Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(N2C3=NC=CC=C3C=C2C([C:26]2[CH:38]=[CH:37][C:29]([C:30]([NH:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=2)=CC2CCCC2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:30]([NH2:32])(=[O:31])[C:29]1[CH:37]=[CH:38][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1
Yield: 318.6 %

Procedure:
A solution of 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (300 mg, 0.57 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5 mL, 5 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford N-tert-butyl-4-[2-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-benzamide (220 mg, quant.) as a white solid: LC/MS m/e calcd for C25H29N3O [M+H]+ 388.53, observed 388.2.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.O>CN(C=O)C>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][CH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:41]
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.6 %

Procedure:
To a solution of Intermediate A (179 mg, 1.10 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 120 mg, 3.00 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 92b (958 mg, 1.10 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The solution was cooled, water added, and the mixture extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-16% MeOH in DCM, to give the title compound as a brown gum (216 mg, 37%). LCMS (Method 3): Rt 3.08 min, m/z 536 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][NH:5][C:6](=[O:30])[N:7]([C@H:9]([CH2:15][O:16][C:17](=[O:29])[NH:18][C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:11][C:12]([O-:14])=O)[CH3:8].[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:63][C:64]1[NH:65][C:66]2[CH2:71][CH2:70][NH:69][CH2:68][C:67]=2[N:72]=1>CN(C=O)C>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:17](=[O:29])[O:16][CH2:15][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=2[Cl:1])=[O:30])[CH2:10][CH2:11][C:12]([N:69]2[CH2:70][CH2:71][C:66]3[NH:65][C:64]([CH3:63])=[N:72][C:67]=3[CH2:68]2)=[O:14])[N:20]=1
Reactant: Cc1nc2c([nH]1)CCNC2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)[O-])COC(=O)Nc1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc2c([nH]1)CCN(C(=O)CC[C@@H](COC(=O)Nc1cc3ccccc3cn1)N(C)C(=O)NCc1cccc(F)c1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a suspension of lithium (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentanoate (0.43 mmol) and HBTU (244 mg, 0.64 mmol) in DMF (5 mL) was added 2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine dihydrochloride. The resulting mixture was stirred at RT for 1 h, filtered, and purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(2-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)-5-oxopentyl isoquinolin-3-ylcarbamate (182.1 mg, 68% for two steps). LRMS (M+H+) m/z 622.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:20](=O)([O:26]C(C)(C)C)[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:21][C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
Ethyl 2-amino-4-thiazole-acetate (5.0 g, 26.8 mmol) and triethylamine (3.8 ml, 26.8 mmol) were dissolved in a dichloromethane (20 ml). Di-t-butyl carbonate (7.0 g, 32.2 mmol) was added to the solution under cooling with ice water. The mixture was stirred overnight at room temperature. After 18 hours, additional di-t-butyl carbonate (1.4 g, 13.4 mmol) was added, and the resultant mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resultant residue was dissolved in ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain 3.1 g of ethyl 2-t-butoxycarbonylamino-4-thiazole-acetate. A part (2.0 g, 7.0 mmol) of this compound was dissolved in a mixed solvent of ethanoltetrahydrofuran (3:2, 50 ml). Lithium chloride (592 mg, 14.0 mmol) and sodium borohydride (528 mg, 14.0 mmol) were added to the solution at room temperature, and the mixture was stirred at room temperature for 6 hours. After 6 hours, sodium borohydride (530 mg, 14.1 mmol) and lithium chloride (592 mg, 14.0 mmol) were additionally added, and the resultant mixture was stirred further for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=1:1 to 2:3) to obtain 959 mg of the title compound (oil).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].NCCN1C[CH2:51][O:50][CH2:49]C1>>[OH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][C@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:6](=[O:7])[NH:5][CH2:4][CH2:3][N:2]1[CH2:1][CH2:51][O:50][CH2:49][CH2:43]1
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: NCCN1CCOCC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)NCCN1CCOCC1)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to aminoethylmorpholine under standard TBTU conditions to yield the title compound of example 135.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](Cl)[CH2:6][CH2:5]2.[CH3:12][NH:13][CH3:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:13]([CH3:14])[CH3:12])[CH2:6][CH2:5]2
Reactant: CNC
Reactant: ClC1CCc2cc(Br)ccc21
Solvent: Cc1ccccc1
Product: CN(C)C1CCc2cc(Br)ccc21
Temperature: 90 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-1-chloro-indane (542 mg, 2.35 mmol) in toluene (9 ml) was added dimethylamine (3 ml) and resulting mixture was heated at 90° C. for 1.5 hr. The reaction mixture is concentrated under reduced pressure to yield the title compound (300 mg, 53%). 1H NMR (CDCl3): 2.06 (m, 2H), 2.24 (s, 6H), 2.81-2.93 (m, 2H), 4.27 (t, 1H), 7.22 (d, 1H), 7.33 (d 1H), 7.36 (s, 1H).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])[OH:11])=[CH:6][CH:5]=1.B(Br)(Br)Br>>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([P:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])[OH:12])=[CH:8][CH:9]=1
Reactant: COc1ccc(P(=O)(O)c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: O=P(O)(c1ccccc1)c1ccc(O)cc1

Procedure:
The latter compound is added dropwise to the reaction mixture which is maintained at 175° C. The mixture slowly darkens during this addition which is conducted over a period of about 2 hours. The reaction vessel is then allowed to cool and the reaction mixture purified. A total of 48 grams of ethyl bromide is collected, indicating the formation of about a 100% yield of ethyl p-methoxyphenylphenylphosphinate. The latter is hydrolyzed (by refluxing with concentrated HCl) to p-methoxyphenylphenylphosphinic acid and then demethylated by treatment with boron tribromide to give the desired p-hydroxyphenylphenylphosphinic acid, the starting material of Example 2.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH3:26])=[C:6]([C:23]([OH:25])=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:9]=1)[CH3:2].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:23]([C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:9]=[C:4]([NH:3][CH2:1][CH3:2])[C:5]=1[CH3:26])=[O:25]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)O)c1C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
5-(Ethylamino)-4-methyl-4′-(morpholinomethyl)[1,1′-biphenyl]-3-carboxylic acid (300 mg, 0.84 mmol) was dissolved in DMSO (2 mL) and 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (257 mg, 1.69 mmol) was added to it. After 15 minutes stirring at room temperature PyBOP (660 mg, 1.26 mmol) was added to the reaction mixture and stirring was continued for overnight. After completion, the reaction mass was poured into ice, extracted with 10% MeOH/DCM (5 times). Combined organic layer was washed with water and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by solvent washings afforded the title compound (100 mg, 24%). LCMS: 489.20 (M+1)+; HPLC: 96.41% (@254 nm) (Rt; 4.060; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 9.90 (s, 1H), 8.06 (t, 1H), 7.73 (d, 2H, J=7.6 Hz), 7.55 (d, 2H, J=7.2 Hz), 6.80 (d, 2H, J=7.6 Hz), 5.86 (s, 1H), 4.38 (s, 2H), 4.27 (d, 2H, J=4 Hz), 3.95 (m, 2H), 3.62-3.65 (m, 2H), 3.28-3.31 (m, 2H), 3.20-3.24 (m, 2H), 3.14-3.19 (m, 2H), 2.20 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.21 (t, 3H, J=6.8 Hz).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:27]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28]2)[NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:31][C:29]1([CH3:32])[CH2:30][CH:27]([CH:14]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:33])=[CH:9][CH:10]=2)[CH2:28]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating 3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester, isomer 1 (intermediate 70) with 1N NaOH (2.5 eq.) in methanol/THF in a similar manner as described in Example 19 to provide the title compound. Analytical chiral SFC: (Chiralpak AD-H column, 4.6 mm×25 cm, 30% methanol/carbon dioxide eluent, 2.5 mL/min flow rate, 2.78 retention time); 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.4 Hz, 2H), 7.56-7.63 (m, 2H), 7.44-7.52 (m, 3H), 7.37-7.44 (m, 1H), 7.11-7.19 (m, 1H), 5.30 (d, J=9.8 Hz, 1H), 3.67 (q, J=5.9 Hz, 2H), 2.62-2.70 (m, 3H), 2.29 (s, 3H), 1.94 (ddd, J=11.2, 8.2, 3.0 Hz, 1H), 1.70-1.82 (m, 1H), 1.62-1.70 (m, 2H), 1.13 (s, 3H), 1.08 (s, 3H); MS (M+1): 446.4.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH2:54][N:55]2[C:63]3[C:58](=[C:59]([O:64][CH3:65])[CH:60]=[CH:61][CH:62]=3)[C:57]([NH:66][S:67]([C:70]3[S:71][C:72]([Cl:75])=[CH:73][CH:74]=3)(=[O:69])=[O:68])=[N:56]2)[CH:51]=[CH:52][CH:53]=1>C(#N)C.C(Cl)Cl.O>[Cl:75][C:72]1[S:71][C:70]([S:67]([NH:66][C:57]2[C:58]3[C:63](=[CH:62][CH:61]=[CH:60][C:59]=3[O:64][CH3:65])[N:55]([CH2:54][C:50]3[CH:49]=[C:48]([CH2:47][NH:46][C:9]([CH:4]4[CH2:5][O:6][CH2:7][CH2:8][N:3]4[CH3:2])=[O:11])[CH:53]=[CH:52][CH:51]=3)[N:56]=2)(=[O:68])=[O:69])=[CH:74][CH:73]=1
Reactant: CN1CCOCC1C(=O)O
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C2COCCN2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
A solution of 4-methyl-3-morpholinecarboxylic acid hydrochloride (Chem-Impex International) (60.0 mg, 0.33 mmol) in acetonitrile (2 mL) was treated with HATU (126 mg, 0.33 mmol) and DIPEA (0.157 ml, 0.901 mmol). The resulting mixture was stirred for 15 min at ambient temperature and then N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (150 mg, 0.300 mmol) was added, and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM (3 mL) and water (3 mL). Organic phase was separated and the aqueous layer was further extracted with 3 mL of DCM. The combined organic solutions were washed with water (3 mL), dried through an hydrophobic frit and concentrated in a nitrogen blow-down apparatus. The residue was dissolved in 1:1 MeOH-DMSO 2 mL and purified by Mass Directed AutoPrep (Method C) on Xbridge column using acetonitrile water with an ammonium carbonate modifier. The solvent was evaporated under reduced pressure to give the required product (53.1 mg, 30%). LCMS (System F) RT=0.85 min, ES+ve m/z 590/592 (M+H)+.
Reaction SMILES: [C:1]1([NH2:12])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:9])=[C:3]([NH2:10])[C:2]=1[F:11].[ClH:13].Cl.[CH3:15][C:16]([C:19]1[CH:28]=[C:27]([C:29](=[O:38])[CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)([CH3:18])[CH3:17].C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:18][C:16]([C:19]1[CH:28]=[C:27]([CH:29]([OH:38])[CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)([CH3:15])[CH3:17].[C:1]1([NH2:12])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:9])=[C:3]([NH2:10])[C:2]=1[F:11].[ClH:13].[ClH:13]
Reactant: CC(C)(C)c1cc(C(=O)CCC2CCNCC2)c2ccccc2n1
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: CC(C)(C)c1cc(C(O)CCC2CCNCC2)c2ccccc2n1

Procedure:
The operation was as in Example 5, starting from 14 g of the dihydrochloride of 1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanone, 4.15 g of sodium methylate and 1.8 g of sodium borohydride in 150 ml of methanol. 4.1 g were finally obtained of 1-[2-(1,1-dimethyl-ethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanol (racemic), in the form of the dihydrochloride melting at 219° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][N:6]([C:23]1([C:28](=[O:38])[NH:29][O:30]CC2C=CC=CC=2)[CH2:27][CH2:26][CH2:25][CH2:24]1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][N:6]([S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:9])=[O:8])[C:23]1([C:28](=[O:38])[NH:29][OH:30])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)CCN(C1(C(=O)NOCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Yield: 99.8 %

Procedure:
A solution of 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester (10.65 grams, 19.2 mmole) in methanol (250 mL) was treated with 5% palladium on barium sulfate and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 3 hours. After filtration through nylon (pore size 0.45 μm) to remove the catalyst, the solvent was evaporated to afford 3-[(4'-fluorobiphenyl-4-sulfonyl)-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid methyl ester as a white foam (8.9 grams, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH3:22].CCN(C(C)C)C(C)C>CC#N>[CH2:21]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:9]1[C@H:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:22]
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: CCOC(=O)CCCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN1[C@@H](c2ncccc2C)CCC[C@H]1c1ncccc1C
Reaction time: 23 h
Yield: 90.2 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (308 mg, 1.15 mmol), 6-bromo-hexanoic acid ethyl ester (283 mg, 1.27 mmol), DIPEA (260 μL, 1.49 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (12 mL) was warmed to 60° C. and stirred for 23 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded 6-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-hexanoic acid ethyl ester (425 mg, 90%) as a yellow oil. 1H NMR (CDCl3) δ 0.60-0.68 (m, 2H), 0.79-0.85 (m, 1H), 1.13-1.25 (m, 5H), 1.58-1.70 (m, 3H), 1.94-1.98 (m, 4H), 2.08-2.25 (m, 7H), 2.48 (bs, 6H), 1.50-2.63 (m, 2H), 4.03 (q, 2H, J=7.1 Hz), 7.05-7.08 (m, 2H), 7.43 (d, 2H, J=7.3 Hz), 8.47 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.B.C1COCC1>C(O)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: B
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1CO
Temperature: 23 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 2-amino-4-fluorobenzoic acid (3.00 g, 19.3 mmol) and THF (40 mL) at 0° C. under argon, borane-THF complex (1M THF solution, 77.0 mmol) was added dropwise over 30 min. After complete addition, the reaction was warmed to 23° C. After 4 h, the reaction mixture was added slowly (5 min) to ethanol (77 mL). After 20 min, the reaction was concentrated in vacuo, diluted with sat'd NaHCO3 (100 mL), extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by passing through a silica gel pad (1:1 ethyl acetate:hexane). Concentration in vacuo afforded 2.02 g of 2-amino-4-fluorobenzyl alcohol as a yellow solid which was sufficiently pure to take on to the next step: 1H NMR (CDCl3) δ 4.54 (br s), 6.28-6.47 (m), 6.93-7.05 (m); 13C NMR (CDCl3) δ 62.7, 101.9 (J=24 Hz), 103.4 (J=21 Hz), 121.5, 130.1 (J=10 Hz), 149.1, 163 (J=360 Hz). MS (EI) 141 (M+), 124, 110. IR (neat) 3500-3000 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]([OH:22])[CH3:21])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:20]([C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11]([C:18]#[N:19])[CH:10]=1)[CH3:21])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3-fluorophenyl)-7-(1-hydroxyethyl)quinoline-5-carbonitrile (20 mg, 0.07 mmol) in methylene chloride (1 mL) was added triethylamine (0.28 mL, 2.0 mmol) followed by methanesulfonyl chloride (0.12 mL, 1.5 mmol). The reaction was stirred at room temperature for 30 minutes, quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was used directly in the next step (28 mg, 100%). LCMS calculated for C19H16FN2O3S (M+H)+: m/z=371.1; Found: 371.1.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[NH:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].[O:22]1CC[CH2:24][CH2:23]1>>[C:23]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1)(=[O:22])[CH3:24]
Reactant: O=C1NCCOc2ccccc21
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(=O)N1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1.5 g of 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one in 20 ml of tetrahydrofuran, was added 0.5 g of lithium aluminium hydride by portion, and the mixture was heated and refluxed for 2 hours. The reaction mixture was cooled to the room temperature. To the reaction mixture were added dropwise 1 ml of water and 0.8 ml of 10% aqueous solution of sodium hydroxide, and the mixture was stirred for 6 hours at room temperature. After the resultant solid mater was removed by filtration, the filtrate was concentrated under reduced pressure, and 20 ml of dichloromethane was added to the residue. The solution was dried over anhydrous sodium sulfate, then to the solution was added 0.94 ml of acetic anhydride, the mixture was stirred for 15 minutes at room temperature. The solvent was distilled off under reduced pressure, and the resulting oily residue was purified by means of column chromatography (developing solvent: dichloromethane-ethyl acetate=5:1 (V/V)) to give 1.8 g of 4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as a colorless oily substance. The compound was used in the following steps without further purification.