Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1)#[N:7].O>C(Cl)Cl>[C:6]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][S:1]([CH3:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(OCCCCO)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCCOc1ccc(C#N)cc1
Reaction time: 4 h

Procedure:
Mesylchloride (2.32 mL; 30 mmol) was added to a stirred 0° C. solution of 4-(4-cyanophenoxy)-1-butanol (5.2 g; 29.7 mmol; from step (c) above) and TEA (4.35 mL) in CH2Cl2 (50 mL), and the reaction mixture was stirred for 4 h. H2O (150 mL) was added and the organic layer separated, dried and concentrated to give the sub-title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:31])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][CH:17]([P:25](=[O:28])([OH:27])[OH:26])[S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:13]([F:29])[C@H:12]3[OH:30])[C:9]=2[N:10]=1.OO.S([O-])([O-])=[O:35].[Na+].[Na+]>O>[NH2:1][C:2]1[NH:3][C:4](=[O:31])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][CH:17]([P:25](=[O:27])([OH:26])[OH:28])[S:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:35])[C@@H:13]([F:29])[C@H:12]3[OH:30])[C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(Sc3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(S(=O)c3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
Compound 35.17 (15 mg, 0.032 mmol) was suspended in 3 mL water, and treated with 30% hydrogen peroxide (100 mL). The mixture was heated to 90° C. for 3 h and sodium sulfite (113 mg, 0.9 mmol) was added to quench the peroxide. The solvent was removed under reduced pressure and the residue was subjected to a reverse phase HPLC to give compound 35.18 (12 mg, 77% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([CH2:16][N:17]5[CH:21]=[N:20][CH:19]=[N:18]5)([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[N:17]1([CH2:16][C:9]23[CH2:15][CH:13]4[CH2:12][CH:11]([CH2:10]2)[C:7]([C:2](=[O:3])[CH3:1])([CH2:14]4)[CH2:8]3)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CC1(C23CC4CC2CC(Cn2cncn2)(C4)C3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)C12CC3CC1CC(Cn1cncn1)(C3)C2
Yield: 98.7 %

Procedure:
A stirred solution of 1-{[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl}-1H-1,2,4-triazole (2.6 g, 9.09 mmol) obtained from Step I and p-toluenesulfonic acid (0.16 g) in acetone (36 mL) was refluxed for 4 h. The volatiles were removed under reduced pressure and the residue was diluted with ethylacetate, washed with 10% aq. NaHCO3 and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain 1-[1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]non-3-yl]ethanone (2.2 g, 86% yield) as a viscous liquid. m/z (M+1) 246; 1H NMR (CDCl3) 300 MHz δ 7.99 (s, 1H), 7.93 (s, 1H), 4.10 (s, 2H), 2.75-2.65 (m, 1H), 2.49-2.42 (m, 1H), 2.16 (s, 3H), 2.0-1.45 (m, 10H). 13C NMR (CDCl3) 75 MHz δ 211.0, 151.6, 143.6, 61.6, 56.9, 48.2, 45.9, 45.7, 42.6, 41.9, 37.3, 36.6, 26.3.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.[OH-].[K+].O>CCO>[CH:14]1([O:13][C:5]2[C:6]([CH3:12])=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[C:3]([OH:18])=[O:2])[CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(CO)cc(C)c1OC1CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CO)cc(C(=O)O)c1OC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
2-Cyclobutoxy-5-hydroxymethyl-3-methyl-benzoic acid methyl ester (410 mg, 1.64 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.90 g, 32.8 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 1 h then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with conc. HCl then extracted with EtOAc (3×10 mL). The combined organic layers are dried over anhydrous MgSO4 and concentrated in vacuo to give product (284) as viscous yellow oil (387 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[NH:35][C:34]=2[CH:41]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[C:23]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[NH:35][C:34]=3[CH:41]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: Fc1cccc(OCCCOCc2ccccc2)c1Nc1nc(Cl)ncc1Cl
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCCCOCc4ccccc4)n3)cc2N1

Procedure:
8-{4-[2-(3-Benzyloxy-propoxy)-6-fluoro-phenylamino]-5-chloro pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from [2-(3-Benzyloxy-propoxy)-6-fluoro-phenyl]-(2,5-dichloro-pyrimidin-4-yl)-amine and 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound was isolated as a white solid (25 mg, 17%), HPLC 99% purity, LCMS: 564.25 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.41 (s, 1H), 9.12 (s, 1H), 8.61 (s, 1H), 8.11 (s, 1H), 7.33-7.23 (m, 4H), 7.19-7.15 (m, 3H), 6.98-6.89 (m, 3H), 6.82 (d, J=8.3 Hz, 1H), 4.26 (s, 3H), 4.06-4.03 (m, 2H), 3.34-3.31 (m, 2H), 2.04-1.95 (m, 4H), 2.00-1.81 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CCCCCC>[C:1]([C:5]1[O:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:19])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)O)o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C2CC2C(=O)Cl)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylic acid (3.6 g, 0.017 mol) and oxalyl chloride (4.4 g, 0.035 mol) in hexane (40 ml) was stirred at room temperature for 2 hours and then warmed at 60° C. for 3 hours. The hexane and excess oxalyl chloride were removed in vacuo to give 2-(5-t-butylfuran-2-yl)-cyclopropanecarbonyl chloride (3.9 g, 100%) as a pale yellow liquid which was used in the next stage without further purification.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:32]([NH:34][CH3:35])=[O:33])=[N:27][C:28](Br)=[CH:29][CH:30]=1.[CH2:36]([O:43][CH2:44][C:45]([F:62])([F:61])[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:24][C:25]1[C:26]([C:32]([NH:34][CH3:35])=[O:33])=[N:27][C:28]([C:50]2[CH:49]=[N:48][N:47]([CH2:46][C:45]([F:62])([F:61])[CH2:44][O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:51]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2cnn(CC(F)(F)COCc3ccccc3)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CC(F)(F)COCc3ccccc3)c2)ccc1N
Yield: 63.6 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 359 mg, 1.56 mmol) and 1-[3-(benzyloxy)-2,2-difluoropropyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 59E, 650 mg, 1.72 mmol) to afford 398 mg of the title compound (64%). MS (ESI): m/z=402.16 [M+H]+. UPLC: tR=0.93 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([C:26]2[N:30]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=4[N:3]=3)[CH:29]=[CH:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1cccc(-c2ncc[nH]2)c1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cccc(Br)c3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 26, with Intermediate C instead of Intermediate B and with 2-(3-bromophenyl)-1H-imidazole instead of 2-phenyl-1H-imidazole. LCMS: 455.0 m/z (M+H)+; ret. Time: 4.34 min (Analytical Method D).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([NH:8][O:9][CH3:10])=[O:7])[NH2:2].[I:15][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=1)[C:19]([C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[O:20].CCOC(C)=O>CCO>[NH2:23][C:22]1[N:1]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=2[CH3:14])[C:6]([NH:8][O:9][CH3:10])=[O:7])[N:2]=[CH:24][C:21]=1[C:19](=[O:20])[C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([I:15])[CH:17]=1
Reactant: CONC(=O)c1ccc(C)c(NN)c1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Temperature: 67.5 °C
Yield: 55 %

Procedure:
To a stirred solution 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (116 mg, estimated 0.14 mmol) in EtOH (10 ml) was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 3 (59 mg, 0.14 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and mixture was heated (bath T=65-70° C.) for 4 hr, when additional 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (80 mg, 0.11 mmol) was added and the mixture was heated at the same temperature for 27 hr. It was cooled to room temperature, concentrated and redissolved in EtOAc before it was washed with water and brine, dried over Na2SO4, concentrated to give a crude semisolid. The mixture was then purified by flash chromatography, eluting with 1:1 EtOAc/hexanes to remove impurities then 100% EtOAc give 3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide 4 as an off-white solid (38 mg, 0.08 mmol, 55%). HPLC (6 minute gradient) tR 3.49 min; MS m/z 476.96 [M+H]+; 1H NMR (CD3OD, 300 MHz) δ 8.10 (s, 1H), 7.95 (d, J=8.0, 1H), 7.88 (d, J=8.0, 1H), 7.82 (m, 2H), 7.78 (s, 1H), 7.58 (d, J=8.0, 1H), 7.33 (t, J=7.8, 1H), 5.02 (s. 3H), 2.33 (s, 3H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 189.3, 154.3, 143.5, 143.3, 142.0, 138.3, 137.4, 133.5, 132.9, 132.0, 130.4, 128.8, 128.4, 104.8, 95.4, 64.8, 18.2 ppm.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH2:23][CH3:24])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH2:23][CH3:24])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: CCCC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CCCC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 51.6 %

Procedure:
Hydrogenolysis of 250 mg of 5-[(1,1′-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-propyl-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 100 mg (52% yield) of a white powder: mp 203-204° C. dec.(acetone/CHCl3/hexanes). 1H NMR (acetone-d6) δ 7.65-7.40 (m, 9H), 2.25-1.95 (m, 2H), 1.45-1.10 (m, 2H), 0.95 (t, J=6.9 Hz, 3H). Anal Calcd for C19H18O4+0.125 H2O: C, 73.01; H, 5.88. Found: C, 72.99; H, 5.86.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:19]([F:22])([F:21])[F:20])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]2[C:15](O)=[O:16].CCN(CC)CC.Cl.[F:31][C:32]([F:51])([F:50])[C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)=[O:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[F:51][C:32]([F:50])([F:31])[C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]2[CH2:49][CH2:48][N:47]([C:15]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][C:19]([F:22])([F:20])[F:21])[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=3)=[O:16])[CH2:46][CH2:45]2)[CH:38]=1)=[O:34]
Reactant: COCCn1cc(C(=O)O)c2c(OC(F)(F)F)ccc(F)c21
Reactant: O=C(NCc1ccc(F)c(C2CCNCC2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)C(F)(F)F)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 8 (19.1 g, 59.6 mmol), Et3N (24.8 mL, 177.9 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride (11, 26.4 g, 77.5 mmol) (14), and EDCI (17.1 g, 89.3 mmol) in CH2Cl2 is stirred at rt overnight. Both TLC and LC/MS indicate that the reaction is completed. The mixture is partitioned between H2O and CH2Cl2. The two layers are separated, and the organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (40/60 to 0/100) as eluant to give 9 (36 g, 99%) as a white foam. 1H NMR (CDCl3) δ 7.37 (s, 1H), 7.20-7.10 (m, 2H), 7.10-6.85 (m, 4H), 4.95 (br s, 1H), 4.60-4.35 (m, 4H), 3.90 (br s, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.32 (s, 3H), 3.25-2.70 (m, 3H), 2.05-1.50 (m, 4H); 19F NMR (CDCl3) δ −57.54 (s, 3F), −75.39 (s, 3F), −119.31 (s, 1F), −134.96 (d, J=11.3 Hz, 1F); MS 608 (M+1, 100%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:27].[Na+]>[Ag]=O>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:27])=[O:21])=[CH:22][CH:23]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [OH-]
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=O)cc1
Agent: O=[Ag]
Agent: [Na+]
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
The above compound was prepared from 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzaldehyde by heating with silver oxide in the presence of 1N sodium hydroxide solution for 20 minutes in a steam bath, subsequent acidification with 2N sulfuric acid at a pH of 5, extraction with ethyl acetate, and purification by column chromatography on silica gel (toluene/acetone=1:1).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[OH-:38].[K+].C1(C)C=CC=CC=1>C(O)C>[CH2:25]([O:38][C:10]1([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH2:11]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCBr
Reactant: CCCCCCC(C)Oc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC1(OC(C)CCCCCC)C=CC(N=Nc2ccccc2)=CC1

Procedure:
The above crude product of 4-(1-methyl-heptyloxy)-4'-hydroxy-azobenzene (16.5 g) was heated with lauryl bromide (16 g) in ethanol in the presence of KOH (3.6 g) under reflux for 10 hours, followed by passing a toluene solution of the product through an alumina chromatographic column and recrystallizing from heptane to obtain 4'-dodecyloxy-4'-(1-methyl-heptyloxy)-azobenzene
Reaction SMILES: O1CCC(N2C=C([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)C=N2)CC1.[C:31]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Nc1cc(-c2cncc(-c3cnn(C4CCOCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CC(C)(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Product: CC(C)(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
This compound is prepared analogously to 5″-[1-(Tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 2.156) by replacing 1-(tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Intermediate B18) with 4-((4-tert-butylpiperazin-1-yl)methyl)phenylboronic acid (Intermediate B10).
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 1.78 mmol) was dissolved in a mixture of MeCN/H2O/HCl 15 mL/15 mL/2 mL at 0° C. A solution of NaNO2 (0.185 g, 2.68 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.8 g, 17.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.528 g) as a yellow oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:17]2[C:24]([I:25])=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.[C:26]([N:33]1[CH2:36][CH:35](O)[CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[C:17]2[C:24]([I:25])=[CH:23][N:22]([CH:35]3[CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:36]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(Cl)ncnc32)C1
Reaction time: 1 h
Yield: 68.8 %

Procedure:
DIAD (1.41 ml) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), N-Boc-3-hydroxyazetidine (930 mg), and triphenylphosphine (1.85 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. After concentrating, the reaction mixture was washed with ethyl acetate to obtain the title compound as a white solid (1.07 g). Physical properties: m/z [M+H]+ 435.0
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].[Cl:33]C(OCCCl)=O.[C:40]([O:43][CH2:44][CH3:45])(=[O:42])C>CC1CCCO1>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:40]([O:43][CH:44]([Cl:33])[CH3:45])=[O:42])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(Cl)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of aripiprazole (2.0 g, 4.46 mmol) in 2-methyltetrahydrofuran (50 mL) was added NaH (357 mg, 8.92 mmol). The reaction was stirred overnight at room temperature then chloroethyl chloroformate (1.46 mL, 13.38 mmol) was added. Further 2-methyltetrahydrofuran (10 mL) was added to aid stirring. The reaction was stirred overnight at room temperature. The reaction was cooled to 0° C., diluted with ethyl acetate (50 mL) and quenched with aqueous saturated NaHCO3 (50 mL). The reaction was extracted with ethyl acetate (3×50 mL). The combined organics were dried (MgSO4) and concentrated to give 1-chloroethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 2.22 g) as a 3:2 mixture of aripiprazole/product. The product was taken onto the next step without purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[F:25][C:26]1[C:27]([NH2:41])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[NH2:41][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:31][C:26]=1[F:25]
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(N)c(F)c2)OC1(C)C
Product: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)c(F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H) and 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (stage 142.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.07 min (Method A); M+H=418 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.05-8.01 (m, 1H), 7.91-7.84 (m, 2H), 7.47-7.42 (m, 1H), 7.35-7.32 (m, 1H), 6.49 (s, 2H), 3.83 (s, 3H), 3.58 (s, 3H), 2.07 (s, 3H), 1.90 (s, 3H))