Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.I[CH3:14].[OH-].[K+]>CN(C)C=O>[CH3:14][N:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:1][N:2]=[N:3]1
Reactant: CI
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1ccc(Br)cn1
Yield: 25.9 %

Procedure:
In 5 ml of dimethylformamide was dissolved 400 mg of 2-(5-tetrazolyl)-5-bromopyridine and the solution was reacted with 502 mg of iodomethane in the presence of 300 mg of potassium hydroxide at room temperature for 1 hour with stirring. After completion of the reaction, a post-treatment similar to that of Preparation Example 3 was conducted to obtain 110 mg of 2-(1-methyl-5-tetrazolyl)-5-bromopyridine (thin layer chromatography eluting with a mixture of 1:4 ethyl acetate:hexane, Rf: 0.3) and 220 mg of 2-(2-methyl-5-tetrazolyl)-5-bromopyridine (thin layer chromatography eluting with a mixture of 1:4 ethyl acetate:hexane, Rf: 0.5).
Reaction SMILES: Br[CH:2]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=O)[C:3]([O:5][CH3:6])=[O:4].[C:17]([NH2:25])(=[S:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([C:17]2[S:24][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccc2)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a solution of methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate from Example 7, Part C (0.51 g, 1.8 mmol) in 20 mL of absolute ethanol was added thiobenzamide (0.25 g, 1.8 mmol). The resulting mixture was stirred at 80° C. for 24 h. The reaction was allowed to cool and then was filtered. The solid was washed with ethanol and dried in vacuo to yield 0.53 g (91%) of the title compound. MS (ESI) 321.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7].[N:24]1([CH:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:39])[CH:36]=3)[CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:39][C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH2:38]3)[CH:11]=1)=[O:7]
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)O)c2)cc1OC
Reactant: Nc1ccc2c(c1)CC(N1CCOCC1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CC(N3CCOCC3)C4)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.4 %

Procedure:
To a suspension of the 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid (100 mg, 0.32 mmol) and 2-morpholin-4-yl-indan-5-ylamine (84 mg, 0.38 mmol) 1.5 mL of DMF. To this was added TBTU (122 mg, 0.38 mmol), and the vial warmed until a clear solution was obtained. The solution was stirred at room temperature. Stirring continued for 20 h total. Diluted with EtOAc and washed with Na2CO3, water and brine. The organic layer was dried over MgSO4, evaporated and purified by column chromatography, CH2Cl2/MeOH gradient 1-10%, to give 103 mg of 3,4-dimethoxy-N-[3-(2-morpholin-4-yl-indan-5-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 516, (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3Cl)cc2)cc1
Temperature: 55 °C

Procedure:
The product from Example 24A (75.0 mg, 0.321 mmol), 4tert-butylaniline (61 μL, 0.383 mmol), PS-DCC (1.35 mmol/g, 0.7132 g, 0.963 mmol), HOBT (44.0 mg, 0.326 mmol), and triethylamine (0.13 mL, 0.93 mmol) in DMF (3 mL) were combined and heated at 55° C. for 16 hours. The mixture was allowed to cool to room temperature, filtered, and the filtrate was diluted with diethyl ether (20 mL). The diethyl ether was washed with 1N HCl (15 mL), brine (15 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.63 (dd, 1H), 7.98 (d, 2H), 7.88 (d, 2H), 7.88 (d, 1H), 7.81 (br s, 1H), 7.59 (d, 2H), 7.41 (d, 2H), 7.29 (dd, 1H), 1.33 (s, 9H); MS (m/z) 365.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:21])=[C:8]([S:13]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:31]([NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[Cl:22])=[O:32])=[C:7]([OH:21])[C:8]=1[S:13]([NH:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)(=[O:14])=[O:15]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 53.8 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-amino-6-chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23 g, 0.77mmol) and 2,3-dichlorophenylisocyanate (100 μL, 0.76 mmol) were coupled to form the desired urea (0.19 g, 53%). LC-MS m/z 464 (M+).
Reaction SMILES: CN(C=C1C(=O)CC(C2C=CC=CC=2)CC1=O)C.Cl.NC(N)=N.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][C:31]1[N:40]=[CH:39][C:38]2[C:37](=[O:41])[CH2:36][CH:35]([C:42]3[CH:47]=[CH:46][C:45](Cl)=[CH:44][CH:43]=3)[CH2:34][C:33]=2[N:32]=1>>[NH2:30][C:31]1[N:40]=[CH:39][C:38]2[C:37](=[O:41])[CH2:36][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:34][C:33]=2[N:32]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Agent: CN(C)C=C1C(=O)CC(c2ccccc2)CC1=O
Agent: Cl
Agent: N=C(N)N
Product: Nc1ncc2c(n1)CC(c1ccccc1)CC2=O

Procedure:
The title compound was prepared from 2-dimethylaminomethylene-5-phenyl-cyclohexane-1,3-dione (600 mg, 2.46 mmol) from stage 1, guanidine hydrochloride (473 mg, 4.94 mmol) and sodium carbonate (783 mg, 7.38 mmol), following the procedure described for the synthesis of 2-amino-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/a stage 2) except that the mixture was heated to reflux for 16 h.
Reaction SMILES: Cl.C(OC([O:7][CH:8]([CH:16]1[CH2:21][CH2:20][C:19]([N:27]([CH3:29])[CH3:28])([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C)C.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:29][N:27]([CH3:28])[C:19]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:17][CH:16]([CH:8]([OH:7])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccs2)(N(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C1(c2cccs2)CCC(C(O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 M hydrochloric acid (20 ml) was added to a solution of {4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]-1-thiophen-2-yl-cyclohexyl}dimethylamine (1.10 g, 2.73 mmol) in tetrahydrofuran (20 ml) and the reaction mixture was stirred at room temperature overnight. It was then rendered alkaline with 4 M sodium hydroxide solution and extracted with methylene chloride (4×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (956 mg) was purified by flash chromatography with cyclohexane/ethyl acetate (3:2) and then methanol. The two product fractions obtained in this way were each taken up in diethyl ether, and 2 M hydrochloric acid (20 ml) was added. The phases were separated. The acid aqueous phases were extracted with diethyl ether (3×10 ml) and thereafter rendered alkaline with 4 M sodium hydroxide solution. The aqueous phases were extracted with methylene chloride (4×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[F:39][C:40]1([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([N:43]4[CH2:44][CH2:45][C:40]([F:46])([F:39])[CH2:41][CH2:42]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: O=C(N1CCC(F)(F)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.19 mmol) of the compound from Example 176A and 91 mg (0.58 mmol) of 4,4-difluoropiperidine hydrochloride were reacted according to the General Method 6. Yield: 48 mg (50% of theory)
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([NH2:13])=[S:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16](Cl)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O>ClC(Cl)C>[C:1]([O:9][CH2:10][C:11]1[S:12][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC(=S)COC(=O)c1ccccc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnc(COC(=O)c2ccccc2)s1
Yield: 91.7 %

Procedure:
A mixture of 9.14 g of 2-benzoyloxythioacetamide, 9 g of ethyl α-formyl-chloroacetate and 100 ml of dichloroethane was refluxed for 4 hours and after the addition of 4.5 g of ethyl β-formyl-chloroacetate, reflux was maintained for 2 hours. The mixture was cooled and was washed first with aqueous sodium carbonate and then water. The mixture was dried and the solvent was evaporated to obtain 14 g of raw product which was chromatographed over silica gel. Elution with a benzene-ethyl acetate mixture yielded 12.5 g of ethyl 2-benzoyloxymethyl-thiazole-5-carboxylate in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:35]=[CH:36][C:37]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[CH:38][C:22]=3[N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([O:53][CH2:54]Cl)(=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:35]=[CH:36][C:37]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:54][O:53][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])=[O:40])=[CH:38][C:22]=3[N:21]=2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(-c2nc3cc(C(=O)NCCC(=O)O)ccc3n2CCCCc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2CCCCc1ccccc1

Procedure:
Prepared by reacting 2-(4-benzyloxycarbonylamidino-phenyl)-5-[(2-carboxy-ethyl)-aminocarbonyl]-1-(4-phenyl-butyl)-benzimidazole with pivaloyloxymethylchloride in dimethylsulphoxide in the presence of potassium carbonate with the addition of potassium iodide at ambient temperature.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OCCC2CCNCC2)c1
Reaction time: 4 h
Yield: 93 %

Procedure:
2.00 g of 1-t-butoxycarbonyl-4-(2-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}ethyl)piperidine [prepared as described in step (a) above] were dissolved in 10 ml of a 4N solution of hydrogen chloride in dioxane, and the solution was allowed to stand at room temperature for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting solid residue was dissolved in a small amount of methylene chloride, after which ethyl acetate was added to the solution. The crystals which precipitated were collected by filtration, to give 1.59 g (yield 93%) of the title compound as colorless crystals, melting at 119°-121° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:20]=[CH:21][C:22]4[C:26]([C:27]([OH:29])=O)=[C:25]([CH3:30])[S:24][C:23]=4[CH:31]=3)[CH:10]=2)=[O:8])[CH2:3]1.[NH2:32][CH2:33][CH:34]1[CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:34]1([CH2:33][NH:32][C:27]([C:26]2[C:22]3[CH:21]=[CH:20][C:19]([O:18][C:15]4[CH:14]=[CH:13][N:12]=[C:11]5[CH:10]=[C:9]([C:7]([N:4]6[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]6)=[O:8])[S:17][C:16]=45)=[CH:31][C:23]=3[S:24][C:25]=2[CH3:30])=[O:29])[CH2:36][CH2:35]1
Reactant: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)O
Reactant: NCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 66.1 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 126a (65 mg, 0.14 mmole) with (aminomethyl)cyclopropane (37 μL, 0.43 mmole), diisopropylethylamine (50 μL, 0.29 mmole), and HBTU (81 mg, 0.22 mmole) in a similar manner previously described for example 117 to give a pale yellow solid (47 mg, 46%). 1H NMR (DMSO-d6, 300 MHz) δ 8.60 (1H, d, J=5.56 Hz), 8.49 (1H, t, J=5.68 Hz), 8.07, 8.01 (1H, s), 7.97 (1H, d, J=2.27 Hz), 7.84 (1H, d, J=8.59 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.78 (1H, d, J=5.31 Hz), 4.38, 4.33 (0.5H, br s), 4.01–3.93 (3H, m), 3.67–3.47 (2H, m), 3.20 (2H, t, J=6.19 Hz), 2.62 (3H, s), 2.07–1.81 (2H, m), 1.08 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]2[CH2:11][C@@H:10]([C:37]([N:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41]3)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCc3ccccc32)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (100 mg), 2,3-dihydro-1H-indole (62 μl) and diisopropylethylamine (96 μl) were dissolved in 1,2-dichloroethane (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (155 mg) was added, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (100 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[N:10][CH2:9][CH2:8]2>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[NH:10][CH2:9][CH2:8]2
Reactant: COc1ccc2c(c1)CCN=C2c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCNC2c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
Sodium borohydride (0.916 g, 24.2 mmol) was added in small portions to a solution of 6-methoxy-1-thiophen-2-yl-3,4-dihydroisoquinoline (1.470 g, 6.04 mmol) in MeOH (50 ml) at 0° C. The reaction mixture was stirred for 30 min, warmed to rt and stirred at rt for 21 hr, then quenched by the dropwise addition of H2O (10 ml). Excess MeOH was removed by evaporation and the resulting aqueous solution was extracted with CHCl3 (4×10 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 1.316 g (89% yield) of yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[CH:11]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1cc(Cl)c2ccccc2n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of 2,4-dichloroquinoline (0.2 g, 1 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.282 ml, 2.2 mmol) in toluene (2 ml) was refluxed during 18 hours then cooled to room temperature. The reaction mixture was diluted with CH2Cl2 and quenched with a saturated solution of NaHCO3. Aqueous phase was extracted with CH2Cl2 (2×). Combined organic phases were washed with H2O, dried over NaSO4, and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 97:3) to provide 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.235 g, 79%) as a yellow oil, MS: m/e=295.3 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][N:25]1[CH2:41][C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:5]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[CH2:15][CH2:14][N:13]([C:42](=[O:43])[CH2:41][N:25]3[CH2:26][CH2:27][C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:24]3=[O:23])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(=C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of bis(4-fluorophenyl)(piperidin-4-yl)methanol (0.30 g, 1.00 mmol, Example 32A) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the mixture was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.49-7.57 (m, 4H), 7.17-7.35 (m, 10H), 7.06-7.13 (m, 4H), 5.49 (s, 1H), 4.36 (d, J=14.0 Hz, 1H), 4.17 (d, J=16.6 Hz, 1H), 4.10 (d, J=15.7 Hz, 1H), 3.81 (d, J=14.3 Hz, 1H), 3.34 (t, J=6.7 Hz, 2H), 2.95-2.98 (m, 1H), 2.73-2.85 (m, 1H), 2.72 (t, J=6.6 Hz, 2H), 2.50-2.62 (m, 1H), 1.20-1.39 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:35])[CH:9]([NH:21][C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH3:34])=[CH:26][CH:25]=2)=[O:23])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.[Cl-].[Mn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:35])[CH:9]([NH:21][C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH3:34])=[CH:26][CH:25]=2)=[O:23])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(=O)c2ccc(F)cc2)c2ccccc12
Agent: [Mn+2]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide (400 mg, 0.83 mmol) in methanol (30 ml) was added manganese (II) chloride (210 mg, 1.67 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution were added sodium borohydride (63 mg, 1.67 mmol) under ice-cooling, and the mixture was stirred for 1 hr. The reaction solution was poured into 1N hydrochloric acid (30 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and the obtained crude crystal was washed with a mixed solvent of hexane:ethyl acetate=10:1 to give the title compound ((1RS,2SR) form: (1RS,2RS) form=1:2, 329 mg, 82%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O1CCCC1.O>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round bottom flask was mixed tert-butyl 4-(5-(ethoxycarbonyl)thiophen-2-yl)piperidine-1-carboxylate (5.00 g, 14.73 mmol) in tetrahydrofuran (50 ml). Aqueous 4N NaOH (38.41 ml, 73.6 mmol) solution was added along with some methanol (10 ml) to get a single phase solution. The mixture was stirred overnight at room temperature. The solvents were removed to give a white slurry that was diluted with water and adjusted to pH of 5 with 1N aqueous hydrochloric acid. Filtration provided the title compound.