Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=1
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nnc(C(F)(F)F)s2)c1
Temperature: 80 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.032 g, 0.1 mmol), 2-chloro-5-(trifluoromethyl)-1,3,4-thiadiazole (0.019 g, 0.1 mmol) and K2CO3 (0.018 g, 0.13 mmol) in DMF was heated at 80° C. overnight. The mixture was purified via preparative-HPLC to obtain the title compound. ESI-MS (m/z): 466 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1.C[Al](C)C.CCCCCCC.[I:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([C:39](OCC)=[O:40])[CH:33]=[N:32]2>ClCCl.O>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:39]([C:34]1[CH:33]=[N:32][C:31]2[C:36](=[CH:37][CH:38]=[C:29]([I:28])[CH:30]=2)[N:35]=1)=[O:40])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCN(CCN)CCOc1cccnc1F
Reactant: CCOC(=O)c1cnc2cc(I)ccc2n1
Agent: C[Al](C)C
Solvent: O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a stirred solution of compound 5 (55 mg, 0.24 mmol) in anhydrous dichloromethane (3 mL) was added at 0° C., under argon, a 2.0 M trimethylaluminium solution in heptane (0.12 mL, 0.24 mmol). After 10 min, a solution of compound 9 (57 mg, 0.17 mmol) in anhydrous dichloromethane (2 mL) was added and the mixture was refluxed for 6.5 h. After cooling to room temperature, water (15 mL) was added. The mixture was decanted and the aqueous layer was extrated with dichloromethane (3×20 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue obtained was chromatographed (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 10 (84 mg, 0.16 mmol) as a brown oil. Yield 94%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.58; IR (CCl4) ν 1453, 1468, 1522, 1684, 2750-3000 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.12 (t, 3H, J=6.8 Hz), 2.76 (q, 2H, J=6.8 Hz), 2.89 (t, 2H, J=5.7 Hz), 3.03 (t, 2H, J=5.3 Hz), 3.64 (q, 2H, J=5.7 Hz), 4.15 (t, 2H, J=5.3 Hz), 6.99 (dd, 1H, J=4.8, 7.3 Hz), 7.23 (m, 1H), 7.59 (d, 1H, J=8.8 Hz), 7.64 (m, 1H), 8.00 (d, 1H, J=8.8 Hz), 8.43 (se, 1H), 8.57 (s, 1H), 9.61 (s, 1H); ESI-MS m/z 509.9 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH3:23])[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: Cc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 52 %

Procedure:
0.5 gm (1.7 millimols) of 3-benzyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were reacted in 5 ml of methylene chloride with a stoichiometric quantity (0.15 ml) of ethyl chloroformate for four hours at room temperature. After distilling off the methylene chloride and recrystallizing the residue from ether, the product was obtained with a yield of 52% of theory; m.p. 125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4ccc(OC)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2CCN(c3nc4ccc(C(=O)O)cc4nc3-c3ccc(F)cc3)CC2)cc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(4-methoxyphenyl)piperidin-1-yl)quinoxaline-6-carboxylate (123.9 mg, 0.24 mmol, 1.00 equiv, 93%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (52.6 mg, 1.31 mmol, 5.00 equiv) in water (3 mL), which was added dropwise with stirring. The resulting solution was stirred for overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 60 mg (52%) of 3-(4-fluorophenyl)-2-(4-(4-methoxyphenyl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](SC)=[N:8][C:6]=2[N:7]=1.O[O:20][S:21]([O-:23])=O.[K+].[CH2:25](Cl)Cl>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([S:21]([CH3:25])(=[O:23])=[O:20])=[N:8][C:6]=2[N:7]=1
Reactant: O=S([O-])OO
Reactant: ClCCl
Reactant: CSc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-(methylthio)-7-morpholinothiazolo[4,5-d]pyrimidine was dissolved in methanol. Oxone (2.2 eq) was added in water (10:1 ratio methanol:water). The solution was heated to 50° C. for 2.5 hours. One additional equivalent of oxone was added (if needed) and solution was stirred at 50° C. for an additional 1 hour. The solution was cooled to room temperature and methylene chloride was added. The resulting solid was filtered off and rinsed with methylene chloride. The organic solution was washed with saturated sodium bicarbonate solution (pH test neutral), dried with magnesium sulfate and concentrated to yield 5-chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2nnn[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1NN=C(c2ccc(Br)cc2)N1

Procedure:
4-Bromophenyltetrazole (225 mg; 1.0 mmol) and potassium carbonate (140 mg; 1.0 mmol) are dissolved in dimethylformamide (3 mL), and a solution of methyliodide (140 mg; 1.0 mmol) in dimethylformamide (1 mL) is added dropwise under stirring. After 2 hours reaction time at room temperature methyliodide (28 mg; 0.2 mmol) is added and the mixture is stirred further for 90 minutes. The reaction is then diluted with water (4 mL), the precipitated white solid is filtered off and is rinsed once with water. After drying under high vacuum the desired product is obtained as a 95:5 mixture of regioisomers (188 mg; 0.79 mmol).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1.CC([O:37]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:37][CH:17]1[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=1)[OH:32])([CH3:19])([CH3:18])[CH3:14]
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: Cc1ccc(C(O)C2OC2C(C)(C)C)cc1
Yield: 85 %

Procedure:
The product was prepared, by General procedure T using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.78 mL (1.55 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, 59 μL (0.50 mmol) p-tolualdehyde, 100 μL, (0.10 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 21 μL (0.10 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 85% yield (93 mg, 0.42 mmol). threo-diastereomer: White solid. m.p.: 36-39° C.; [α]D20=−40.0 (c=0.26, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.81 (s, 9H), 2.28 (s, 3H), 2.35 (br d, 1H, J=3.9 Hz), 2.78 (d, 1H, J=2.2 Hz), 2.97 (dd, 1H, J=5.5, 2.2 Hz), 4.39 (br t, 1H), 7.10 (d, 2H, J=7.8 Hz), and 7.22 (d, 2H, J=7.9 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 21.1, 25.7, 30.6, 59.4, 65.1, 74.1, 125.9, 129.2, 137.5, and 137.7 ppm; IR (film): 3416, 3095, 2957, 2867, 1614, 1514, 1482, 1463, 1417, 1393, 1365, 1260, and 1239 cm−1; HRMS-CI m/z 203.1431 [(M−OH)+; calcd for C14H19O: 203.1436]. erythro-diastereomer: White solid. m.p.: 65-68° C.; [α]D20=−58.2 (c=0.57, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.82 (s, 9H), 2.16 (br s, 1H), 2.28 (s, 3H), 2.95 (d, 1H, J=2.1 Hz), 2.97 (t, 1H, J=2.7 Hz), 4.76 (br s, 1H), 7.10 (d, 2H, J=7.7 Hz), and 7.19 (d, 2H, J=8.0 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): □ 21.2, 25.8, 30.4, 58.3, 62.8, 71.1, 126.5, 129.2, 136.8, and 137.9 ppm; IR (film): 3418, 3018, 2965, 2923, 2867, 1919, 1515, 1478, 1458, 1412, 1381, and 1322 cm−1; HRMS-CI m/z 203.1431 [(M−OH)+; calcd for C14H19O: 203.1436].
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH2:23][NH2:24])[C:17]=2[O:16][CH2:15][CH2:14]1.[NH2:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2>>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH2:23][NH:24][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([NH:25][CH2:26][C:27]5[CH:35]=[CH:34][CH:33]=[C:32]6[C:28]=5[CH:29]=[CH:30][NH:31]6)=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=3)[C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NCc1cccc2c1OCCO2
Reactant: NCc1cccc2[nH]ccc12
Product: c1cc(CNc2ccc3c(NCc4cccc5[nH]ccc45)cccc3n2)c2c(c1)OCCO2

Procedure:
The title compound, MS: m/e=437.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 2,3-dihydro-1,4-benzodioxin-5-ylmethylamine and 4-aminomethylindole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc(C)cc2)c1

Procedure:
4-Methylphenylboronic acid (161 mg) and ethyl 2-chloroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH3:18][C:19]1[C:24](B(O)O)=[C:23]([CH3:28])[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:18][C:19]1[C:24]([Pb+3:17])=[C:23]([CH3:28])[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Temperature: 40 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of lead tetraacetate (4.3 g, 9.7 mmol) in dry chloroform (15 ml) at 40° C. is added 3,5-dimethylbiphen-4-ylboronic acid (2.0 g, 8.8 mmol) in one portion under an atmosphere of nitrogen. The reaction mixture is stirred at 40° C. for 4 hours, and then is cooled to room temperature and filtered, washing the residual solid with chloroform (50 ml). The filtrate is filtered through a plug of potassium carbonate supported on diatomaceous earth and the filtrate is evaporated under reduced pressure to afford 3,5-dimethylbiphen-4-yllead triacetate as a brown oil (3.37 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[C:38]([F:37])[CH:39]=4)[CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The above free amine (1.23 g, 2.49 mmol, Example 65) and 3-fluorobenzaldehyde (0.62 g, 4.98 mmol) were placed in a 100 mL flask and sealed under nitrogen. Tetrahydrofuran (40 mL) and 0.31 mL of acetic acid (5.47 mmol, 2.20 equiv.) was added. The reaction was stirred at room temperature for 20 minutes, and then sodium triacetoxyborohydride (1.32 g, 6.22 mmol) was added and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogencarbonate (25 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residual dark brown oil (2.01 g) was purified by chromatography on a Biotage column (SiO2-F Flash Cartridge, 8 g, 32-63 μm, 60 A) eluting first with dichloromethane to remove the less polar contaminant, then using 2.5% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under reduced pressure. The title product (4-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-acetic acid ethyl ester was obtained as a light yellow solid (0.75 g, 50%). 1H NMR (300 MHz, d6-DMSO): □ 0.81-1.01 (m, 6H); 1.14-1.19 (t, 3H), 1.89-2.01 (m, 2H); 2.48 (s, 4H); 2.57-2.66 (m, 4H); 3.24 (s, 2H); 3.29-3.36 (m, 4H); 3.50-3.56 (m, 1H); 3.71-3.76 (dd, 1H); 4.03-4.10 (q, 2H); 4.94 (s, 1H); 6.62-6.71 (m, 3H); 6.97-7.19 (m, 4H); 7.29-7.43 (m, 5H); 9.35 (s, 1H). Calculated for C35H43FN4O4.0.12 CH2Cl2: C, 68.82; H, 7.11; N, 9.14; F, 3.10. Found: C, 68.85; H, 7.17; N, 9.11; F, 3.18.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([O:16]C)[CH:12]=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[C:32](O)(=O)CC>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][C:24]([CH3:28])([CH3:29])[C:25]([O:27][CH3:32])=[O:26])=[CH:4][CH:3]=1
Reactant: CCC(=O)O
Reactant: COc1cccc2c1c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Product: COC(=O)C(C)(C)Cc1cc2c(O)cccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound was prepared using methodology from Step A of Example 8 but substituting 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-4-methoxy indol-2-yl]-2,2-dimethylpropanoic acid (Step B of Example 20) for the propanoic acid in Example 8 (Step A).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].C[O:16][C:17](=[O:50])[C@@H:18]([CH2:45][C:46]([O:48]C)=[O:47])[NH:19][C:20](=[O:44])[C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C:27]1[O:28][C:29]([C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[NH:43])[NH2:42])=[CH:37][CH:36]=2)=[O:33])=[CH:30][CH:31]=1.Cl>O1CCOCC1.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:41]([C:38]1[CH:37]=[CH:36][C:35]([O:34][C:32]([C:29]2[O:28][C:27]([CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@@H:21]3[C:20]([NH:19][C@@H:18]([C:17]([OH:50])=[O:16])[CH2:45][C:46]([OH:48])=[O:47])=[O:44])=[CH:31][CH:30]=2)=[O:33])=[CH:40][CH:39]=1)(=[NH:42])[NH2:43]
Reactant: COC(=O)C[C@@H](NC(=O)[C@H]1CCCN1Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)o1)C(=O)OC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)c1ccc(OC(=O)c2ccc(CN3CCC[C@@H]3C(=O)N[C@H](CC(=O)O)C(=O)O)o2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
To the compound obtained in step 1 were added 4N hydrochloric acid in 1,4-dioxane and water (1/1), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (2 steps yield 5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[N:29]1[CH:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31][CH:30]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:35]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)=[O:36])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: O=C(O)c1cncnc1
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)c3cncnc3)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and pyrimidine-5-carboxylic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. MS: 513.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:11])[NH:9][NH:10][C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.Cl[C:14]([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:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].[C:35](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[Cl:1][C:2]1[C:7]2[C:8]([O:11][CH3:35])=[N:9][N:10]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: O=c1[nH][nH]c2cc(Cl)nc(Cl)c12
Reactant: O=C([O-])[O-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
4,6-dichloro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (1160 mg, 5.69 mmol) was dissolved in DMF (20 ml), charged with (chloromethanetriyl)tribenzene (1744 mg, 6.25 mmol) followed by sodium hydride (341 mg, 8.53 mmol) and allowed to stir at rt for 1 h. The tritylation was complete by LC/MS. The reaction was charged with potassium carbonate (1572 mg, 11.37 mmol) followed by iodomethane (0.533 ml, 8.53 mmol) and allowed to stir overnight at rt. The alkylation was complete by LC/MS. The reaction was charged with 40 mL water, cooled to 0° C. and the precipitate was filtered and washed 2×20 mL water. The yellow solid was dissolved in 20 mL DCM and poured onto a 100 g Biotage SNAP column and purified 5-25% EtOAc/hexanes to provide 4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (37B, 1.64 g, 3.56 mmol, 62.7% yield) as a white solid. MS: [M+H]+ m/z 460.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:35][CH2:36][CH2:37][C:38](O)=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]3[CH3:28])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC1CCCCN1CCCC(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2C)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(2-methylpiperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-(2-methylpiperidino)butyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (133 mg, 54.7%)
Reaction SMILES: [BH3-]C#N.[Na+].C([OH:9])(C)(C)C.I[CH:11]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=O>O>[C:14]1([CH2:13][CH2:12][CH:11]([OH:9])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)O
Reactant: CCCCC(I)CCc1ccccc1
Agent: O=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCCCC(O)CCc1ccccc1
Reaction time: 24 h
Yield: 55 %

Procedure:
A reaction vessel (30 ml, a two-neck, eggplant type flask) is subjected to nitrogen gas purging and NaBH3CN (0.5 mmol, 31.4 mg), Bu2(t-Bu)SnCl (0.0125 mmol, 4.1 mg, 3.5 μl) and tert-butanol (1 ml) are added. Then, 3-iodo-1-phenylheptane (0.25 mmol, 75.5 mg, 57.5 g 1) is added to the solution. The introduction of nitrogen gas is discontinued, a nitrogen gas-filled black butyl rubber balloon is set instead, and oxygen (0.375 mmol, 9 ml) is bubbled into the solution using a syringe. The reaction mixture is then incubated on an oil bath at 60° C. After 24 hours, heating is discontinued and the reaction mixture is diluted with pure water (10 ml) and extracted with ether (15 ml×4). The residue is purified by column chromatography (silica gel 2 g, ethyl acetate/hexane 20%) to provide 1-phenyl-3-heptanol (26.9 mg, 55%). 1H NMR revealed that the crude product comprised the alcohol/reduced compound/starting compound in a molar ratio of 56/28/16.