Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH:36]1[CH2:37][CH2:38][N:39]([C:24]([C:13]2[CH:12]=[N:11][C:10]3[N:9]([N:8]=[CH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]=2[NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[F:23])=[O:25])[CH2:40][CH2:41]1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4F)CC3)cnc12
Yield: 47.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (160 mg, 0.46 mmol) obtained in Example 90, step 2 and 4-(2,4-difluorophenyl)piperidine hydrochloride (WO2007/018998, 160 mg, 0.69 mmol), the title compound (117 mg, 47%) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.CO>CN1C(=O)CCC1>[C:3]1([S:9][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Sc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To NaH (60 wt % in mineral oil; 0.050 g, 1.259 mmol) in 1 mL NMP was added benzenethiol (0.129 ml, 1.259 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became orange. After 1 h, the reaction was sealed and heated to 70° C. for 1 h. The reaction was cooled and was partitioned between saturated aq. NaHCO3 and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (3×) and saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford a yellow solid. The material was treated with 1 mL MeOH, sonicated, and filtered, rinsing with MeOH, to give 2-(2-(phenylthio)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.042 g, 0.113 mmol, 45% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18-11.45 (1H, m), 8.28 (1H, d, J=8.6 Hz), 8.09 (1H, dd, J=7.5, 1.5 Hz), 7.67-7.79 (3H, m), 7.48-7.61 (4H, m), 7.36 (1H, d, J=8.8 Hz), 7.05 (1H, d, J=2.3 Hz), 6.92-6.98 (1H, m), 3.33-3.42 (2H, m), 2.50-2.55 (2H, m). m/z (ESI, +ve) 371.9 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:26][CH2:25]C(=O)[CH2:23][CH2:22]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:34][CH:33]4[O:35][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].CO[CH:38]([O:41][CH3:42])[O:39][CH3:40].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:42][O:41][C:38]1([O:39][CH3:40])[CH2:25][CH2:26][CH:21]([N:18]2[C:16]3=[N:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=4)=[N:13][C:14]([N:28]4[CH2:34][CH:33]5[O:35][CH:30]([CH2:31][CH2:32]5)[CH2:29]4)=[C:15]3[CH:20]=[N:19]2)[CH2:22][CH2:23]1
Reactant: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(OC)(OC)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (80 mg) (0.17 mmol) in DCM (2.0 mL) was added trimethylorthoformate and methanol in excess and a catalytic amount of p-toluene sulfonic acid along with molecular sieves and stirred at room temperature overnight. The added water and extracted 3 times with EtOAc. The organics were dried (MgSO4) and filtered off through a pad of Magnesol and concentrated in vacuo. to afford a solid. The solid was triturated with diethyl ether to give a white solid that was filtered and washed with diethyl ether to give (54 mg) MS m/z=476.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]3OCC[O:18]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][O:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=[O:18])[CH2:11][CH2:10]2)[CH2:7][CH2:8]1
Reactant: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
6.2 g of 2-[2-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]ethyl]-1,3-dioxolane were treated with 100 ml of water, 50 ml of glacial acetic acid and 20 ml of dioxan while gassing with nitrogen. The mixture was stirred at 100° C. (bath temperature) for 1.5 hours, then neutralized with dilute sodium hydrogen carbonate solution and extracted three times with diethyl ether. The combined ether phases were washed once with water and twice with dilute sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and evaporated. Recrystallization of the crude aldehyde obtained (4.34 g) from 150 ml of petroleum ether at -20° C. gave 2.8 g of 3-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]propionaldehyde in a purity of 96%; m.p. 36° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[NH:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:17][CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[C:14](=[O:19])[NH:15]1
Reactant: O=C1CCN(c2ccc(CC3NC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4NC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-imidazolidine-2,4-dione (which was obtained in Example 44) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >105° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.50-2.75 (m, 5H), 2.86 (d, J=4.8 Hz, 2H), 2.93 (s, 3H), 3.50-3.65 (m, 2H), 4.24 (t, J=4.8 Hz, 1H), 4.51 (dd, J=8.2, 4.0 Hz, 1H), 6.81 (d, J=6.3 Hz, 1H), 6.84 (d, J=5.7 Hz, 2H), 7.18 (d, J=1.8 Hz, 1H), 7.85 (brs, 1H); MS (ES) m/z: 518.0 (MH+); HRMS Calcd. for C24H32N5O6S(MH+): 518.2073. Found: 518.2056.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:10]([O:12]CC3C=CC=CC=3)=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C1(OC)C=CC=CC=1.Cl>C(Cl)Cl.[N+](C)([O-])=O.[Ti](Cl)(Cl)(Cl)Cl>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 32 %

Procedure:
To a solution of benzyl 7β-amino-3-methyl-3-cephem-4-carboxylate (1.2 g) and anisole (5.2 ml) in methylene chloride (100 ml) is added a solution of titanium tetrachloride (2.6 g) in nitromethane under ice cooling, and the mixture stirred for 9.5 hours at room temperature. The reaction mixture is adjusted to pH 1 or less with diluted hydrochloric acid (70 ml), washed with ethyl acetate, and neutralized with 6 N-sodium hydroxide. The resulting titanium hydroxide is removed by filtration, and the filtrate concentrated under reduced pressure at a temperature below 50° C. The resulting crystals are collected by filtration to give 7β-amino-3-methyl-3-cephem-4-carboxylic acid (270 mg). Yield: 32%. This product was identical with an authentic specimen in NMR and IR spectra.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:34](O)[CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH3:53].[C:55]([OH:58])(=[S:57])[CH3:56]>C1COCC1.CCCCCCC>[C:55](=[O:58])([S:57][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH3:53])[CH3:56]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Triphenylphosphine (21.0 g, 80 mmol) was dissolved in dry THF (170 mL) at 0° C. under inert atmosphere and added DIAD (15.8 mL, 80 mmol) dropwise. After 40 minutes at 0° C. the white suspension was added dropwise to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (11.5 g, 40 mmol) and thioacetic acid (5.7 mL, 80 mmol) in dry THF (50 mL) during 15 minutes. The resulting turbid mixture was stirred at 0° C. for 30 minutes, followed by ambient temperature for 1.5 hour. Heptane was added (200 mL), the mixture was stirred for ten minutes and the precipitated white solid removed by filtration and rinsed with heptane (150 mL). The residue was concentrated to remove most of the THF and stirred at ambient for 18 hours. The mixture was filtered, concentrated and added heptane (200 mL). The resulting mixture was stirred for 2 hours, filtered and evaporated. The residue was purified by flash chromatography on silica gel, using EtOAc:Heptane (2:98), followed by EtOAc:Heptane (4:96) and finally EtOAc:Heptane (5:95). Concentration of the appropriate fractions provided 11.0 g (79% yield) of the title compound as oil.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1nc(Cc2ccccc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoate (5.2 g, 21.1 mmole) in methanol (30 ml) was added 50 ml of 1N NaOH aqueous solution. The mixture was stirred at room temperature for 2 hours. After the reaction solution was adjusted to be acidic (pH=3-4) at 0° C., the reaction mixture was extracted with EtOAc 3 times. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to give the desired product as colorless oil (4.8 g, 98%). LCMS calculated for C12H13N2O3 (M+H): 233.1. found: 233.1.
Reaction SMILES: [Mg:1].Br[CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:16])[CH:9]=1>C(OCC)C>[CH2:3]([Mg:1][Br:7])[CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([OH:13])[CH2:3][CH2:4][CH2:5][CH3:6])=[C:10]([F:16])[CH:9]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCCCBr
Reactant: [Mg]
Solvent: CCOCC
Product: CCCCC(O)c1ccc(Br)cc1F
Product: CCCC[Mg]Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
A solution of butylmagnesium bromide was prepared in the usual manner with diethyl ether (5 ml), magnesium (111 mg) and 1-bromobutane (624 mg). A solution of 4-bromo-2-fluorobenzaldehyde (925 mg) in diethyl ether (5 ml) was added dropwise to the Grignard solution. After the addition was completed, the reaction mixture was stirred for 30 minutes at room temperature. The reaction was quenched with aqueous ammonium chloride and the organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (85:15) to give 1-(4-bromo-2-fluorophenyl)pentanol (635 mg) as an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C@H:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15]O.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.O1CCCC1>[CH3:13][C@H:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27]
Reactant: C[C@@H](CO)CC(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)CC(F)(F)F
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Diethyl azodicarboxylate (15.4 mL) was added to a 0° C., stirred slurry of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (about 12.0 g), phthalimide (13.4 g), and triphenylphosphine (23.7 g) in diethyl ether (about 6.5 g, see above) and dry tetrahydrofuran (110 mL), warmed to rook temperature overnight, and stirred an additional 8 h. The mixture was evaporated, methylene chloride was added to the residue, and the slurry was filtered. The filtrate was purified by flash chromatography, eluting with 1:1 methylene chloride:hexanes, to give (R)-2-(2-methyl-4,4,4-trifluorobutyl)-1H-isoindol-1,3(2H)-dione (17.1 g, 75%) as a white solid; mp 45°-47 ° C.; partial NMR (400 MHz, CDCl3): 1.08 (d, 3H, CH3), 1.94-2.07 (m, 1H, CF3CH2), 2.14-2.31 (m, 1H, CF3CH2), 2.36-2.50 (m, 1H, CHCH3), 3.58 (dd, 1H, CH2N), 3.64 (dd, 1H, CH2N).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3([OH:18])[CH2:16][CH2:15][CH:14]([N:19]4[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:26])[CH2:27][NH:28][C:29](=[O:40])[C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=5)[CH2:20]4)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(O)(c2ccc(N3CCC3)nc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3ccc(N4CCC4)nc3)CC2)C1
Reaction time: 16 h

Procedure:
To a solution of 4-(6-azetidin-1-ylpyridin-3-yl)-4-hydroxycyclohexanone (115 mg, 0.467 mmol) and N—((R)-pyrrolidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (140.4 mg, 0.445 mmol) in dry CH2Cl2 (19 mL) was added Na(OAc)3BH (198 mg, 0.934 mmol) in one portion under N2 at rt. The reaction mixture was stirred under N2 overnight (16 h) and treated with Na2CO3 (aq), extracted with CH2Cl2×3, dried, filtered and concentrated to give a crude, which was purified by column chromatography (20:80:0.5 MeOH/EtOAc/NH4OH) to provide 60 mg (25%) of desired isomer product (top spot on TLC) as a white solid. MS (M+H+)=546.1. 1H NMR (CD3OD) δ 8.24 (m, 2H), 8.17 (m, 2H), 7.88 (m, 2H), 7.74 (m, 2H), 6.56 (d, 1H), 4.36 (m, 2H), 4.27 (m, 3H), 4.06 (m, 3H), 3.86 (m, 1H), 3.48 (m, 2H), 3.20 (m, 1H), 2.69 (m, 1H), 2.60 (m, 2H), 2.35-2.30 (m, 4H), 2.20-1.97 (m, 4H), 1.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])O.[BrH:17].O>C(O)(=O)C>[Br:17][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OC(c1ccccc1Cl)c1ccccc1Cl
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccccc1C(Br)c1ccccc1Cl
Temperature: 22.5 °C

Procedure:
Under N2, bis(2-chlorophenyl)methanol (70 g, 0.28 mol) was added in 4 portions at 20 to 25° C. to HBr (97 ml) in acetic acid (33% by weight). The mixture was stirred at 20 to 25° C. and the reaction was followed by HPLC. After complete reaction (60 to 90 min), the mixture was cooled to 0 to 10° C. and water (700 ml) was added over 30 min. The suspension was stirred at 0 to 10° C. for a further 30 min. The product was isolated by filtration and washed with water (4×140 ml). The product was dried under vacuum at 25° C. to constant weight. Yield: 82.6 g (95%). Assay (HPLC): 100% pure vs. standard
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[N:7][N:8]2COCC[Si](C)(C)C)=[CH:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CO>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC(=O)N2CCCCC2)c2cc(-c3ccccc3)c(F)c(F)c21
Agent: Cl
Solvent: CO
Product: O=C(Nc1n[nH]c2c(F)c(F)c(-c3ccccc3)cc12)N1CCCCC1

Procedure:
80 mg of piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl)amide in 2.5 ml of methanol are treated with 0.82 ml of 2N HCl for 1 hour at reflux. After evaporation and purification by preparative LC/MS (acetonitrile/pH 9 buffer), 11 mg of piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide are obtained.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23].O>CN(C=O)C>[CH2:22]([NH:24][C:25](=[S:26])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CCN=C=S
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=S)OCCOc1ccc(SC(C)CC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above alcohol (2.16 g, 10.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 10 ml of DMF is cooled to 5° and ethyl isothiocyanate (1.10 ml, 12.0 mmol) in 10 ml of DMF is added dropwise. After addition is complete, the mixture is allowed to warm to RT and is stirred at RT overnight. Water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, the solvent removed and the residue is purified by column chromatography to give O-2-[4-(1-methylpropylthio)phenoxy]ethyl N-ethylthiocarbamate (compound 38, Table A).
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([CH2:22][C:23]([NH:25][NH2:26])=O)#[N:21]>CO>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:23]([CH2:22][C:20]#[N:21])=[N:25][N:26]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: N#CCC(=O)NN
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Solvent: CO
Product: N#CCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
1.2 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed for 1.5 hours together with 2 g of cyanoacetic acid hydrazide in 80 ml of absolute methanol, a dry nitrogen stream being conducted through the solution. The solution is concentrated to 10 ml and left to crystallize. The 7-chloro-5-(o-chlorophenyl)-2-(2-cyanoacetylhydrazino)-3H-thieno[2,3-e]-1,4-diazepine, which is filtered off under a vacuum and dried, is refluxed for 2 hours in 150 ml of absolute xylene. The solution is evaporated and the residue recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-9-cyanomethyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 217°-220° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:10](=[O:11])[N:9]2[CH:4]1S[S:6][C:7]([S:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([CH:3]1[C:10](=[O:11])[N:9]2[CH:4]1[S:6][C:7]([S:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(C)=O)SSC12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(C)=O)SC12
Reaction time: 0.17 h

Procedure:
To a solution of 0.90 g of 4-nitrobenzyl 7-ethyl-8-oxo-3-acetylthio-4,5-dithia-1-azabicyclo[4,2,0]oct-2-ene 2-carboxylate in 2 ml of dichloromethane was added, in one batch, a solution of 0.59 g of triphenylphosphine in 3 ml of dichloromethane. After 10 minutes, the reaction mixture was chromatographed directly on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title compound as a yellow crystalline solid. (Yield 0.25 g)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27](=[O:34])[CH2:26][CH2:25][C:24]1=[O:35]>>[ClH:18].[C:1]([C:5]1[N:6]=[C:7]([N:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27](=[O:34])[CH2:26][CH2:25][C:24]3=[O:35])[CH2:16][CH2:17]2)[CH:8]=[C:9]([CH3:11])[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Product: Cc1cc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)nc(C(C)(C)C)n1
Product: Cl

Procedure:
Analogously to Example 3b, reaction of 2-tert-butyl-4-methyl-6-piperazin-1-ylpyrimidine (1.97 mmol, 0.46 g) with 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione afforded 0.31 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCN(c2ccc(C(F)(F)F)cn2)C1
Yield: 7 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (100 mg, 0.30 mmol), 2-bromo-5-(trifluoromethyl)pyridine (67 mg, 0.36 mmol), and triethylamine (91 mg, 0.90 mmol) in acetonitrile was heated to reflux for 3 h. The reaction mixture was concentrated. The residue was purified by preparative TLC and preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(5-(trifluoromethyl)pyridin-2-yl) piperidin-3-yl)-1,3-oxazinan-2-one (10.09 mg, 7%). LC-MS Method 2 tR=1.34 min, m/z=482. 1H NMR (400MHz, CDCl3): 1.28 (m, 1H), 1.64 (m, 2H), 1.76 (m, 3H), 1.92 (m, 2H), 2.18 (m, 1H), 2.27 (m, 1H), 2.77 (m, 3H), 3.21 (m, 1H), 3.52 (t, 2H), 3.83 (broad, 1H), 4.11 (d, 1H), 4.25 (d, 1H), 6.57 (d, 1H), 7.03 (t, 2H), 7.23 (m, 2H), 7.54 (d, 1H), 8.29 (s, 1H).