Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47](F)(F)F)[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1>Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)[C@@H](Cc3cccc(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Product: Cc1cccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)c1

Procedure:
A solution of 131 mg (0.17 mmol) tert-butyl 4-{1-[(R)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-3-(3-trifluoromethyl-phenyl)-propionyl]-piperidin-4-yl}-piperazine-1-carboxylate (Example 149) in 1.5 mL of 4 M HCl was stirred overnight at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC.CN(C=O)C>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNC(=O)[C@@H]1CCCN1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.0 g of Boc-Pro-OH, 7.4 g of H-Gly-OBzl, 3.0 ml of NEM and 3.1 g of HOBt are dissolved in 50 ml of EA with the addition of 5 ml of DMF. 4.8 g of DCC are added, and the mixture is left to stir at room temperature for 48 hours. After concentration in vacuo, the residue is dissolved in 50 ml of EA, and the solution is extracted by shaking twice with 30 ml of aqueous citric acid solution and twice with saturated aqueous sodium bicarbonate solution, and the organic phase is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 10 ml of trifluoroacetic acid, reaction is allowed to take place at room temperature for 1 hour, and the mixture is concentrated in vacuo. The residue crystallizes from EA/pentane.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:23])[CH2:4][N:5]1[CH2:9][C@@H:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[O:7][C:6]1=[O:22].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.[BH4-].[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[OH:23][C@H:3]([CH2:4][N:5]1[CH2:9][C@@H:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[O:7][C:6]1=[O:22])[CH2:2][NH:1][CH2:35][C:33]1[CH:32]=[CH:31][C:28]2[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=2[N:34]=1
Reactant: COc1ccc2nccc([C@@H]3CN(C[C@@H](O)CN)C(=O)O3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2nccc([C@@H]3CN(C[C@@H](O)CNCc4ccc5c(n4)NC(=O)CS5)C(=O)O3)c2n1
Reaction time: 15 h
Yield: 75.1 %

Procedure:
To (R)-3-((S)-3-Amino-2-hydroxy-propyl)-5-(6-methoxy-[1,5]naphthyridin-4-yl)-oxazolidin-2-one (0.069 g, 0.22 mmol) in CH2Cl2 (7 mL) and MeOH (1.8 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2,b][1,4]thiazine-6-carbaldehyde (SB-735214, 0.043 g, 0.22 mmol) and the reaction mixture was stirred for 15 hours. Sodium borohydride (0.01 g, 0.26 mmol) was added followed by methanol (5 mL). After 1 hour, the reaction mixture was diluted with chloroform and washed with saturated aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated. Flash chromatography on silica gel using a gradient of 0-10% MeOH/CHCl3 afforded the product as a white solid (0.082 g, 76%) 1H NMR (400 MHz, CDCl3): δ8.80 (d, J=4.6 Hz, 1H); 8.25 (d, J=9.1 Hz, 1H); 7.70 (d, J=4.4 Hz, 1H); 7.55 (d, J=7.6 Hz, 1H); 7.16 (d, J=9.1 Hz, 1H); 6.87 (d, J=7.9 Hz, 1H); 6.32 (dd, J=8.7, 7.2 Hz, 1H); 4.57 (t, J=9.4 Hz, 1H); 4.04 (s, 3H); 3.91 (m, 1H); 3.75-3.84 (overlapping signals, 2H); 3.63 (dd, J=9.2, 6.9 Hz, 1H); 3.47-3.50 (overlapping signals, 2H); 3.46 (s, 2H); 3.22 (dd, J=14.4, 6.8 Hz, 1H); 2.79 (dd, J=12.4, 3.6 Hz, 1H); 2.57 (dd, J=12.4, 8.3 Hz, 1H). MS (ES) m/e 497 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:30]([OH:32])=[O:31])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(F)c(Cl)c3)cc12
Yield: 32 %

Procedure:
1-Benzyl-5-(3-chloro-4-fluoro-phenyl)-1H-indole-3-carboxylic acid was prepared from 1-benzyl-5-(3-chloro-4-fluorophenyl)-1H-indole (17.99 g, 53.6 mmol), n-butyllithium (26 mL, 65 mmol), crushed dry ice (20 g, 450 mmol) in dry THF (180 mL) according to the procedure described in Example 60. Purification by HPLC using 85% acetonitrile in water as the mobile phase afforded the title compound as a light pink solid (6.51 g, 32%), mp: 189-194° C. Mass spectrum (+APCI, [M+H]+) m/z 380. 1HNMR (400 MHz, DMSO-d6): δ 13.5-13.8 (br s, 1H), 8.05 (dd, 1H, J=6.5 Hz and 2.6 Hz), 8.0 (dd, 1H, J=6.1 Hz and 2.4 Hz), 7.9 (d, 1H, J=1.5 Hz), 7.5-7.55 (m, 2H), 7.4 (dd, 1H, J=8.5 Hz and 2.0 Hz), 7.3-7.35 (m, 2H), 7.2-7.25 (m, 3H), 6.55 (dd, 1H, J=3.2 Hz and 0.75 Hz) and 5.45 ppm (s, 2H). Elemental Analysis for C22H15ClFNO2: Calculated: C, 69.57; H, 3.98; N, 3.69. Found: C, 69.87; H, 3.83; N, 3.69.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:15]=[C:16]([CH3:17])[C:3]=12.Cl.C([OH:27])C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[NH:5][C:4]1[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:15]=[C:16]([CH3:17])[C:3]=1[C:2]2=[O:27]
Reactant: Cc1nn(-c2ccccn2)c2nc3cc(F)c(F)cc3c(Cl)c12
Reactant: CCO
Agent: Cl
Product: Cc1nn(-c2ccccn2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 4-chloro-6,7-difluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.21 g, 6.68 mmol) in ethanol (120 mL), 6N hydrochloric acid (6 mL, 36.0 mmol) was added and the mixture was heated under reflux for 3 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (2.08 g, 99% yield).
Reaction SMILES: O=S(Cl)[Cl:3].[Cl:5][C:6]1[N:11]=[N:10][C:9]([CH2:12]O)=[C:8]([O:14][CH3:15])[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[N:11]=[N:10][C:9]([CH2:12][Cl:3])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)nnc1CO
Solvent: ClCCl
Product: COc1cc(Cl)nnc1CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Excess SOCl2 is added to a stirred solution of (6-chloro-4-methoxy-pyridazin-3-yl)-methanol (140 mg, 0.8 mmol) in CH2Cl2 (4 mL). The reaction mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo; toluene (4 mL) is added and evaporated to dryness. Flash column chromatography (silica gel) purification of the residue provides 6-chloro-3-chloromethyl-4-methoxy-pyridazine as a clear oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=O)[N:20]=2)=[CH:12][CH:11]=1.B.O1CCCC1.[OH-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:20]=2)=[CH:12][CH:11]=1
Reactant: CC1CCCN1CCOc1ccc(-c2nc(CC(=O)N3CCCCC3)co2)cc1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1CCCN1CCOc1ccc(-c2nc(CCN3CCCCC3)co2)cc1
Yield: 23 %

Procedure:
A solution of 1-[(2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetyl]piperidine i54 (0.13 g, 0.33 mmol, 1 eq) in tetrahydrofuran (5 ml) is treated with borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 1.3 ml, 1.3 mmol, 4 eq) and the resulting mixture is refluxed overnight. A 2 N sodium hydroxide solution is added to reach pH 10 and the mixture is refluxed for 6 h. A saturated solution of aqueous ammonium chloride is added and the solution is extracted two times with ethyl acetate. The organic layers are dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96/3.6/0.4) gives 0.115 g of 1-[2-(2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)ethyl]piperidine 121.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[N:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[OH:26].CCOCC>N1C=CC=CC=1>[OH:26][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[CH:12]=2)[N:17]=[N:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)c1nnc2ccc(NS(C)(=O)=O)cc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulphonic anhydride (1.392 g.) was added to a solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.) in dry pyridine (20 ml.), and the mixture was stirred at room temperature overnight. The resulting solution was poured into ether (500 ml.) and the amorphous solid which precipitated was filtered off and applied to a silica column (100 g. Kieselgel 60). Elution with a mixture of 15% v/v ethanol and 85% v/v chloroform, and evaporation of the appropriate fractions gave ethyl 4-hydroxy-6-(methanesulphonylamino)cinnolin-3-yl carboxylate, m.p. 274°-5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[N:1]1([CH2:24][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=3)=[CH:30][CH:31]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccc(CN3CCc4ccccc43)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
To a solution of indoline (13 μL, 0.116 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (74 mg, 0.35 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 25 mg, 0.116 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with EtOAc (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (12.5-20% acetone/CH2Cl2) to give 3-[4-(2,3-dihydro-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (24 mg, 65%), as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.27 (br. s., 1H), 7.90 (br. s., 1H), 7.79 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.41 (d, J=8.2 Hz, 2H), 6.95 (d, J=6.9 Hz, 1H), 6.88 (t, J=7.7 Hz, 1H), 6.42-6.55 (m, 2H), 4.23 (s, 2H), 3.14-3.21 (m, 2H), 2.75-2.87 (m, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.C([NH:44][C:45]([NH:47]C(OC(C)(C)C)=O)=S)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl.[Hg]Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:45]([NH2:47])=[NH:44])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Agent: Cl[Hg]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NC(=N)N)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 34-1 (72.5 mg, 0.18 mmol) and triethylamine (0.15 mL, 1.07 mmol) in 1 mL of DCM, was added mercury chloride (60 mg, 0.22 mmol) and di-Boc-thiourea (60 mg, 0.22 mmol). The mixture was stirred at room temperature for 4 h. It was then diluted with DCM (40 mL), filtered through a pad of celite, water (40 mL) was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (2×40 mL), the combined extracts were dried over magnesium sulfate, filtered and the solvent was removed under vacuum to give a yellow oil. The oil was dissolved in DCM (5 mL) and TFA (2 mL, 25.96 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated and dissolved in DCM for purification on preparative HPLC to give 36-1: LC-MS 453.1 (MH), tR=5.05 (Method 2). EC50: 1320 nM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)[C:8]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)Nc2cc(Br)cnc21
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CNc2cc(Br)cnc21

Procedure:
Prepared according to procedure K using 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (300 mg, 1.244 mmol), sodium bis(2-methoxyethoxy)-aluminium hydride (1.131 mL, 3.73 mmol) in toluene (3 mL). After purification 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine was obtained as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1)(C)(C)C.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+].C(=O)(O)[O-].[Na+].[CH3:52][O:53][C:54]1[N:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C(Cl)Cl>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:60]([C:57]3[CH:56]=[N:55][C:54]([O:53][CH3:52])=[CH:59][N:58]=3)=[O:61])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
tert-Butyl((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (Preparation Example 1, 56 mg) was dissolved in DCM (2 mL) and 5-methoxypyrazine-2-carboxylic acid (40 mg), N,N-diisopropylethylamine (80 mg) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (135 mg) were added. The reaction mixture was stirred at RT for 18 h, and sodium bicarbonate (sat., aq., 25 mL) was added. The mixture was extracted with EtOAc (2×40 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (EtOAc/hexanes gradient) to afford the amide (40 mg) as a white solid. The amide was dissolved in DCM (2 mL) and TFA (1 mL) was added. After stirring at RT for 2 h, the reaction mixture was evaporated and sodium bicarbonate (sat., aq., 25 mL) was added. The mixture was extracted with EtOAc (2×25 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound as a white solid (34 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.78-2.87 (m, 1 H), 3.11-3.21 (m, 1 H), 3.38-3.48 (m, 1 H), 3.82-4.06 (m, 4 H), 4.48-4.72 (m, 2 H), 6.96-7.10 (m, 1 H), 7.52 (d, J=4.8 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H), 8.09 (s, 1 H), 8.95 (s, 1 H), 9.46 (br. s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:12]=[CH:11]2
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cccc2cc[nH]c12
Temperature: -50 °C
Reaction time: 1 h

Procedure:
2 Fluoronitrobenzene (20.0 g, 0.142 mol) was dissolved in dry tetrahydrofuran (400 ml) and cooled to -50° C. Vinylmagnesium chloride (288 ml, 15% wt/vol) was added at -45° C. and stirred at this temperature for one hour. Poured onto saturated ammonium chloride (600 ml). Separated and aqueous extracted with diethyl ether (2×200 ml). Dried (MgSO4), filtered and concentrated in vacuo to yield a dark oil which was purified by column chromatography on silica using toluene as mobile phase. Fractions concentrated to yield a crystalline solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C:6](=[O:15])[C:5]=12.[CH3:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][Mg]Cl>O1CCCC1>[OH:15][C:6]1([CH2:20][CH2:19][CH2:18][N:17]([CH3:23])[CH3:16])[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]12
Reactant: CN(C)CCC[Mg]Cl
Reactant: O=C1c2ccccc2CCn2cccc21
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2CCn2cccc21
Reaction time: 0.67 h

Procedure:
To a solution of 16 g., (0.081 mole) of 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 300 ml. tetrahydrofuran (THF) is added 150 ml. of 1.0N solution of 3-dimethylaminopropyl magnesium chloride in THF. After stirring for 40 minutes at ice-bath temperature and for 1.5 hours at 25° C., the bulk of the solvent is distilled below 45° C. under reduced pressure. The residue is dissolved in 500 ml. of methylene chloride and the Grignard adduct is hydrolyzed by the dropwise addition of 15 ml. water with cooling in an ice bath. The methylene chloride solution is decanted and the gelatinous precipitate is extracted three times with 80 ml. portions of boiling benzene. The combined organic extracts are washed with water and then evaporated under reduced pressure to yield, after crystallization from ethanol, 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepine, m.p. 68°-70° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[C:16](Br)([CH2:19][CH3:20])[CH2:17][CH3:18]>CS(C)=O.C1COCC1.CCOC(C)=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:16][CH2:17][CH2:18]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCC(Br)(Br)CC
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
A slurry of NaH (711 mg, 29.6 mmol) in DMSO (10 mL) and THF (3 mL) was treated portionwise slowly with (4-nitro-phenyl)-acetonitrile (2.00 g, 12.3 mmol) and stirred at RT for 5 min until H2 evolution ceased. A solution of dibromopentane (2.02 mL, 14.8 mmol) in THF (10 mL) was added to the slurry over 10 min. The mixture was stirred at RT for an additional 5 min, placed in an oil bath at RT, slowly warmed to 70° C., and stirred at 70° C. for 1 h. The cooled mixture was diluted with EtOAc (250 mL) and washed with water (3×100 mL) and brine (2×100 mL). The combined aqueous layers were extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 10% EtOAc-hexane afforded the title compound (1.46 g, 51%) as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 8.26 (d, 2H, J=8.4 Hz), 7.69 (d, 2H, J=8.4 Hz), 2.21-2.13 (m, 2H), 1.98-1.74 (m, 8H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1>C(N(CC)CC)C>[CH:1]([NH:4][CH2:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: CC(C)N
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(CNC(C)C)c1
Yield: 69.9 %

Procedure:
The procedure described in Referential Example 4 was repeated, except that isopropylamine (instead of triethylamine) (11.82 g; 200 mmol) and 3′-bromomethylacetophenone (4.26 g; 20 mmol) were used, to thereby yield 2.67 g of the target compound (yield: 69.9%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@:7]23[CH2:16][CH2:15][CH2:14][CH2:13][C@H:8]2[O:9]C(=O)O3)=[CH:5][CH:4]=[N:3]1>[C].[Pd].C1COCC1>[CH3:1][N:2]1[C:6]([C@H:7]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:8]2[OH:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@]12CCCC[C@H]1OC(=O)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CCCC[C@H]1O
Yield: 21.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 167b by using the (3aR,7aR)-3a-(1-methyl-1H-pyrazol-5-yl)hexahydro-1,3-benzodioxol-2-one (760 mg, 3.42 mmol) prepared in Example 168b, palladium carbon (10%; 760 mg) and THF (10 mL), to yield the title compound (133 mg, 22%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C@H:3]1[CH2:16][C@@H:15]([CH3:17])[O:14][CH:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:4]1[OH:18].[H-].[Na+].[CH3:22]OS(OC)(=O)=O>O1CCCC1.C(OCC)(=O)C.O>[CH3:22][O:18][C@@H:4]1[C@@H:3]([N:2]([CH3:1])[CH3:19])[CH2:16][C@@H:15]([CH3:17])[O:14][CH:5]1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: C[C@@H]1C[C@H](N(C)C)[C@@H](O)C(OCc2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1C(OCc2ccccc2)O[C@H](C)C[C@@H]1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Benzyl 3,4,6-trideoxy-3-(dimethylamino)-D-xylohexopyranoside (Korte, F., A. Bilow and R. Heinz, Tetrahedron, 1962, 18, 657,666, 10.01 g, 38.06 mmoles) was dissolved in tetrahydrofuran (300 mL) with stirring at room temperature under an argon atmosphere. The solution was treated with small portions of sodium hydride (60% oil dispersion, 1.83 g, 45.68 mmoles). After one hour, dimethylsulfate (5.28 g, 41.87 mmoles) was added and the reaction mixture was stirred for two hours. The reaction mixture was quenched by the careful addition of water and the solution was evaporated in vacuo leaving an oily residue which was resuspended in ethyl acetate and water. The organic layer was separated, dried (MgSO4) and filtered to afford 9.74 g (93%) of the title compound as a slightly yellow oil which solidified on standing.