Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=O)[C:11]=2[N:10]=1.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28].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>CN(C=O)C.O>[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH:28][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:22])[F:21])[NH:13][C:12]=2[CH:14]=[CH:15][CH:16]=1)=[O:20]
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (3; 75 mg, 0.24 mmol) was taken up in DMF (2 mL) along with thiazol-2-amine (4; 24 mg, 0.24 mmol) and HATU (186 mg, 0.49 mmol). DIEA (81 μL, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and filtered. The collected solids were further purified by silica gel chromatography to afford the desired product, namely N-(thiazol-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound 208), as a white solid (35 mg, yield: 38%). MS (ESI) calcd for C18H11F3N4OS: 388.06; found: 389 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]5)=[O:41])=[CH:51][CH:52]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Yield: 70.8 %

Procedure:
A mixture of 0.10 g (0.30 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.086 g (0.45 mmole) of toluenesulfonic acid monohydrate, 0.075 g (0.30 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.115 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-benzamide (I-261).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])(=[O:3])[CH3:2].[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18](OC)=O.[NH3:25]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:2][CH2:1][CH2:4][CH:5]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:17]3[C:16]=2[N:25]=[C:9]([NH2:11])[CH:8]=[CH:18]3)[CH3:6])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Product: CC(=O)c1ccc(OCCCC(C)Oc2cccc3ccc(N)nc23)c(C(N)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 5-acetyl-2-hydroxybenzamide for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 8.66 (d, 1H), 8.06 (dd, 1H), 7.96 (d, 1H), 7.32 (t, 1H), 7.22 (m, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 4.71 (m, 1H), 4.38 (m, 1H), 4.26 (m, 1H), 2.58 (s, 3H), 2.24 (m, 2H), 1.92–2.13 (m, 2H), 1.48 (d, 3H); MS (DCI/NH3) m/z 408 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:48]=1[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:46](=[O:57])[C:45]2([CH3:59])[CH3:58]>>[CH3:58][C:45]1([CH3:59])[C:44]2[C:48](=[C:40]([CH2:39][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:3]3)[CH:41]=[CH:42][CH:43]=2)[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:46]1=[O:57]
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)C3(C)C)cc1

Procedure:
Analogously to Method D, 0.600 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 0.574 g of 7-bromomethyl-3,3-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,3-dihydroindol-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.16 (1:2 EtOAc-heptane); Rt=6.79.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][Cl:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>C(O)C>[ClH:15].[ClH:15].[CH3:16][N:17]([CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)[CH3:18]
Reactant: CNC
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Solvent: CCO
Product: CN(C)CC1CN(Cc2ccccc2)CCO1
Product: Cl
Temperature: 150 °C

Procedure:
A mixture of 22.5 g of 4-benzyl-2-chloromethylmorpholine, 200 ml of ethanol and 200 ml of an aqueouos 26,7% dimethylamine solution is heated at 150° C. for 5 hours in an autoclave. After completion of the reaction, the solvent is distilled off under reduced pressure. After adding water, the residue is extracted with toluene three times. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is treated with 37% hydrochloric acid-ethanol to give 2-(N,N-dimethylaminomethyl)-4-benzylmorpholine dihydrochloride as white crystals. A mixture of 22.9 g of the hydrochloride compound, 200 ml of ethanol and 100 ml of water is subjected to catalytic reduction with 2.3 g of 10% palladium-carbon at ordinary temperature and atmospheric pressure. After absorbing a theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol to give 2-(N,N-dimethylaminomethyl)morpholine dihydrochloride as white crystals, melting at 270°-271° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:40]([O:50][C@@H:51]2[O:80][C@H:79]([CH3:81])[C@@H:70]([O:71][CH2:72][C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C@H:61]([O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C@H:52]2[O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:39]([CH2:82][O:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[O:38][CH:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16]([C:20]([O:22][CH2:23]C3C=CC=CC=3)=[O:21])[O:17][CH2:18]2)[CH2:14][C@H:13]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[O-].[Na+].C(OCC)C>CO>[CH2:1]([O:8][C@@H:9]1[C@@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:40]([O:50][C@@H:51]2[O:80][C@H:79]([CH3:81])[C@@H:70]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=3)[C@H:61]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:52]2[O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:39]([CH2:82][O:83][CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[O:38][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16]([C:20]([O:22][CH3:23])=[O:21])[O:17][CH2:18]2)[CH2:14][C@H:13]1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)C(O[C@@H]3[C@H]4CON(C(=O)OCc5ccccc5)[C@H]4C[C@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)N1OC[C@@H]2[C@@H](O[C@H]3O[C@H](COCc4ccccc4)[C@@H](O[C@@H]4O[C@H](C)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)C[C@@H]21
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 36.1 %

Procedure:
The compound (516 mg, 0.42 mmol) synthesized in Example 6 (6i) was dissolved in methanol (6 mL) and toluene (6 mL) and sodium methoxide (221 μL, 1.15 mmol) was added thereto, followed by stirring of the mixture at 50° C. for 40 minutes. After cooling to room temperature, Dowex 50W×8 was added thereto until the reaction mixture became neutral and it was filtered, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:diethyl ether, 1.5:1-1:1, v/v) to obtain the desired title compound (173 mg, yield 47%) as colorless amorphous matter.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]3[C:12](=[O:34])[C:13]4[N:14]([CH:16]=[C:17]([C:22]([NH:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[O:23])[C:18](=[O:21])[C:19]=4[OH:20])[CH2:15][C@@H:6]23)[CH2:4][CH2:3][CH2:2]1.N[C@@H](C)CCN[CH:40]1[CH2:43][CH2:42][CH2:41]1.[C:45](O)(=O)[CH3:46].[Cl:49][CH2:50]Cl>>[ClH:49].[ClH:49].[NH2:7][C@@H:8]([CH3:11])[CH2:9][CH2:10][NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1.[CH:1]1([N:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]3[C:12](=[O:34])[C:13]4[N:14]([CH:16]=[C:17]([C:22]([NH:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[O:23])[C:18](=[O:21])[C:19]=4[OH:20])[CH2:15][C@@H:6]23)[CH2:2][CH2:3][CH2:4]1.[CH:1]1([N:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]3[C:12](=[O:34])[C:13]4[N:14]([CH:16]=[C:17]([C:22]([NH:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[O:23])[C:18](=[O:21])[C:19]=4[O:20][CH2:50][C:40]4[CH:43]=[CH:42][CH:41]=[CH:46][CH:45]=4)[CH2:15][C@@H:6]23)[CH2:2][CH2:3][CH2:4]1
Reactant: ClCCl
Reactant: CC(=O)O
Agent: C[C@H](N)CCNC1CCC1
Agent: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Product: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCc4ccccc4)c3C(=O)N12
Product: Cl
Yield: 70 %

Procedure:
[(3S)-3-Aminobutyl]cyclobutylamine dihydrochloride was prepared in a similar manner as described in example Z-47, 1H NMR (400 MHz, CDCl3/CD3OD) δ 1.23 (d, J=6.4 Hz, 3H), 1.69-2.26 (m, 8H), 2.83 (m, 2H), 3.31-3.33 (m, 1H), 3.55 (m, 1H), 8.08 (br, <1H), 9.07 (br, <1H). b) (4S,12aS)-1Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16a (80 mg, 0.17 mmol) and free based [(3S)-3-aminobutyl]cyclobutylamine (96 mg, 0.68 mural) were reacted in dichloromethane (2 in L) with acetic acid to give (4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (68 mg, 70%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (57 mg, 100%) as an off-white solid, 1H NMR (4.00 MHz, CDCl3) δ 1.31 (d, J=6.8 Hz, 3H), 1.46-1.70 (m, 4H), 1.91-2.12 (m, 4H), 2.52 (m, 1H), 2.90-2.93 (m, 1H), 3.06 (m, 1H), 4.16-4.29 (m, 3H), 4.57-4.66 (m, 2H), 4.99-5.05 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.20 (s, 1H), 10.44 (s, 1H), 12.51 (s, 1H); ES+ MS: 473 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][CH2:8][NH2:9].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][CH2:8][NH:9][C:26](=[O:27])[CH2:25][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: COc1ccc(OCCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)NCCOc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
To a cold (0° C.) solution of 2-(3,4-dimethoxy-phenoxy)-ethylamine (2.3 g, 11.8 mmol) in anhydrous THF (21 ml), were added TEA (1.4 ml, 19.2 mmol) and portionwise 3,4-dimethoxyphenylacetylchloride (2.49 g, 11.6 mmol). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was combined with H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude solid. Recrystallisation from diethylether gave the title product (3.59 g, 80%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][C@H:22]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][C:24](OC)=[O:25].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:21][C@H:22]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][C:24](=[O:25])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCC[C@@H](C)CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@@H](C)CC(=O)CC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
In a 1 flask were charged 370 ml of dried THF and 38.4 g of diisopropylamine in a nitrogen stream, and the solution was cooled to -10° to -5° C. To the solution was added dropwise a 1.6 mole/l hexane solution of 238 ml of n-butyllithium at that temperature over 30 minutes, followed by stirring at that temperature for 1 hour. To the mixture was further added dropwise a solution of 44 g of t-butyl acetate in 44 ml of dried THF over 30 minutes while keeping at that temperature, followed by stirring for 1 hour. The resulting reaction mixture was cooled to -50° C., and a solution of 24 g of methyl (R)-3-methylheptanoate in 24 ml of dried THF was added thereto dropwise over 30 minutes, followed by allowing the mixture to further react at that temperature for 1.5 hours. After the reaction, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed twice with a sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure to obtain 45.2 g of a crude product. Purification by silica gel column chromatography gave 31.0 g (84.0%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Cl[CH2:14][C:15]1[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][C:15]1[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:6]=[CH:5]2
Reactant: Fc1ncccc1CCl
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ncccc1Cn1ccc2cc(Cl)ccc21
Reaction time: 0.3 h
Yield: 59 %

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, 5-chloro-1H-indole x70 (1.13 g, 7.43 mmol) is dissolved in dry DMF (20 ml). At 0° C., NaH (327 mg, 8.18 mmol, 60% in mineral oil) is added and the mixture is stirred at this temperature for 0.3 h. A solution of 3-(chloromethyl)-2-fluoropyridine x71 (obtained from (2-fluoropyridin-3-yl)methanol and SOCl2 (1.3 g, 8.92 mmol)) in DMF (5 ml) is then added and stirring is continued for 0.5 h at 0° C. The reaction mixture is poured on ice and the aqueous phase is extracted three times with AcOEt. The combined organic phases are dried over MgSO4, filtered and concentrated. Purification by chromatography on silicagel (Hexane/AcOEt:9/1 (v/v)) affords 5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1H-indole x72 as a solid (1.13 g).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:23]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(NCc2ccccc2)cc1Cl
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (1.47 mL, 8.45 mmol) and then methyl bromoacetate (1.29 g, 8.45 mmol) were added to a solution of N-benzyl-3-chloro-4-fluoroaniline (7-1, 1.00 g, 4.23 mmol) in DMF (7 mL), and the resulting mixture was stirred at 50° C. for 2 h, 60° C. for 3 h, and then 50° C. for 18 h. Methyl bromoacetate (0.4 mL, 4 mmol) was added and mixture was heated to 60° C. for 7 h and then 50° C. for 18 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (3×100 mL), H2O (100 mL), and brine (50 mL). The reaction was concentrated and purified residue by flash column chromatography (SiO2, 0-20% EtOAc/hexanes gradient) to provide methyl N-benzyl-N-(3-chloro-4-fluorophenyl)glycinate (7-2). 1H NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 6.97 (dd, J=8.9, 8.9 Hz, 1H), 6.69 (dd, J=6.1, 3.1 Hz, 1H), 6.50 (ddd, J=8.9, 3.4, 3.4 Hz, 1H), 4.59 (s, 2H), 4.05 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[BH4-].[Na+]>CO>[F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[F:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Product: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Reaction time: 4 h

Procedure:
To a solution of benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (200 g, 0.797 mol) in methanol (1 L) was added NaBH4 (24.4 g, 0.636 mol) in portions at 0° C. After the addition, the mixture was stirred for 4 h and then quenched with water (200 mL). The mixture was concentrated, and then ethyl acetate and water were added to the residue. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified via column chromatography (EtOAc/petroleum ether=1:6) to afford benzyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate and benzyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (600 MHz, CDCl3-D6) 7.50-7.30 (m, 5H); 5.13 (s, 2H); 4.70-4.50 (d, 1H); 4.10-3.70 (m, 3H); 3.48 (s, 1H); 3.23 (s, 1H); 2.50 (s, 1H); 1.90-1.70 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:8]=[C:9]([OH:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:5])[CH3:4].[H][H].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:12][C:11](=[O:13])[C:10]1[C:9](=[CH:8][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=1)[OH:16])[CH:20]=[CH2:19]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Reactant: [H][H]
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(NC(C)=O)cc1O
Reaction time: 8.6 h
Yield: 62745.5 %

Procedure:
To a stirred suspension of sodium hydride (4.0 g of 60%, 0.1 mmol) in 25 mL DMF was added dropwise a solution of 4-acetamidosalicylic acid (19.5 g, 0.1 mmol) in 50 mL DMF. After the evolution of hydrogen was over, allyl bromide (12.1 g, 0.1 mmol) was added and the mixture was stirred for 8.6 hours. DMF was removed in vacuo and the residue crystallized from methanol/water to give 14.76 g (62.76%) of the title compound as a white solid, mp 156-8° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([CH3:37])[CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:17]([C:13]1([OH:16])[CH2:14][CH2:15][N:10]([CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][NH:1][C:25]([NH:24][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[O:26])[CH2:11][CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(c1ccccc1)N1CCC(O)(Cc2ccccc2)CC1
Reactant: Cc1cc(N=C=O)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCC(c2ccccc2)N2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(2-amino-1-phenyl-ethyl)4-benzyl-piperidin-4-ol (54.3 mg, 0.18 mmol) in CH2Cl2 is added a freshly prepared solution of 4-isocyanato-2-methyl-quinoline (33.8 mg, 0.16 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C. Evaporation of the solvent and purification by HPLC provides the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([Mg]Cl)[CH:13]=[CH2:14]>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH:13]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(O)COCc1ccccc1
Temperature: 0 °C

Procedure:
2-(Benzyloxy)acetaldehyde (5 g, 33.3 mmol) in dry THF (10 mL) was added dropwise to a stirred and cooled solution of allylmagnesium chloride (25 mL, 2 M in THF, 50 mmol) in THF (100 mL) at −78° C. After the addition, the solution was allowed to warm to 0° C. and quenched with saturated NH4Cl solution. After standard aqueous work up, the residue was purified over silica using EtOAc and hexane to give 1-(benzyloxy)pent-4-en-2-ol (11).