Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:34]([CH:32]2[CH2:33][N:30]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:31]2)[CH2:35]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1(F)CCN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)C4)C3)n(C)c2n1
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 1-azetidin-3-yl-3,3-difluoropyrrolidine (46 mg, 0.28 mmol) and 4 Å powdered molecular sieves in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.52 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 589 as an orange foam (97 mg, 69%). LCMS (method I): RT 2.74 min [M+H]+ 538.2 1H NMR (CDC3, 300 MHz): δ 8.00 (m, 1 H), 7.75 (m, 1 H), 7.27 (m, 2 H), 4.42-4.27 (m, 4 H), 3.87-3.84 (m, 9 H), 3.54 (t, J=6.5 Hz, 2 H), 3.32-3.30 (m, 3 H), 3.19 (t, J=6.5 Hz, 2 H), 2.89 (t, J=13.1 Hz, 2 H), 2.70 (t, J=6.9 Hz, 2 H), 2.29-2.28 (m, 2 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:25]1[CH2:28][C:27]([CH2:31][NH2:32])([CH2:29][NH2:30])[CH2:26]1>>[NH2:30][CH2:29][C:27]1([CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:28][O:25][CH2:26]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(CN)COC1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 7.86-7.75 (m, 3 H), 7.59-7.51 (m, 3 H), 7.67 (t, J=3.6 Hz, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 6.22 (s, 1 H), 5.45 (d, J=16.4 Hz, 1 H), 5.10 (brs, 1 H), 4.76 (brs, 1 H), 4.60 (m, 4 H), 3.94 (d, 2 H), 4.52 (s, 2 H), 3.47 (s, 2 H), 2.46 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][Cl:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: ClCC1CCN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
To a refluxing solution of 15.3 g (0.08 mole) (3RS)-1-benzyl-3-hydroxymethyl pyrrolidine in 220 ml CHCl3 was slowly added a solution of 330 ml thionyl chloride in 60 ml CHC13, and the reflux was continued for one hour. The mixture was evaporated and the residue was dissolved in water. The water layer was washed with ethyl acetate and then made alkaline with 0.2M NaOH-solution. The water layer was extracted three times with ethyl acetate and the combined organic layer was dried (Na2SO4), filtered and evaporated to give the product in a quantitative yield (16.8 g)
Reaction SMILES: CC([N:5]([C@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@@H](C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl((1S)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 66, 70 mg) in dichlorometane (2.5 mL) cooled down to 0° C. TFA (0.779 mL, 10.11 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 hours and then evaporated. The residue was diluted with dichloromethane (10 mL) and neutralized with a saturated aqueous solution of NaHCO3 (15 mL). The organic phase was separated, dried over sodium sulphate, filtered and evaporated to afford the title compound as a yellow pale oil (53.1 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:31]1[C:35]([CH:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[N:34][N:33]=[N:32]1>>[NH:34]1[C:35]([CH:36]2[CH2:37][CH2:38][CH:39]([C:42]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]5[N:17]=[C:18]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[O:19][C:20]=5[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=4)[CH2:3][CH2:2]3)=[O:43])[CH2:40][CH2:41]2)=[N:31][N:32]=[N:33]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)C1CCC(c2nnn[nH]2)CC1
Product: O=C(Nc1ccc(C2CCN(C(=O)C3CCC(c4nnn[nH]4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[4-(1H-tetrazol-5-yl)-cyclohexanecarbonyl]-piperidin-4-yl}-phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (212 mg, 0.51 mmol) and 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid (100 mg, 0.51 mmol) as an off white solid (147 mg, 49%). LCMS calcd for C30H30F3N7O3 (m/e) 593, obsd 594 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Cl:1][C:2]1[C:3]([NH:9][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[S:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Cl)cc1Cl
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ncc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To 3,5-dichloropyridin-2-amine (3.87 g, 23.73 mmol) in acetone (20 mL) was added benzoyl isothiocyanate (3.2 mL, 23.73 mmol). The mixture was stirred at ambient temperature for 1 h, and the resultant precipitate was collected by filtration (3.89 g). The filtrate was returned to the reaction flask and heated to reflux 1 h. At this time, the reaction had gone dry. The solids were suspended in acetone and collected by filtration to give 2.24 g. of N-(3,5-dichloropyridin-2-ylcarbamothioyl)benzamide (5.93 g, 18.18 mmol, 77% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 12.78 (br. s., 1H) 9.25 (br. s., 1H) 8.46 (br. s., 1H) 7.94 (d, J=7.63 Hz, 2H) 7.88 (d, J=2.44 Hz, 1H) 7.69 (t, J=7.48 Hz, 1H) 7.58 (t, J=7.78 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:12])([O-:3])=[O:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]OS(C)(=O)=O)=[C:29]([CH3:39])[CH:28]=1>O>[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:12][C:5]2[CH:6]=[C:7]([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[C:29]([CH3:39])[CH:28]=1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C
Reactant: COC(=O)c1ccc(COS(C)(=O)=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2[N+](=O)[O-])c(C)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Under atmosphere of argon, a mixture of 2-nitro-4,5-dimethylphenol (4 g), DMF (100 ml), potassium carbonate (6.6 g) and 4-mesyloxymethyl-3-methylbenzoic acid methyl ester (6.8 g) were stirred for 15 minutes at 60° C. After the termination of reaction, the mixture was cooled and poured into iced water. The mixture was extracted with ethyl acetate-hexane. The organic layer was washed, dried, concentrated under reduced pressure to give the title compound (7.22 g) having the following physical data.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[BH4-]>C1COCC1.CO>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][CH:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution containing 3-(tert-Butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (12 g, 33 mmol) in THF (50 mL) was cooled to 0° C. LiBH4 in THF (2M, 20 mL) was added in a dropwise fashion. After 1 h, the solution was warmed to ambient temperature. After 2 h, the solution was diluted with MeOH, then H2O, and concentrated. The residue was extracted with EtOAc, washed with 1M HCl, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 9.5 g (87%) of 3-(tert-Butyldimethylsilanyloxy)-2-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (1) as a colorless oil (See: Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry, 1994, 5, 119).
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:8][CH:9]=1.N.CO>C(OCC)(=O)C>[NH2:13][CH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][C:2]([CH3:28])([OH:1])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:9]=[CH:8][CH:7]=1
Reactant: CCCCC(C)(O)Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(C)(O)Cc1cccc(CCCN)c1

Procedure:
Deprotection of 2-(3-(3-(2-hydroxy-2-methylhexyl)phenyl)propyl)isoindoline-1,3-dione followed by flash chromatography (0-10% (7N NH3/MeOH)/ethyl acetate) gradient gave Example 121 a colorless oil. Yield (0.144 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.18-7.24 (m, 1H), 7.00-7.08 (m, 3H), 2.68-2.78 (m, 4H), 2.60-2.68 (m, 2H), 1.71-1.80 (m, 2H), 1.24-1.50 (m, 9H), 1.12 (s, 3H), 0.91 (t, J=7.2 Hz, 3H). ESI MS m/z 250.3 [m+H]+, 232.3 [m+H−H2O]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=2)[CH2:3][CH2:2]1>[Pd].CO>[NH2:13][C:11]1[CH:10]=[C:9]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=1
Reactant: CC(C)C(=O)Nc1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)Nc1cc(N)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure V by stirring N-(3-morpholino-5-nitrophenyl)-isobutyramide (0.298 g, 1.016 mmol), 10% palladium on carbon (0.216 g, 0.203 mmol), and methanol (3 mL) for 30 minutes to afford N-(3-amino-5-morpholinophenyl)isobutyramide as a beige amorphous solid. Mass Spectrum (ESI) m/e=264.2 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([F:17])[F:16])=[N:12][CH:13]=1)=[CH2:7])CCC.[Br:18]N1C(=O)CCC1=O>C1COCC1.O.O>[Br:18][CH2:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1ccc(OC(F)F)nc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OC(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A solution of 100 mg (0.41 mmol) of 5-(1-butoxyvinyl)-2-difluoromethoxypyridine in 4 mL of THF/H2O (3/1: v/v) is cooled to 0° C. 74 mg (0.41 mmol) of N-bromosuccinimide are then added in a single portion. The yellow solution is stirred at 0° C. for 1 hour and then taken up in water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaHCO3 solution and then with saturated NaCl solution, dried over magnesium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 20/80 EtOAc/heptane to 40/60 EtOAc/heptane over 15 minutes) to give 82 mg of 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: [CH2:1]([S:13](Cl)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[F:27])[NH:23][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH2:34])[CH:33]=1)=[CH:21]2.O.Cl>N1C=CC=CC=1>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[F:27])[NH:23][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH:34][S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:33]=1)=[CH:21]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(-c2cc3cc(F)c(F)cc3[nH]2)ccc1OC
Yield: 44.9 %

Procedure:
1-Dodecanesulfonyl chloride (0.3 g, 1.1 mmol) was added to a stirred solution of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl-amine from Example 3 (0.3 g, 1.11 mmol) in pyridine (3 mL) under an inert atmosphere at room temperature. After approximately 20 hours the mixture was poured into water (30 mL), stirred, and acidified with aqueous HCl. After several hours the precipitate was filtered off, rinsed three times with water, and dried. Recrystallization from ethanol afforded the product (0.25 g), mp 148-149° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>C1COCC1>[C:10]([C:9]1[CH:12]=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:6]=[CH:7][C:8]=1[F:13])#[N:11]
Reactant: N#Cc1cc(C(=O)CBr)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(Bromoacetyl)-2-fluorobenzonitrile (590 mg, 2.44 mmol) and (S)-4-N—BOC-2-hydroxymethyl-piperazine (527 mg, 2.44 mmol) were dissolved in THF (40 mL) at 0° C. then TEA (247 mg, 2.44 mmol) was added. The reaction mixture was stirred at RT for 16 h, then poured into water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by MPLC through an 80 g Redi-sep column using 0-100% EtOAc/hexane to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([CH2:24]Cl)(=[O:23])=[O:22])[C:15]=2[OH:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[O:26][CH2:24][S:21](=[O:23])(=[O:22])[N:20]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NS(=O)(=O)CCl)c2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCS(=O)(=O)N3Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.3 %

Procedure:
To a flask containing 7 mL methanol was added 4-(3-chloromethanesulfonylamino-2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (190 mg., 0.471 mmol) and potassium carbonate (195 mg, 1.4 mmol). The suspension was refluxed for two hours under nitrogen and allowed to cool to room temperature. To the reaction mixture was added benzyl bromide (0.083 mL, 0.7 mmol) and potassium carbonate (87 mg., 0.7 mmol), and the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the resulting crude solid was dissolved in ethyl acetate. The solution was washed with 50 mL water and 50 mL brine, and the ethyl acetate was removed in vacuo. The resulting residue was purified by flash chromatography to give 57 mg of 4-(1-Benzyl-2,2-dioxo-2,3-dihydro-1H-benzo[4,2,1]oxathiazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a light purple oil (26%). (M+H)+=460
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([Li])(C)(C)C.C(N([CH2:29][C:30]1[C:31](=[O:43])[CH2:32][C@@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:34]=1)CC)C.CCCCCC>CCOCC>[CH2:29]=[C:30]1[C@@H:34](/[CH:2]=[CH:3]/[C@@H:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C@H:33]([O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])[CH2:32][C:31]1=[O:43]
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H](/C=C/I)C1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 0 °C

Procedure:
(1E,3S)-1-Iodo-3-(tert-butyldimethylsiloxy)-3-cyclohexyl-1-propene (2.66 g) was dissolved in ether (28 ml), tert-butyl lithium (1.7 M, pentane solution, 8.24 ml) was added at −78° C. After stirring at the same temperature for an hour, lithium 2-thienylcyanocuprate (0.25 M, tetrahydrofuran solution, 39.2 ml) was added, followed by stirring at the same temperature for 20 minutes, and (4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)cyclopent-2-en-1-one (0.25 M, ether solution, 28 ml) was added. The temperature was raised to 0° C. with stirring over 1.5 hours. To the reaction solution were added hexane (70 ml) and a saturated aqueous ammonium chloride solution (105 ml) and, after extraction with hexane, the extract was washed with a saturated aqueous sodium chloride solution, dried, concentrated and purified by a silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=30:1) to give (3R, 4R)-2-methylene-3-[(1E,3S)-3-(tert-butyldimethylsiloxy)-3-cyclohexyl-1-propenyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one (910 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[OH-].[K+]>Cl.C1(C)C=CC=CC=1>[CH3:14][C:13]1[CH:12]=[CH:11][C:9]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[N:8]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: C/C=C/C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 100 °C

Procedure:
4-Nitroaniline (6 g, 38 mmol) was dissolved in HCl (6N, 200 mL), the mixture was heated at 100° C. A solution of (E)-but-2-enal (7.2 mL, 76 mmol) in toluene (60 mL) was added dropwise, and the reaction was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and basified with aqueous KOH until pH=12. The mixture was extracted with EtOAc and the organic layer was washed with brine and dried over anhydrous Na2SO4. 2-Methyl-6-nitroquinoline was obtained after purification by column chromatography (hexane:EtOAc=20:1) (5.8 g, 81.2%). MS [M++1]=189, LC-MS: tR=1.64 min.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[NH2:11][C:12]1[C:21]2[N:22]=[C:23]3[CH2:28][O:27][CH2:26][CH2:25][N:24]3[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:5]1([C:3](=[O:4])[CH2:2][O:29][C:16]2[CH:15]=[C:14]3[C:19]([C:20]4[N:24]5[CH2:25][CH2:26][O:27][CH2:28][C:23]5=[N:22][C:21]=4[C:12]([NH2:11])=[N:13]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=C(CBr)N1CCOCC1
Reactant: Nc1nc2cc(O)ccc2c2c1nc1n2CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc2cc(OCC(=O)N3CCOCC3)ccc2c2c1nc1n2CCOC1
Temperature: 90 °C
Yield: 12.5 %

Procedure:
A glass vial was charged with 4-(bromoacetyl)morpholine (0.05 g, 0.26 mmol, 1.1 eq), 6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.06 g, 0.23 mmol), DMF (3 mL), and cesium carbonate (0.42 g, 1.3 mmol, 5 eq). The reaction mixture was heated at 90° C. overnight. The reaction was quenched with 30 mL water to provide an off-white precipitate. The solid was collected by vacuum filtration and recrystallized from acetonitrile to provide 0.011 g of 3-(2-morpholin-4-yl-2-oxoethoxy) 10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine, mp 204-206° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1c(OCc2ccccc2)ccc2ccccc12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-bromo-2-naphthol (15.0 g, 67.3 mmol) and K2CO3 (18.6 g, 135 mmol) in DMF (100 mL) was added benzyl bromide (9.6 mL, 81 mmol) and the mixture was stirred at 60° C. for 5 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue, dissolved in a small amount of CH2Cl2, passed through a thin pad of flash silica. Fractions containing the product were evaporated in vacuo to give an off-white solid. Crystallisation from CH2Cl2/petrol gave the title compound, 1-bromo-2-(phenylmethoxy)naphthalene, as a white crystalline solid (16.0 g, 76%). The mother liquor was concentrated and purified by flash chromatography (petrol/CH2Cl2, 2/1) to give an additional amount of the product (3.7 g, 17%; total yield: 93%). Rf=0.50 (petrol/CH2Cl2, 2/1); mp 104-106° C. (CH2Cl2/petrol); 1H NMR (250 MHz, CDCl3) δ5.35 (s, 2H), 7.32 (d, J=9.0 Hz, 1H), 7.38-7.50 (m, 4H), 7.57-7.66 (m, 2H), 7.79-7.86 (m, 3H), and 8.31 (d, J=8.5 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ71.81, 110.0, 115.6, 124.6, 126.3, 127.2, 127.8, 128.1 (2C), 128.7, 128.9, 130.1, 133.2, 136.7 and 153.0; IR (CHCl3) νmax 1626, 1596, 1502, 1350, and 1268 cm−1; MS (EI+) m/z (rel intensity) 314/312 (25%, M+) and 91 (100); HRMS calcd for C17H13BrO (M+) 312.0150. found 312.0150. Anal. Calcd for C17H13BrO: C, 65.19; H, 4.18; Br, 25.51. Found: C, 64.94; H, 4.12; Br, 25.71.