropylethylamine (8.6 mL, 50 mmol) in dichloromethane (8 mL) at 0° C. was added dropwise isobutyryl chloride (1.04 mL, 9.9 mmol); the mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water and extracted with dichloromethane (3×). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to a dark sticky solid. The residue was purified by flash chromatography (eluting with ethyl acetate/hexanes 3:1) to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1.N12CCCN=C1CCCCC2.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([O:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CC(O)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N1CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
In 50 mL of methylene chloride was dissolved 10.0 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and 31.2 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene and 29.1 g of trityl chloride were added thereto under ice-cooling, after which the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 mL of ice water and the organic layer was separated. The organic layer was washed with diluted hydrochloric acid, water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue and the crystals precipitated were collected by filtration to obtain 21.7 g of 1-[3-(trityloxy)-1-azetidinyl]-1-ethanone as light-yellow crystals.
Reaction SMILES: [CH:1]12[CH2:7][NH:6][CH:5]1[CH2:4][N:3](C1C=NC3C(=CC=CC=3)N=1)[CH2:2]2.Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][N:20]=1>>[C:25]1([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:3]3[CH2:4][CH:5]4[CH:1]([CH2:7][NH:6]4)[CH2:2]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc2nc(N3CC4CNC4C3)cnc2c1
Reactant: Clc1nccc(-c2ccccc2)n1
Product: c1ccc(-c2ccnc(N3CC4CNC4C3)n2)cc1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 8, using 2-chloro-4-phenyl pyrimidine. MS (ESI) mass calcd. for C15H16N4, 252.31; m/z found 253.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4][CH2:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:6]1[CH2:5][O:4][CH2:3][C:2]([CH3:10])([CH3:1])[O:7]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)COCC(CO)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COCC(COS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
TEA (0.52 mL, 3.74 mmol) and (6,6-dimethyl-1,4-dioxan-2-yl)methanol (390 mg, 2.67 mmol) were dissolved in DCM (10 mL). Methanesulfonyl chloride (0.249 mL, 3.20 mmol) was slowly added at 0° C. After the addition was completed the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4:1 to 1:1) to give the product as a colorless oil (584 mg, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 4.00-4.09 (3H, m), 3.74 (1H, dd, J=11.2, 2.8 Hz), 3.42 (1H, d, J=11.6 Hz), 3.16-3.23 (2H, m), 2.99 (3H, s), 1.27 (3H, s), 1.05 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:19]=[CH:18][C:17]([C@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(C(F)(F)F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (148 mg, 0.40 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3 mL, 17.13 mmol) and the solution stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (50 mg, 40%). 1H NMR (600 MHz, dmso) δ 1.75-1.83 (m, 2H), 1.84-1.92 (m, 1H), 2.00-2.06 (m, 1H), 2.70 (dt, 1H), 2.79-2.86 (m, 1H), 3.09-3.15 (m, 1H), 3.77 (d, 1H), 5.95 (s, 1H), 7.59 (d, 2H), 7.64 (d, 2H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1166
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[O:13]>>[OH:13][CH:12]([CH:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=O
Reactant: CCC(=O)c1ccccc1
Product: CCOC(=O)C(O)C(C)C(=O)c1ccccc1
Temperature: 135 °C

Procedure:
A mixture of 13.4 g of propiophenone and 15.3 g of ethyl glyoxylate is heated at 135° C. for 5 hours.
Reaction SMILES: [C:1]1([C:7]2[C:15](C)=[C:14]([C:17]([O-:19])=O)[CH:13]=[CH:12][C:8]=2[C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.[CH2:21]1COCC1>C1COCC1>[CH3:21][O:11][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:14]([CH2:17][OH:19])=[CH:15][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: Cc1c(C(=O)[O-])ccc(C(=O)[O-])c1-c1ccccc1
Agent: B
Product: COC(=O)c1ccc(CO)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a 0° C. solution in THF (40 mL) of 2-phenylmonomethylterephthalate (10.5 g, 41 mmol) was added borane-THF (1.0 M, 82 mL, 82 mmol) such that the reaction temperature remained below 6° C. The reaction mixture was stirred for 0.5 hours, then the cold bath was removed and stirring was continued for 2 hours. The reaction mixture was again cooled to 0° C. and aqueous HCl (3 M, 100 mL) was added slowly. The cold bath was removed and the reaction mixture was stirred for 1 hour. The THF was evaporated and the residue was extracted with ethyl acetate (3×). The combined organic extracts were washed with 1M aqueous NaOH (2×), water (2×) and brine, dried, filtered, and concentrated in vacuo to give 4-hydroxymethyl-2-phenylbenzoic acid methyl ester (9.75 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:18]([O-:20])=[O:19])[CH:12]=[C:13]([CH:17]=2)[C:14]([O-:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[K+]>O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])c1cc(C#Cc2ccccc2)cc(C(=O)[O-])c1
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C#Cc2ccccc2)cc(C(=O)O)c1
Yield: 99.5 %

Procedure:
Dipotassium 5-(2-phenylethynyl)isophthalate in an amount of 6.5 g (0.019 moles) was dissolved into 20 ml of ion-exchanged water and insoluble substances were removed by filtration with a 5C filter paper. To the obtained filtrate, a 5 moles/liter hydrochloric acid was added under stirring until the pH became 1. The formed solid substance was separated by filtration, washed with ion-exchanged water and filtered. The filtration and the washing were repeated twice. The obtained solid substance was dried at 50° C. under a reduced pressure and 5.0 g of 5-(2-phenylethynyl)isophthalic acid was obtained (the yield: 99.5%).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.288 g, 1.14 mmol) was treated with 1.0 M KOtBu in THF (1.10 mL, 1.10 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline (0.200 g, 0.757 mmol) was added as a solid, followed by the addition of DMF (3.3 mL), and the resultant mixture was stirred at ambient temperature for 40 hours. The crude reaction mixture was chromatographed on SiO2 eluting with a gradient of (2% NH4OH in isopropanol)/methylene chloride. The desired product was isolated as a pale yellow solid (196 mg). MS APCI (+) m/z 498.2 (M+1) detected.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:21])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26].O>CN(C)C=O>[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][S:21][C:10]1[CH2:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 11.4 g of 1,3-dihydro-5-phenyl-7-nitro-2H-1,4-benzodiazepin-2-thione in 140 ml of anhydrous dimethylformamide is added under ice cooling with stirring 3.6 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 15 minutes. To this mixture is added dropwise at room temperature with stirring 13.2 g of N,N-dimethyl-2-chloroethylamine over a period of about 1 hour, followed by stirring for 1 hour. The reaction mixture is poured into iced water and then extracted with chloroform. The extract is washed with water and dried over magnesium sulfate, and the solvent is then distilled off under reduced pressure. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with a benzene-chloroform (5:1) eluant. The eluate is concentrated under reduced pressure to obtain an oily 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with maleic acid and then recrystallized from an anhydrous ethanol-acetone mixture to obtain 9.0 g of 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro-3H-1,4-benzodiazepine maleate, m.p. 131°-134° C.
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH2:8]([O:15][CH2:16][CH:17]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][CH2:16][CH:17]1[O:6][CH2:5][C:2]([F:7])([F:1])[CH2:3][O:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC(F)(F)CO
Reactant: O=CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC1(F)COC(COCc2ccccc2)OC1
Yield: 42.8 %

Procedure:
A mixture of 2,2-difluoropropane-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1.34 g, 8.9 mmol), p-toluenesulfonic acid monohydrate (154 mg, 0.81 mmol) and toluene (20 ml) was heated under reflux by a condenser equipped with a Dean-Stark apparatus for one hour. The resultant mixture was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and silica gel was added thereto. The resultant mixture was concentrated to dryness and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=10/1) to obtain the title compound (930 mg, 42.8%).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:25][C@H:26]([C:30]([NH:32][C@H:33]([C:46]([O:48][CH3:49])=[O:47])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:37][CH:36]=1)=[O:31])[CH:27]([CH3:29])[CH3:28].Cl>CN(C)C=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@@H:2]([C:12]([NH:25][C@H:26]([C:30]([NH:32][C@H:33]([C:46]([O:48][CH3:49])=[O:47])[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[CH:39][CH:40]=1)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
4.04 g (12 mmoles) of Z-D-Glu(OBut)-OH are subjected to a condensation reaction with 4.64 g (12 mmoles) of H-Val-Tyr(But)-OMe.HCl in 25 ml of dimethylformamide analogously to Example 38 A. Yield 6.72 g. The substance is purified further by chromatography on silica gel. The eluting agent is a mixture of methylene chloride and acetone in proportions such as 9:1. Yield 6.63 g (70%), melting point 100°-104°, [α]D27 =-8.4° (c=1, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([O:13][C:14](=[O:35])[N:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][N:23]2[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)C>[C:9]([O:13][C:14](=[O:35])[N:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])=[CH:22][N:23]2[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])([CH3:12])([CH3:10])[CH3:11]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3Br)cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
—Sulfuryl chloride (1.08 ml, 13.4 mmol) was added to a solution of 2-bromobenzenethiol (1.27 g, 6.69 mmol) in dichloromethane (45 ml). The reaction mixture was stirred at room temperature for 15 min. and concentrated under reduced pressure. The resulting material was dissolved in diethyl ether and added dropwise to a solution of [1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (Example 6, method 1, step i; 2.50 g, 6.71 mmol) in diethyl ether (45 ml). The reaction mixture was stirred for 3.5 h and then poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→8:2) afforded [3-(2-bromo-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (3.02 g).
Reaction SMILES: B1(C2C=CC(O)=CC=2)O[C:4](C)(C)[C:3](C)(C)O1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([OH:31])=[O:30])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([O:31][CH2:3][CH3:4])=[O:30])=[CH:20][CH:19]=1
Reactant: O=C(O)c1occc1-c1ccc(O)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CCOC(=O)c1occc1-c1ccc(O)cc1

Procedure:
Using 4-hydroxyphenylboronic acid pinacol cyclic ester, a reaction and treatment was carried out in the same manner as in Reference Example 2, thereby giving 3-(4-hydroxyphenyl)-2-furancarboxylic acid. A reaction and treatment was further carried out in the same manner as in Reference Example 1, thereby giving the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[Cl:26])=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[Cl:26])=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:36](=[O:37])[C:30]2[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=2)[C:39]1=[O:38]
Reactant: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4Cl)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4Cl)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(2,3-dichlorophenyl)benzoxazole (238 mg, 0.60 mmol) and 1,2,4-benzenetricarboxylic anhydride (119 mg, 0.60 mmol) the title compound was obtained (191 mg, 57%). 1H NMR (DMSO) δ 8.46(dd, 1H), 8.35(m, 3H), 8.13(d, 1H), 7.84(m, 2H), 7.70(m, 1H), 7.47(m, 4H), 3.87(s, 3H). MS 560 m/z (M+H)+.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([C:9]2[C:10](=[O:20])[N:11]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH:12]=[CH:13][C:14]=2O)[CH2:8][CH2:7]1>CN(C=O)C>[Br:3][C:14]1[CH:13]=[CH:12][N:11]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:10](=[O:20])[C:9]=1[CH:6]1[CH2:8][CH2:7]1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1c(C2CC2)c(O)ccn1CC1CC1
Solvent: CN(C)C=O
Product: O=c1c(C2CC2)c(Br)ccn1CC1CC1
Temperature: 110 °C

Procedure:
Phosphorus oxybromide (2.4 g, 8.28 mmol) was added to a solution of intermediate D35 (0.85 g, 4.14 mmol) in DMF (60 ml), and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath, the solution was partitioned between water and EtOAc. The mixture was extracted with EtOAc (3×200 ml), the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D36 (0.99 g, 89%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[N:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[N:43]=[N:42][N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnnn4CC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnnn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-ethyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.45 g) in methylene chloride (13.5 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.12 g) in methylene chloride (9.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-ethyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 242) (221 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To a solution of 742 mg (2.5 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 50 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg (56.7%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1020.