Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH:4]([O:10][C:11](=[O:13])[CH3:12])[CH2:5][O:6][C:7](=[O:9])[CH3:8].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:11]([O:10][CH:4]([CH2:5][O:6][C:7](=[O:9])[CH3:8])[CH:3]=[CH:2][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCC(CC(Br)c1cnccn1)OC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCC(C=Cc1cnccn1)OC(C)=O
Yield: 66.2 %

Procedure:
7.0 g of 2-(1-bromo-3,4-diacetoxybutyl)pyrazine (4102 and 4103) was dissolved in 100 ml of toluene, 3.3 g of 1,8-diazabicyclo [5.4.0]undec-7-ene added under an argon atmosphere and the solution heated overnight at 65°-70°. It was then cooled, the toluene solution decanted and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate) to yield 3.5 g of 2-(3,4-diacetoxy-1-butenyl)pyrazine (4104) as a pale yellow oil. UV EtOH max: 240 (4.14), 292 (3.85), 298 (3.86).
Reaction SMILES: C1(C(=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([Cl:31])[C:27](Cl)=[N:28][CH:29]=1>CN(C=O)C>[NH2:14][CH:15]([C:27]1[C:26]([Cl:31])=[CH:25][C:24]([Br:23])=[CH:29][N:28]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(N)c1ncc(Br)cc1Cl
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 1H), 5.09 (s1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381, 3306, 1742, 759, 523 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](F)=[CH:8][CH:9]=2)[N:4]([CH3:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:20][CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:12])[CH:3]=1
Reactant: Cn1cc(Br)c2ccc(F)nc21
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccc(OCc3ccncc3)nc21
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 3-bromo-6-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (0.4 g, 1.74 mmol) and pyridine-4-ylmethanol (0.21 g, 1.93 mmol) in DMF (5.0 mL) is added portionwise sodium hydride (0.05 g, 2.11 mmol) at room temperature and the resulting reaction mixture is stirred for 1 h. The reaction is quenched with cold brine solution and extracted with EtOAc (4×100 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by crystallization from Et2O/pentane to give the title compound (0.300 g, 0.942 mmol) as an orange-red solid. MS (m/z): 318, 320 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.73 (s, 3H), 5.48 (s, 2H), 6.76 (d, 1H), 7.47 (d, 2H), 7.50 (s, 1H), 7.78 (d, 1H), 8.56 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.P([O-])(OCC)(SCC)=[S:14]>C1COCC1.O>[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])(=[S:14])[NH2:11]
Reactant: CCOP([O-])(=S)SCC
Reactant: COC(=O)c1cccc(C#N)c1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(N)=S)c1
Temperature: 80 °C
Yield: 102.4 %

Procedure:
Preparation H11, Step 2: A solution of 2 g (0.01 mol) of methyl-3-cyanobenzoate in 32 ml of THF and 8 ml of water was charged with 2.3 g (0.012 mol) of diethyl dithiophosphate and heated at 80° C. for 24 h. THF was removed and the residue was taken in ethyl acetate. The extract was washed with water and concentrated to afford methyl 3-carbamothioylbenzoate (2.0 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CNCCNC.O>[Cu].CS(C)=O>[CH3:10][S:11]([C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1)(=[O:13])=[O:12]
Reactant: Cc1cc(Cl)ncc1N
Reactant: CS(=O)[O-]
Agent: [Cu]
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(S(C)(=O)=O)ncc1N
Temperature: 150 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A mixture of 6-chloro-4-methyl-pyridin-3-ylamine (1.53 g, 11 mmol), sodium methanesulfinate (1.60 g, 16 mmol), copper catalyst (0.50 g, 0.99 mmol), and N1,N2-dimethylethane-1,2-diamine (0.214 mL, 2.0 mmol) in 20 mL DMSO was heated under microwave irradiation at 150° C. After 2 h, mixture was poured into ca. 200 mL water and extracted five times with ca. 200 mL AcOEt. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (AcOEt/hexane 5:1→AcOEt) to give 6-methanesulfonyl-4-methyl-pyridin-3-ylamine as a white solid (0.534 g, 27%). 1HNMR (DMSO-d6, 400 MHz) 32.4 (s, 3H), 3.08 (s, 3H), 6.08 (s, 2H), 7.59 (s, 1H), 7.97 (s, 1H). Exact mass calculated for C7H10N2O2S 186.05 found 187.0 (MH+).
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-:9])=O)[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][N:32](C)[CH2:33][CH2:34][CH2:35]N=C=NCC.CNCCC>ClCCl>[CH2:13]([O:12][C:10](=[O:11])[C:3]1[CH:4]=[C:5]([C:7](=[O:9])[N:32]([CH3:31])[CH2:33][CH2:34][CH3:35])[CH:6]=[C:1]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1)[CH3:14]
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)OCC)c1
Yield: 67.7 %

Procedure:
Stir a solution of diethyl 1,3,5-benzene tricarboxylate (2.47 g, 9.28 mmol), 1-hydroxybenzotriazole (1.38 g, 10.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.96 g, 10.2 mmol), N-methylpropylamine (1.04 mL, 10.2 mmol) in dichloromethane (50 mL) at room temperature overnight. Dilute with dichloromethane (300 mL) and extract the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated aqueous sodium chloride (50 mL). Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (2.02 g, 68%).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])[CH:2]=[CH2:3].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CCCCCC>[CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCc1ccc2ccccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 2-(2-propenyl)-1-naphthol (Example 118 Part A; 101.9 g, 0.550 mole), t-butyldimethylsilyl chloride (100.0 g, 0.660 mole), and imidazole (93.6 g, 1.375 mole) in N,N"-dimethylformamide was stirred at room temperature for 6.5 hours. It was then poured into saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with hexane. The residue was distilled at reduced pressure to provide the title compound (155.2 g, 95%), bp 135°-140° (0.1 torr).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:17]([Br:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:13]=1F>>[Br:11][C:12]1[C:17]([Br:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:13]=1[O:10][CH:9]1[CH2:8][NH:7][CH2:6][C:5]2[O:1][CH:2]=[CH:3][C:4]1=2
Reactant: Fc1ccc(Br)c(Br)c1Br
Reactant: OC1CNCc2occc21
Product: Brc1ccc(OC2CNCc3occc32)c(Br)c1Br

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3,4-tribromo-1-fluorobenzene instead of 1-fluoronaphthalene 1 to give the objective compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]3[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]4[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]4)[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:34][CH2:33]1
Reactant: NCC1CC1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CCl)cc3)c2C(F)(F)F)C1
Product: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CNCC4CC4)cc3)c2C(F)(F)F)C1
Yield: 98 %

Procedure:
The benzyl chloride (195) (34 mg, 0.075 mmol) and cyclopropylmethylamine (1 mL, 12 mmol) were heated to 50° C. for 18 h. The reaction mixture was cooled, excess amine was removed under reduced pressure and the residue partitioned between ethyl acetate and sodium hydroxide (1M). The organic phase was washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the crude product. Purification by SCX-2 cartridge afforded the title compound (197) as a colourless gum (36 mg, 98% yield).
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[NH4+].[Cl-].CCOCC>C1COCC1>[CH3:1][C@H:2]1[C@@:7]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc([C@]2(O)OCC(C)(C)N[C@H]2C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A solution of morpholin-2-one 15 (270 mg, 1.88 mmol) in anhydrous THF (1.9 mL) was cooled to −78° C. and treated with p-tolylmagnesium bromide (1.2 equiv., 2.26 mmol, 2.26 mL, 1 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. for 1.5 h, saturated aqueous solution of NH4Cl (30 mL) was added to the reaction vessel, and the mixture was allowed to warm to room temperature. Ether (30 mL) was added to the reaction flask, the organic layer was separated. The aqueous phase was extracted with ether (twice). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to give 271 mg (41%) of 4j as a yellow foam: [α]22D +21.2° (c 0.9, CHCl3); 1H NMR (CDCl3) δ 7.47 (d, 2H, J=8.2 Hz), 7.16 (d, 2H, J=8.0 Hz), 3.85 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.2 Hz), 3.20-3.07 (m, 1H), 2.35 (s, 3H), 1.39 (s, 3H), 1.08 (s, 3H), 0.81 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 129.6, 128.60, 128.49, 125.9, 103.2, 96.2, 69.4, 53.9, 53.4, 49.6, 27.3, 22.8, 16.5; LCMS (ESI) m/z 236.3 [(M+H)+, M=C14H21NO2].
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].N[C:28]1C=C2C(=C[CH:37]=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CCCC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:37][CH2:28][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: O=C(O)C(=O)CC1(c2ccccc2)CCCC1
Product: O=C(CC1(c2ccccc2)CCCC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclopentyl)-2-oxo-propionic acid, melting point 140-144° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:21]1COCC1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:21][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([F:20])=[C:4]([F:19])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3) (4.50 g, 12.4 mmol) in a 3:1 mixture of THF:MeOH (32 mL) was added (trimethylsilyl)-diazomethane (8.10 ml of a 2 M solution in hexanes) at room temperature. After stirring for 2 hours, the reaction mixture was quenched with acetic acid, diluted with EtOAc, and washed with water. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4.35 g (93%) of the desired methyl ester (4).
Reaction SMILES: [C:1]([O:5][O:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24]C1C=CC(C(C2C=CC(C(O)=O)=CC=2)=O)=CC=1>CCOCC.ClCCl>[C:1]([O:5][O:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][C:18]([O:24][CH3:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(=O)c2ccc(C(=O)OOC(C)(C)C)cc2)cc1

Procedure:
Tert-butyl-4-(4'-methoxybenzoyl)perbenzoate is prepared by the above discussed procedure for the preparation of t-butyl-4-benzoylperbenzoate, except that the acid employed is 4-(4'-methoxybenzoyl)-benzoic acid, and during the preparation, the corresponding acid chloride is dissolved in a mixture of ether and dichloromethane.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]2([CH2:11][CH2:10][N:9]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH2:8][CH2:7]2)[CH2:5]1)#[N:2].[Sn]([N:31]=[N+:32]=[N-:33])(C)(C)C>C1(C)C=CC=CC=1>[NH:31]1[C:1]([CH2:3][CH:4]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]3([CH2:11][CH2:10][N:9]([C:12]([NH:14][CH:15]4[CH:20]5[CH2:26][CH:4]6[CH2:5][CH:18]([CH2:17][CH:16]4[CH2:3]6)[CH2:19]5)=[O:13])[CH2:8][CH2:7]3)[CH2:5]2)=[N:2][N:33]=[N:32]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CCC1CC2(CCN(C(=O)NC3CCCCC3)CC2)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(Cc1nnn[nH]1)c1ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (30 mg, 0.075 mmol) in toluene (2 mL), Me3SnN3 (80 mg, 0.375 mmol) was added. The reaction mixture was stirred at 80° C. overnight. The mixture was concentrated. The crude product was purified by preparative HPLC to afford (±)-3-((1H-tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (15 mg, 45%). LC-MS Method 5 tR=1.28 min, m/z=447.3; 1H NMR (CD3OD): δ=1.62-1.69 (m, 2H), 1.71-1.86 (m, 4H), 1.89-2.24 (m, 13H), 2.56-2.68 (m, 1H), 3.09-3.29 (m, 3H), 3.49 (s, 1H), 3.66-3.74 (m, 1H), 3.1-3.90 (m, 1H), 3.99 (s, 1H), 4.09-4.21 (m, 2H), 7.27 (d, 1H), 7.30-7.49 (m, 3H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: Cc1cc(-c2nnnn2C)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnnn6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-bromo-3,5-dimethylphenyl)-1-methyl-1H-tetrazole and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.20 min; Mass spectrum (ESI+): m/z=529 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](O)([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[NH:20]=[N+:21]=[N-:22]>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:20]=[N+:21]=[N-:22])([CH3:11])[CH3:10]
Reactant: [N-]=[N+]=N
Reactant: CC(C)(O)c1c(F)cccc1F
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1c(F)cccc1F
Reaction time: 24 h

Procedure:
20.6 g (120 millimoles) of 2-(2,6-difluorophenyl)propan-2-ol are dissolved in 300 ml of hydrazoic acid solution (1N, in benzene) and 22.8 g (200 millimoles) of trifluoroacetic acid are added to this solution. After 24 hours at room temperature, the reaction solution is diluted with 500 ml of hexane, washed with water and then with sodium bicarbonate until free of acid and dried over sodium sulfate. The solvent is removed by evaporation and the residue is distilled, affording 2-(2,6-difluorophenyl)-2-azidopropane of bp15 =85°-87° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:23]1([NH2:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:29][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][CH:3]=1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-morpholinamine (CAN 4319-49-7) as starting materials; LC-MS (UV peak area/ESI) 100%, 415.0911 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[O:12]=[C:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:7]1[C:8]2[C:3](=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C:13]3=[O:12])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)C(=O)C1
Temperature: 130 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To 5-bromoisoquinoline (0.3 g, 1.442 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (0.289 g, 1.442 mmol) was added DMSO (4 mL), 1,10-phenanthroline (0.026 g, 0.144 mmol), K2CO3 (0.498 g, 3.60 mmol). The mixture was degassed for 10 min. to the above mixture was then added Cut (0.055 g, 0.288 mmol). The reaction was heated in a sealed tube in oil bath at 130° C. After 24 h, the reaction was incomplete. Cooled and degassed with Ar, added more Cut and heating was repeated. After 24 h, the reaction was quenched with dilute NH4OH (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). The product was purified by normal phase chromatography followed by prep. HPLC. After partitioning with saturated NaHCO3 (15 mL) and EtOAc (50 mL), the organic layer was washed with brine and dried (MgSO4) to afford 0.157 g (54%) of Intermediate 18A as a white solid with recovered starting material. MS (ESI) m/z: 328 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH2:29]>>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CC1CCCCC1N
Product: CC1CCCCC1Nc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with 2-methylcyclohexylamine to obtain 4-(2-methylcyclohexylamino)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, which is reacted with potassium ethoxide to yield the corresponding potassium salt, m.w., 448.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.C([O:12][C:13]1[CH:38]=[CH:37][C:16]([C:17]([NH:19][C:20]2[CH:28]=[C:27]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=1)(=O)C>O1CCCC1>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:28]=[C:27]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])=[CH:37][CH:38]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10 mg of potassium carbonate were added to a mixed solution of 1.0 mL of methanol and 1.0 mL of tetrahydrofuran containing 20 mg of 2-(4-acetoxybenzamido)-4-phenethylbenzoic acid and stirred at room temperature for 3 hours. After insoluble were removed by filtration, 3.0 mL of 10% citric acid aqueous solution was added and a solid substance was separated by filtration to obtain 15 mg of 2-(4-hydroxybenzamido)-4-phenethylbenzoic acid as white solid.