Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14](=[O:32])[C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].F[C:34]1[CH:47]=[CH:46][C:37]([C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=1>O>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:43]2[CH:44]=[CH:45][C:40]([C:38](=[O:39])[C:37]3[CH:46]=[CH:47][CH:34]=[CH:35][CH:36]=3)=[CH:41][CH:42]=2)=[CH:27][CH:26]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 23.6 %

Procedure:
To a solution of N,N-Dimethylformamide (DMF) (3.16 mL) and potassium carbonate (0.222 g, 1.605 mmol) was added Boc-D-Tyrosine-Methyl ester (0.158 g, 0.535 mmol) and 4-Fluorobenzophenone (0.160 g, 0.802 mmol) at 100° C. under an atmosphere of nitrogen for 42 hours. The mixture was poured into 30 mL water solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.060 g, 24%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 2.99-3.17 (m, 2H), 3.71-3.74 (m, 3H), 4.53-4.61 (m, 1H), 4.96-5.16 (m, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.97-7.03 (m, 4H), 7.16 (d, 2H, J=8.4 Hz), 7.46-7.50 (m, 2H), 7.56-7.58 (m, 1H), 7.77-7.83 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24]>CO.CCOCC>[ClH:24].[ClH:24].[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Reaction time: 2 h

Procedure:
2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (1.03 g, 3.23 mmol) was dissolved in methanol (25 mL) and a solution of 2N hydrochloric acid in ether (8 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (0.92 g). MS 219 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.01 (dd, J=1, 6 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=6, 8 Hz, 1H), 4.60 (m, 1H), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq, J=4, 13 Hz, 2H), 2.12 (d, J=13 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1F.[NH2:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1[O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccnn1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Product: CS(=O)(=O)c1cccc(F)c1Oc1ccc2ncnc(Nc3cccnn3)c2c1

Procedure:
The compound of Example 143 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-difluoro-3-(methylsulfonyl)benzene, 3-amino-pyridazine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [C:1]1([C:7]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:1]1([C:7](=[N:8][O:9][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: ON=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone oxime (Example 39) (100 mg, 0.42 mmol) and sodium hydride (17 mg of a 60% in mineral oil, 0.43 mmol) in N,N-dimethylformamide (4 mL) was stirred for 0.5 h. tert-Butyl bromoacetate (60 μL, 0.41 mmol) was added dropwise and the reaction mixture was heated at 60° C. for 3 h. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (10 mL) and extracted with diethyl ether (3×15 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over sodium sulfate and concentrated to an oil. Purification by Biotage chromatography (1-10% methanol in methylene chloride) provided tert-butyl [[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]acetate as a tan solid: mp 47-52° C.; 1H NMR (500 MHz, CDCl3) δ 1.46-1.61 (9H, m), 4.63 (0.66H, s), 4.85 (1.33H, s), 6.37 (0.33H, s), 6.53 (0.66H, s), 7.26-7.62 (6H, m), 8.23-8.28 (0.66H, m), 8.84 (0.33H, br s), 8.96 (1H, br s), 9.13 (0.33H, br s), 11.04 (0.66H, br s); ESI MS m/z 352 [C20H21N3O3+H]+; HPLC (Method A) 97.8% (AUC), tR=18.3 and 18.5 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[N:25]([CH:28]([CH3:30])[CH3:29])=[C:26]=[O:27]>O1CCCC1>[CH:28]([NH:25][C:26]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:27])([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (65 μL), is dissolved in tetrahydrofurane (2 mL), treated with triethylamine (890 μL) and 2-isocyanatopropane (420 μL) and the mixture is stirred for 12 hours at 80° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[NH:33][CH:34]=[CH:35][C:28]=12.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[NH:33][CH:34]=[CH:35][C:28]=23)[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: Brc1ccnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.5 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (Ref Org. Lett. 5(26), 5023-5024, 2003) (6.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.25 mmol) in a 1:1 solution of 1,4-dioxane (12 mL):2M potassium carbonate (12 mL) was stirred for 18 h at 100° C. in a sealed tube. Upon cooling to room temperature, product precipitated out of solution which was filtered and dried to provide the title product as a light yellow powder (80%). ESMS [M+H]+: 334.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c2cc(F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c2cc(F)ccc2c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a mixture of 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (4.6 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol) and acetone (100 mL) was added benzyl bromide (5.47 g, 32 mmol). After being stirred vigorously at reflux for 4 hours under a nitrogen atmosphere, the resulting mixture was cooled to room temperature, and filtered. The organic solution was concentrated in vacuo to give 4-benzyloxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (5.85 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=2[OH:12])[CH2:5][CH2:4][CH2:3]1.[CH3:16][Br:17]>C(#N)C>[Br-:17].[CH3:1][N+:2]1([CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=2[OH:12])[CH2:5][CH2:4][CH2:3]1
Reactant: CBr
Reactant: CCCc1ccc2c(c1O)N(C)CCC2
Solvent: CC#N
Product: CCCc1ccc2c(c1O)[N+](C)(C)CCC2
Product: [Br-]
Reaction time: 90 h
Yield: 76.1 %

Procedure:
Into a tube, one introduces 7.5 g of N-methyl-1,2,3,4-tetrahydro-7-propyl-8-hydroxyquinoline (i.e. 0.035 mole) and 4 g of methyl bromide (i.e. 0.035 mole). One adds 10 ml of acetonitrile, one seals the tube and one heats in an oil bath, at 70°C, for 90 hours. After cooling, one dries the compound that is formed, washes with anhydrous ether, and recrystallizes in boiling isopropanol (1 g of product, 2 ml of alcohol). One collects whitish crystals, which one washes again with ether, then one dries the resulting quaternary salt in a drier over sulfuric acid. One obtains 8 g of product, i.e. a yield of 735/1000.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[N:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[N:39][CH:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS 335255-65-7] (302 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (420 mg, 80%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>O1CCCC1.CS(C)=O>[Br:33][C:34]1[CH:35]=[C:36](/[CH:37]=[CH:13]/[CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CC/C=C/c1cccc(Br)c1
Reaction time: 18 h

Procedure:
A 1M solution of potassium tert-butoxide in tetrahydrofuran (80 mL) was added dropwise to (3-carboxypropyl)triphenylphosphonium bromide (17 g, 40 mol) in anhydrous DMSO (20 mL) under nitrogen at 24° C., and the solution was stirred 30 min. before addition of 3-bromobenzaldehyde (4.7 mL, 40 mmol). After several minutes a precipitate was observed and an additional 20 mL of DMSO was added to aid solvation, and the reaction was stirred 18 h. The solution was poured onto water (120 mL) and washed with chloroform. The aqueous layer was acidified with conc. HCl and extracted with chloroform (3×250 mL). The organic phase was concentrated and applied to a 65i Biotage silica gel column, gradient elution from 15-65% B (A=Hexanes; B=ethyl acetate) over 2 L to give J.1, (E)-5-(3-bromophenyl)pent-4-enoic acid, 8.2 g (82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (t, J=1.5 Hz, 1H), 7.30 (dt, J=7.7, 1.5 Hz, 1H), 7.2-7.16 (m, 1H), 7.12 (t, J=7.7 Hz, 1H), 6.40-6.32 (m, 1H), 6.23-6.14 (m, 1H), 2.52 (s, 4H). LC (Cond.-J1): RT=2.0 min; LRMS: Anal. Calcd. for [M−H]− C11H11BrO2: 252.97; found: 252.98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][NH:19][C:20]3[C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][N:23]=[C:22]4[N:31]([CH3:35])[N:32]=[C:33]([CH3:34])[C:21]=34)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][NH:19][C:20]3[C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=[C:22]4[N:31]([CH3:35])[N:32]=[C:33]([CH3:34])[C:21]=34)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1NCS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)c2ncc(C(=O)O)c(NCS(=O)(=O)c3ccc(Oc4ccc(Cl)cc4)cc3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A mixture of 1.90 g (3.69 mmol) of the preceding ester and 4.05 ml (4.06 mmol) of 1 N KOH in 15 ml of tetrahydrofuran was stirred at room temperature for 2 days and then 0.75 ml of 1 N KOH was added and the mixture was refluxed overnight. The solvent was removed under vacuum and the toluene (25 ml) added to the residue and removed under vacuum. The residue was triturated with ethyl acetate and the solid filtered and dried under vacuum to give 1.6 g of 4-{[4-(4-chlorophenyloxy) benzenesulfonyl]methylamino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, potassium salt. Following the procedure of Example 52, 1.60 g of the preceding potassium salt was converted to the title compound to obtain 1.82 g of solid. This solid was purified on thick layer silica gel plates with 4% CH3OH in ethyl acetate as solvent to give 0.59 g of light yellow solid, m.p. 120° C. dec.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>CO.O>[CH2:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: NCC(=O)O
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCNCC(=O)O
Yield: 41.6 %

Procedure:
A! A 32% solution of sodium hydroxide (123 ml) was added to a mixture of glycin (50 g, 0.66 mole) and butyl bromide (75 ml, 0.66 mole) in methanol (600 ml) and water (600 ml), the reaction mixture was refluxed for 24 hours, then the solvend was evaporated under vacuum. The crude was dissolved in ethanol, the salts were filtered off 3 times, and the solvent was evaporated under vacuum. The resulting crude was purified by flash chromatography (eluent: chloroform/methanol/concentrated ammonia 6:4:0.5) yielding 36 g of N-butyl-glycine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH3:20])[O:9][CH:10]2[C:15](OCC)=O.C[N:22]([CH:24]=O)[CH3:23].IC.CCOC(C)=O.C(Cl)Cl.[CH2:37]([N:39](CC)CC)C>>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH3:20])[O:9][C:10]2([C:23]1[NH:39][CH2:37][CH2:24][N:22]=1)[CH3:15]
Reactant: CCOC(=O)C1O[C@H](C)Cc2c(OC)cccc21
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1C[C@@H](C)OC2(C)C1=NCCN1
Reaction time: 2 h

Procedure:
The mixture of NaH (0.17 g), (3R)-ethyl 5-methoxy-3-methylisochroman-1-carboxylate (0.3 g) and DMF (7 ml) was stirred for 2 hrs in ice-bath temperature. Iodomethane (0.7 ml) was added and the mixture was stirred at ambient temperature for 16 hrs. The intermediate (3R)-ethyl 5-methoxy-1,3-dimethylisochroman-1-carboxylate (0.4 g) was purified with separation method A and the title compound was synthesized using the procedure of synthesis method A step 3 and separation method E (EtOAc/DCM/triethyl amine 10/20/1). (Yield 0.3 g).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:26]([CH3:27])[C:25]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[CH3:33])=[N:24][N:23]=1>>[ClH:17].[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:26]([CH3:27])[C:25]([C:28]4[O:32][CH:31]=[N:30][C:29]=4[CH3:33])=[N:24][N:23]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2]
Reactant: CCc1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ncoc1-c1nnc(SCCCCl)n1C
Product: CCc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2ocnc2C)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 rom 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.28 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole and was obtained as a faint yellow slightly hygroscopic solid (0.07 mmol).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13]([CH3:21])=[C:12]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[NH4+:11].[OH-:2].[Cl:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=1)[C:12]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[C:13]2[CH3:21]
Reactant: COC(=O)c1ccc(Cn2c(-c3cccnc3)c(C)c3cc(Cl)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc12
Product: [NH4+]
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
4-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid methyl ester (Example 11, 200 mg, 0.51 mmol) in methanol (5 mL) is added to 5M aqueous NaOH (1 mL, 5 mmol) and the mixture is stirred at room temperature for 5 h. Concentrated HCl (4.4 mL) is added to neutralize the reaction mixture and the solvents are removed in vacuo. The residue is redissolved in methanol and purified by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% NH4OH in acetonitrile gradient to afford 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid. 1H NMR (400 MHz, MeOD) δ ppm 2.25 (s, 3H), 5.34 (s, 2H), 6.82 (d, J=8.1 Hz, 2H), 7.15 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.50 (dd, J=7.7, 4.9 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.78-7.80 (m, 1H), 7.81 (d, J=8.1 Hz, 2H), 8.50 (s, 1H), 8.56 (br. s, 1H). HRMS (ESI) m/z 377.1072 [(M+H)+ Calcd for C22H18ClN2O2: 377.1057].
Reaction SMILES: C[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=2)[CH:5]=[CH:4][CH:3]1[OH:16].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]3=2)[CH:20]=[CH:19][CH:18]=1.[CH2:31]1[CH2:37][S:34](=[O:36])(=[O:35])[O:33][CH2:32]1.CI>>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=2)[CH:5]=[CH:4][CH:3]=1.[CH3:3][O:16][C:22]1[CH:23]=[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]2=[C:26]2[C:21]=1[CH:20]=[CH:19][CH2:18][N:17]2[CH2:32][CH2:31][CH2:37][S:34]([OH:33])(=[O:36])=[O:35]
Reactant: O=S1(=O)CCCO1
Reactant: CN1c2c(ccc3ccccc23)C=CC1O
Agent: c1ccc2c(c1)ccc1cccnc12
Solvent: CI
Product: COc1cc2ccccc2c2c1C=CCN2CCCS(=O)(=O)O

Procedure:
Compound 13 was synthesized according to the procedure outlined above in Example 3 for the synthesis of the N-methyl-hydroxybenzoquinoline derivative 15. Compound 13 was then alkylated according to the general amino group alkylation procedure described above in Example 3, this time using 1,3-propane sultone as the alkylating agent rather than MeI, to give a 5-methoxybenzoquinoline-N-propanesulfonic acid intermediate 16 (1HNMR: CD3OD d 7.94 (d, 1 H, J=8.7 Hz), 7.65 (d, 1 H, J=8.4 Hz), 7.32 (t, 1 H), 7.27 (t, 1 H), 6.85 (s, 1 H), 4.89 (s, 3 H), 3.20 (m, 2 H), 3.08 (bt, 2 H, J=6 Hz), 2.91 (m, 2 H), 2.72 (t, 2 H, J=6.6 Hz), 2.33 (m, 2 H), 1.89 (m, 2 H). Subsequent methoxy group deprotection of compound 16 by the general boron tribromide procedure described above in Example 1 resulted in the 3-(5-hydroxybenzoquinolin-1-yl) propanesulfonic acid 17.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.CC(C)=[O:24]>>[F:21][C:2]([F:1])([F:20])[C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:24])=[O:13])=[CH:14][CH:15]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Product: O=C(O)c1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol) in acetone (25 mL) was added Jones's reagent (1.0 mL, 2.0 M) at 0° C. After stirring at room temperature for 2 h, the mixture was partitioned between EtOAc and saturated NaHCO3 solution. After usual workup, the crude material was separated by silica gel chromatography (50% Hexane/EtOAc to EtOAc) to afford the intermediate acid 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzoic acid as a while solid (490 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[C:2]#[CH:3].[CH2:15]([Sn:19]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])N(C)C)[CH2:16][CH2:17][CH3:18].[CH2:31]([N:38]=[N+:39]=[N-:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCCCCC>[CH2:31]([N:38]1[C:2]([CH2:1][N:4]2[C:8](=[O:9])[C:7]3[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:14])=[C:3]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][CH3:30])[N:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-Propargylphthalimide (2.35 g mg, 12.7 mmol) was added to 1,1,1-tributyl-N,N-dimethylstannanamine (4.23 mg, 12.7 mmol) in hexane (3.0 mL) and stirred in a sealed vial at 70° C. for 2 hours. The mixture was cooled to ambient temperature and the vial was stirred unsealed for 10 minutes. Benzyl azide (2.0 mL, 16.0 mmol) was added and the vial was resealed and heated to 130° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 609.3 (M+H)+.