Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH:18]=[N:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([OH:23])[CH3:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[H][H]>C1COCC1.[Ni]>[F:1][C:2]1[C:3]([CH2:18][NH:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([OH:23])[CH3:22])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)[C@@H](N=Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1F)C(C)O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)[C@@H](NCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1F)C(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
Example 17A (767 mg, 2.85 mmol) and Example 107B (460 mg, 2.99 mmol) were dissolve in methanol (20 mL) and triethylamine (0.434 mL, 3.13 mmol). The orange solution was stirred at ambient temperature for 2 hours and 20 minutes, followed by the addition of sodium borohydride (237 mg, 6.27 mmol). After 4 hours, additional sodium borohydride (237 mg, 6.27 mmol) was added. The reaction was stirred overnight at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated to provide (3R)-3-[({3-fluoro-6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}methylene)amino]-4-methylpentan-2-ol (1.009 g, 2.74 mmol) as an orange oil. The imine (1.009 g, 2.74 mmol) in THF (40 mL) was added to Raney Nickel (1.009 g) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 20 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-30% EtOAc in dichloromethane (30 mL/min) to provide the title compound (0.533 g, 1.439 mmol, 52.5% yield) as a yellow oil, a 3:1 mix of diastereomers by proton NMR. MS (ESI+) m/z 371.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=8.3, 2H), 8.05 (dd, J=8.6, 3.7, 1H), 7.89-7.77 (m, 3H), 4.43 (d, J=4.8, 0.75H), 4.38 (d, J=5.2, 0.25H), 4.14-3.95 (m, 2H), 3.71-3.58 (m, 1H), 2.40-2.29 (m, 0.75H), 2.25-2.17 (m, 0.25H), 2.15-2.06 (m, 1H), 1.93-1.73 (m, 1H), 1.11-1.04 (m, 3H), 0.96-0.79 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH3:21])[C:15]=2[O:22][CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:19]([N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([O:22][CH3:23])[C:16]([CH3:21])=[N:17]1)[CH3:20]
Reactant: CCn1nc(C)c(OC)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nc(C)c(OC)c1C1CCNCC1

Procedure:
A solution of 16 mg (0.0.49 mmol) of 1-tert-butoxycarbonyl-4-(1-ethyl-4-methoxy-3-methyl-(1H)-pyrazol-5-yl)piperidine (from Step E) in 0.1 mL of trifluoroacetic acid and 0.15 mL of CH2Cl2 at 0° C. was stirred for 30 min. Volatiles were removed under reduced pressure. The crude product was partitioned between 25 mL of 1 N NaOH and 25 mL of CH2Cl2. After separating phases, the aqueous layer was extracted with 3×25 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound as a yellow film: 1H-NMR (500 MHz) δ 1.36 (t, J=7.2, 3H), 1.72–1.74 (m, 2H), 1.91–2.03 (m, 2H), 2.07 (s, 1H), 2.21 (s, 3H), 2.65–2.73 (m, 3H), 3.19–3.21 (m, 2H), 3.71 (s, 3H), 3.99 (q, J=7.2, 2H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:45]1[CH2:50][CH2:49][S:48][CH2:47][CH2:46]1>>[F:1][C:2]([F:43])([F:44])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:45]3[CH2:50][CH2:49][S:48][CH2:47][CH2:46]3)=[O:30])[CH2:18]2)[CH3:41])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C1CSCCN1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCSCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and thiomorpholine, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4
Reactant: COC(=O)CCCBr
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid methyl ester (24.9 μl, 0.198 mmol) and cesium carbonate (64.5 mg, 0.198 mmol) were dissolved in DMA (0.20 ml) and stirred at room temperature for 4 hr. Water was added to the reaction solution, which was then extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride/MeOH) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric acid methyl ester as an intermediate.
Reaction SMILES: Cl[Si:2]1(Cl)[CH2:5][CH2:4][CH2:3]1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>>[N:7]1([Si:2]2([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: Cl[Si]1(Cl)CCC1
Product: C1CCN([Si]2(N3CCCC3)CCC2)C1
Reaction time: 48 h
Yield: 34 %

Procedure:
Bis(pyrrolidino)silacyclobutane was synthesized by reacting 1,1-dichlorosilacyclobutane with an excess amount of pyrrolidine (Equation 3). To do so, 23.7 ml (0.200 mol) 1,1-dichlorosilacyclobutane was added to 100.0 ml (1.20 mol) pyrrolidine in 1 L hexanes at −10° C. After bodying for two day at the room temperature, the reaction slurry was filtered to remove pyrrolidine hydrochloride salt. The filtrant was vacuum dried to give a liquid crude product which was then vacuum distilled. 15.4 g Product was isolated at 99.7% purity in 34% yield at 51° C. under 1 torr pressure. The structure of the product analyzed with 1H, 13C and 29Si NMR, FT-IR and GC-MS was in consistence with bis(pyrrolidino)silacyclobutane.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:33]=[C:32](I)[CH:31]=[CH:30][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C.C(Cl)Cl>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:32]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([F:22])[CH:33]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)N(c1ccc(C)cc1)CCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 0.20 g (0.72 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)-7-ethynylquinoline (Compound 3) and 0.39 g (1.5 mmol) of ethyl 2-fluoro-4-iodobenzoate were added 2.9 g (4.0 mL, 29 mmol) of triethylamine, 0.029 g (0.15 mmol) of copper(I) iodide, and 0.113 g (0.16 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was stirred at room temperature for 20 hours. Methylene chloride was added and the reaction was adsorbed onto silica gel. The product was obtained by flash chromatography (5% ethyl acetate in hexanes) followed by recrystallization in ethanol to give the title compound as orange crystals. PNMR (300 MHz, CDCl3) d 1.37 (6 H, s), 1.40 (3 H, t, J=7.1 Hz), 1.86 (2 H, t, J=6.0 Hz), 2.38 (3 H, s), 3.61 (2 H, t, J=6.0 Hz), 4.39 (2 H, q, J=7.1 Hz), 6.77 (1 H, d, J=1.7 Hz), 6.87 (1 H, dd, J=7.9, 1.7 Hz), 7.23-7.28 (7 H, m), 7.86 (1 H, t, J=7.8 Hz).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)CCC>FC(F)(F)C(O)=O>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CCCCOC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 97.1 %

Procedure:
A solution of 1.26 g (2.80 mmole) of 7-[3-(butoxycarbonyl)amino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 25 ml of trifluoroacetic acid was stirred at room temperature until gas evolution ceased. The solvent was removed in vacuo and the residue dissolved in 1.0N sodium hydroxide. The solution was diluted to 20 ml with water and acidified to pH 5.5 with 6N hydrochloric acid. The precipitate was removed by filtration, washed with water, ethanol, and ethyl ether. The residue was dried in vacuo to give 0.95 g (97%) of the title compound, mp 290°-292° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH-].[Na+]>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCOCc3ccccc3)s1)CC2

Procedure:
To compound 55A (138 mg, 0.230 mmol) in THF (3 ml) and MeOH (3 ml) was treated with 10% sodium hydroxide (0.46 ml, 1.152 mmol) for 1 day. The reaction mixture was concentrated and acidified by conc. HCl. The precipitate was collected by filtration and dried to provide the title compound: 1H NMR (500 MHz, DMSO-D6) δ ppm 12.89 (2H, s), 8.03 (1H, d), 7.80 (1H, d), 7.67 (1H, d), 7.42-7.51 (2H, m), 7.33-7.42 (2H, m), 7.25-7.31 (4H, m), 7.17-7.21 (1H, m), 4.82 (2H, s), 4.46 (2H, s), 3.74 (2H, t), 3.60 (2H, t), 3.28-3.35 (2H, m), 3.03 (2H, t); LCMS (APCI) m/e 571.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].[OH-].[Na+:38]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([O-:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:25])[C:6]1=[O:29].[Na+:38]
Reactant: NCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCCO)c([O-])c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol employing methods similar to those described in Example 245. The resulting material was triturated with water, covered with EtOH and treated with 1 equivalent of 1N NaOH solution. Concentration in vacuo afforded the product as a white solid: 1H NMR (d6-DMSO) δ 10.53 (1H, br), 8.14 (1H, s), 7.25 (3H, m), 7.10 (2H, t, J=9 Hz), 4.92 (2H, s), 4.49 (1H, br), 3.98 (2H, s), 3.43 (2H, m), 3.25 (2H, m), 3.07 (3H, s), 2.78 (3H, s), 1.58 (2H, m, J=6 Hz); AP+ MS: 457 (M+H+, 100).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCCCCl)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 4-(3-chloropropoxy)naphthalen-1-amine (2.85 g, 10.5 mmol) and 3-fluoro-5-piperidin-1-ylbenzoic acid (3.52 g, 15.7 mmol), in DMF (30 ml) is added HBTU (7.1 g, 18.9 mmol), and Hunig's base (6.0 ml, 33.6 mmol). The mixture is stirred overnight at room temperature then diluted with ethyl acetate (200 ml) and washed with water (3×100 ml). The organic layer is dried over Na2SO4 and evaporated. The residue is purified by column chromatography on silica gel to yield N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide as a white solid (3.0 g, 65%). Mp: 181-182° C. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.26 (m, 1H), 7.87 (m, 1H), 7.55 (m, 2H), 7.46 (s, 1H), 7.43 (d, J=8.1Hz, 1H), 7.17 (d, J=9.3 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.97 (d, J=10.5 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.6, Hz, 2H), 3.29 (m, 4H), 2.34 (m, 6H), 1.59 (m, 6H). MS: 441.3 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([NH2:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[N:12]=2)=[CH:6][CH:5]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][C:27](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]3[N:17]=[C:27]2[CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][N:22]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)CCc1nccs1
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCCl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c2nc(CCc3nccs3)n(-c3ccc(CCCl)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of N2-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine (step 2, 276 mg, 1.0 mmol) and 3-(1,3-thiazol-2-yl)propanoic acid (157 mg, 1.0 mmol) in dichloromethane (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (192 mg, 1.0 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene (20 mL) and heated at 150° C. for 5 h. The reaction mixture was poured into water (50 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 210 mg (53%) of the title compound: MS (EI) m/z 396 (M+); 1H-NMR (CDCl3) δ 7.63 (1H, d, J=3.4 Hz), 7.39 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.15 (1H, d, J=3.4 Hz), 6.93 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.69–3.50 (2H, m), 3.39–3.20 (2H, m), 3.15 (2H, t, J=7.4 Hz), 2.66 (3H, s), 2.53 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>C1COCC1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:10][N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Temperature: 100 °C
Yield: 34 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* (571 mg, 1.60 mmol) and potassium phthalimide (340 mg, 1.84 mmol) in THF (5 mL) and DMSO (2 mL) was heated at 100° C. for 20 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine (×2), dried (MgSO4), filtered and concentrated to give a crude product which was purified by column chromatography (SiO2), eluting with a gradient of ethyl acetate/petrol (2.5% to 100%) then 10% methanol/dichloromethane to give the title compound (273 mg, 34%); LCMS (PS-A2) Rt 3.22 min [M+H]+ 504.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[CH2:16][O:15]C3=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>[OH-].[Na+].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][OH:15])=[CH:9][CH:8]=2)=[CH:27][CH:28]=1
Reactant: COc1cccc(C2COC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C(CO)Nc2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A solution of the product from step 1 (293 mg) in 3 mL of NaOH/MeOH (10%, w/w) is heated to 60° C. for 6 h, then subsequently cooled to room temperature and concentrated. The residue is dissolved in EtOAc (30 ml) and is washed with brine, and dried over MgSO4, filtered, and concentrated to give the crude product, which is by purified flash chromatography on silica gel (EtOAc/Hex: 1/1) to provide 2-[4-(4-chloro-phenoxy)-phenylamino]-2-(3-methoxy-phenyl)-ethanol (202 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=O)=[CH:4][CH:3]=1.B.O1CCCC1.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1NCCCC1c1ccc(Br)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Brc1ccc(C2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To an ice-cooled solution of 3-(4-bromo-phenyl)-piperidin-2-one (37.97 g, 149 mmol) in tetrahydrofuran (250 ml) was added borane-tetrahydrofuran complex (335 ml, 1.0 M solution in THF, 335 mmol). The solution was stirred overnight at room temperature, and then refluxed 1.5 hr after addition of 10% aqueous hydrochloric acid. Solvents was removed in vacuo, and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The aqueous layer was extracted with dichlorometane. The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in water (100 mL) and concentrated hydrochloric acid (100 mL) and refluxed for 3 hr. Sodium hydroxide was added to the solution and the resulting solution was extracted with dichlorometane. The organic layer was washed with water and brine, dried over sodium sulfate Concentration in vacuo afforded 3-(4-bromo-phenyl)-piperidine (32 18 g, 90%).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.B(O)(O)O.C1(C)C(C)=CC=CC=1>O>[O:9]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCCCC(=O)[O-]
Reactant: Nc1ccccc1O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCCCc1nc2ccccc2o1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of monoethyl heptanedioate (9.41 g), o-aminophenol (5.46 g), boric acid (3.09 g), and xylene (100 ml) was refluxed with water being azeotropically removed for 16 hours. After cooling to room temperature, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to provide ethyl 6-(benzoxazol-2-yl)hexanoate (10.1 g).
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([C@@H:14]([OH:22])[C@@H:15]([NH:17][C@H:18]([CH3:21])[CH2:19]O)[CH3:16])[CH:10]=[CH:11][C:12]=1[F:13].[ClH:23]>ClCCl.C(OCC)C>[ClH:23].[F:6][C:7]1[CH:8]=[C:9]([C@@H:14]2[O:22][CH2:19][C@@H:18]([CH3:21])[NH:17][C@H:15]2[CH3:16])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: C[C@H](CO)N[C@@H](C)[C@H](O)c1ccc(F)c(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CO[C@@H](c2ccc(F)c(F)c2)[C@H](C)N1
Yield: 49.8 %

Procedure:
To concentrated H2SO4 (100 ml) was added a solution of (1R,2S)-1-(3,4-difluorophenyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]propanol (17.1 g, 0.07 mole) in dichloromethane (100 ml). The reaction was worked up as in Example 1 to yield the crude reaction product as the free base. The crude product was dissolved in diethyl ether and treated with ethereal hydrogen chloride. The hydrochloride salt was recrystallized from ethanol-diethyl ether mixtures to give 9.2 g (49.8% of theory) of (2S,3S,5R)-2-(3,4-difluorophenyl)-3,5-dimethylmorpholine hydrochloride as a white solid. m.p. 318° C. [α]20D =+24.6° (c=0.710, 95% ethanol).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([CH:12]2[O:16][C:15](=[O:17])[NH:14][CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[O:16][C:15](=[O:17])[NH:14][CH2:13]2)[C:5]([O:18][CH3:19])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CNC(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(C)c1C1CNC(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-1,3-oxazolidin-2-one (21 mg, 0.072 mmol) (single enantiomer from step 1) in methanol (1 mL) was added sodium tetrahydroborate (5.5 mg, 0.14 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. It was diluted with methanol and purified on preparative LCMS using pH 10 buffer to give the desired compound as a racemic mixture of two diastereomers, 17 mg, 83%. LCMS calculated for C13H15ClNO3 (M-OH)+: m/z=268.1; found: 268.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, 8-bromo-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-bromo-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.