Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccccc1C(=O)O
Product: COc1ccccc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Methoxy-benzoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[O:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([N:32]4[C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=[C:31]4[CH3:30])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)([CH3:23])[C:19]([NH2:21])=[O:20]
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2oc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Temperature: 110 °C
Yield: 66.7 %

Procedure:
A mixture of 2-[4-(2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (500 mg, 1.18 mmol), 2-methyl-1H-benzoimidazole (180 mg, 1.36 mmol), Pd2dba3 (27 mg, 0.029 mmol), Xphos (57 mg, 0.12 mmol) and cesium carbonate (580 mg, 1.78 mmol) in 1,4-dioxane (10 mL) was heated at 110° C. for 18 h. The reaction mixture was cooled to ambient temperature, then loaded onto an Isolute® SCX-2 cartridge, which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) followed by trituration from hot EtOAc to afford 240 as a white solid (408 mg, 67%). LCMS (Method G): RT=5.23 min, M+H+=519. 1H NMR (CDCl3, 400 MHz) δ 8.03-7.98 (m, 1 H); 7.73-7.69 (m, 1 H); 7.28-7.23 (m, 2 H); 7.05 (bs, 1 H); 6.76 (s, 1 H); 5.27 (bs, 1 H); 4.08 (t, J=4.7 Hz, 4 H); 3.89 (t, J=4.7 Hz, 4 H); 3.76 (s, 2 H); 2.90 (s, 3 H); 2.62 (m, 8 H) and 1.24 (s, 6 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](O)=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:65]([O:72][C:73](=[O:79])[C@@H:74]1[CH2:78][CH2:77][CH2:76][NH:75]1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:44])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:75]3[CH2:76][CH2:77][CH2:78][C@H:74]3[C:73]([O:72][CH2:65][C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)=[O:79])=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccc(F)c(F)c3)n2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccc(F)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.5 g 4-((S)-4-tert-Butoxycarbonyl-2-{[5-carboxymethoxy-1-(3,4-difluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 30 ml DMF were added 0.614 g HOBt, 1.32 ml DIPEA and 0.969 g L-proline benzyl ester hydrochloride at RT. Then 0.769 g EDC were added portionwise and the suspension stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCOCC1>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: Nc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccccc2)nc(N2CCOCC2)n1
Yield: 49.1 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and aniline (58 mg, 0.625 mmol) in dioxane (5 mL) was heated under reflux for 1 hr and cooled. Dilution with water gave a white precipitate, which was recrystallised from MeOH to give 52 mg (49% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-phenyl-1,3,5-triazin-2-amine: mp 171-174° C.; 1H NMR (CDCl3) δ 8.40 (m, 1H), 7.89 (m, 1H), 7.58 (t, JHF=54.7 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.43-7.38 (m, 4H), 7.20 (t, J=7.3 Hz, 1H), 7.09 (br, exchangeable with D2O, 1H), 3.93 (m, 4H), 3.81 (m, 4H); Anal. Calc. for C21H19F2N7O: C, 59.6; H, 4.5; N, 23.2. Found: C, 59.6; H, 4.5; N, 23.3%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C@H:45]1[CH2:47][C@H:46]1[C:48](O)=[O:49].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:44][C@H:45]1[CH2:47][C@H:46]1[C:48]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][N:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:19])[CH:17]=2)=[O:49]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cc1c(F)cncc1-c1cc2cnc(N)cc2cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)[C@@H]3C[C@@H]3F)cc2cn1
Temperature: 70 °C
Yield: 42 %

Procedure:
A mixture of 7-(5-fluoro-4-methyl-3-pyridyl)-2,6-naphthyridin-3-amine (35 mg, 0.14 mmol), HATU (113 mg, 0.29 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (29 mg, 0.28 mmol), and N,N-diisopropylethylamine (0.10 mL, 0.55 mmol) in DMF (1 mL) was heated at 70° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% ACN in water w/0.1% NH4OH, 14 min). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (20 mg, 43%). 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 9.35 (s, 1H), 8.70 (s, 1H), 8.59 (sz, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 4.98 (m, 1H), 2.37 (d, J=1.9 Hz, 3H), 2.31 (m, 1H), 1.72 (m, 1H), 1.23 (m, 1H). LCMS (Method E): RT=3.978 min, M+H+=341.2.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH2:13][CH2:12][C:11]([CH2:16][CH:17]3[CH2:19][CH2:18]3)([C:14]#[N:15])[CH2:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.O1CCCC1.B>O1CCCC1.CO.ClCCl>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:14][NH2:15])([CH2:16][CH:17]3[CH2:18][CH2:19]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N#CC1(CC2CC2)CC=C(S(=O)(=O)CC2CC2)CC1
Agent: B
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
A cooled (0° C.) solution of 4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohex-3-enecarbonitrile (3.5 g, 12.4 mmol) in tetrahydrofuran (10 ml) was treated with borane tetrahydrofuran complex (1M in tetrahydrofuran, 62 ml) dropwise over 20 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 4 hours. The solution was cooled to 0° C. and quenched by the slow addition onto cooled (0° C.) methanol (30 ml). On complete addition concentrated hydrochloric acid (3.5 ml) was added and the mixture was allowed to warm to ambient temperature and stirred for 1 hour. The solvent was evaporated and the residue azeotroped with toluene to give a white solid. The solid was dissolved in methanol:dichloromethane (1:1) and purified using an SCX cartridge. The product was washed with methanol then eluted with 2M ammonia in methanol and evaporated to give the desired product as a colourless oil (2.87 g, 81%). 1H NMR δ (ppm) (d6-DMSO): 3.21 (2H, s), 3.05-2.98 (3H, m), 2.62 (2H, s), 1.88-1.84 (2H, m), 1.80-1.74 (2H, m), 1.60-1.53 (2H, m), 1.28-1.22 (2H, m), 1.15 (2H, d, J=6.7 Hz), 1.10-1.02 (1H, m), 0.64-0.62 (3H, m), 0.43-0.36 (4H, m), 0.13-0.06 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:12]>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([Br:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cccc(F)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(Br)c1cccc(F)c1
Yield: 78.6 %

Procedure:
Dissolve (±)-1-(3-fluorophenyl)ethanol (250 mg, 1.786 mmol) in carbon tetrachloride (10 mL). Add phosphorus tribromide (0.1 mL, 1.786 mmol) at 0° C. and stir the solution at room temperature overnight. Dilute the reaction mixture with dichloromethane and wash with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain the title compound (285 mg) that was used without any further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C.O>[CH2:41]([S:42]([NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:11][N:10]=2)[CH2:7][CH2:8]1)(=[O:44])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CS(=O)(=O)c1cnc(N2CCC(CN)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1cnc(N2CCC(CNS(=O)(=O)Cc3ccccc3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To 0.028 g (0.066 mmol) of N-(4-aminomethyl-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide in a mixture of acetonitrile (0.5 mL) and saturated aqueous sodium carbonate (0.5 mL) is added 0.015 mg (0.079 mmol) of phenylmethanesulfonyl chloride. The mixture is stirred overnight at room temperature then diluted with water and extracted with ethyl acetate. The combined organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography to give 0.027 g (72%) of the title compound (109) as a clear resin. [M+H]+=577.7.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16]C.[O:19]1CCC[CH2:21][CH:20]1OC1CCCCO1.C(Cl)(=O)C>C(O)(=O)C>[C:20]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:19])[CH3:21]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CCCCC/C=C\CCCCCCCCCCO
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCCC/C=C\CCCCCCCCCCOC(C)=O
Reaction time: 3 h
Yield: 55.7 %

Procedure:
9 g. of (Z)-11-hexadecenol-tetrahydropyranyl ether (Formula III, R=H, Y=tetrahydropyranyl) are dissolved in 25 ml. of acetic acid. 6 ml. of acetyl chloride are added, and the solution is boiled on an oil bath of about 80° C. for 3 hours. The mixture is cooled, poured onto 50 g. of ice, and extracted thrice with a total amount of 200 ml. of hexane. The extracts are combined, washed with 30 ml. of water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled off in fine vacuo. 5.3 g. (55.7%) of (Z)-11-hexadecenyl acetate are obtained; b.p.: 142°-144° C./0.25 mmHG.; 120°-122° C./0.05 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(OCC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:16][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)COc2ccccc2C(N)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cccc(C2=COc3ccccc3C(=O)N2)c1
Yield: 89.7 %

Procedure:
A well stirred suspension of 9 g (31.5 mmol) of 2-[2-(3-Methoxy-phenyl)-2-oxo-ethoxy]-benzamide and 0.3 g (1.58 mmol) of p-toluensulphonic acid in toluene (0.3 L) was refluxed with a Dean-Stark apparatus for 2 hours. After concentration of the solvent under reduced pressure, the residue was treated with ethyl acetate and diethyl ether and the resulting solid was filtered, washed with a mixture of the aforementioned solvents, dried in vacuo, affording 7.55 g of the title compound (83%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[OH:39])[N:23]=1>C(Cl)Cl>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])[N:23]=[C:22]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Reaction time: 1 h

Procedure:
At 0° C. under an N2 atmosphere, a solution of tert-butyl (R)-pyrrolidin-3-ylcarbamate (264 mg, 1.42 mmol) and triethylamine (0.33 mL, 2.36 mmol) in CH2Cl2 was rapidly added to a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (325 mg, 1.18 mmol) in 15 mL CH2Cl2. The reaction mixture was stirred for 1 h before it was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 yielded tert-butyl (R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 425.5 (M+H)+ at 2.74 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[C:5]([F:11])[CH:6]=1)([CH3:26])[CH3:25])[CH3:24]
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(F)c1
Temperature: 50 °C
Yield: 79.9 %

Procedure:
A suspension of 12.0 g (77.9 mmol) of 2-fluoro-4-hydroxyacetophenone, 27.9 g (85.6 mmol) of cesium carbonate and 11.6 ml (77.9 mmol) of ethyl 2-bromo-2-methyl-propionate in 200 ml of DMF was heated at 50° C. for 3 days. Twice a day additional 12.7 g (38.9 mmol) of cesium carbonate and 5.8 ml (38.9 mmol) of ethyl 2-bromo-2-methyl-propionate were added (total of 2.5 equivalents). The mixture was neutralized with aqueous 10% KHSO4 and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4, aqueous 10% NaCl solution, dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with n-heptane/AcOEt 9:1 to 6:1, to give 16.7 g of the title compound as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][CH2:12][C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Product: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow waxy solid (54 mg, 48% yield) following Scheme 3 and in analogy to Example 40 using 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (42 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=O.[N+]([O-])(O)=O>>[CH2:1]([OH:13])[C:2]([C@@H:3]([OH:11])[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6])=[O:12]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O=[N+]([O-])O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)C(=O)CO

Procedure:
2-keto-L-gulonic acid is an important intermediate in vitamin C manufacture. Condensation of L-sorbose with acetone in the presence of sulfuric acid followed by oxidation with permanganate and hydrolysis of the diisopropylidene derivative by boiling yields 2 keto-L-gulonic acid as described in Helv. Chim. Acta., 17, 311 (1934) and U.S. Pat. No. 2,301,811. The preparation of 2-keto-L-gulonic acid by careful oxidation of L-sorbose with nitric acid is claimed in British Pat. No. 443,901 and Dutch Pat. No. 59,584. The selective reduction of 2,5-diketogluconic acid to yield a mixture of 2-ketogluconic acid and 2-ketogulonic acid is described in co-pending application, Ser. No. 749,509 filed Oct. 10, 1976.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][C:13]([C:15]1[C:16](=[O:23])[O:17][C:18]([CH3:22])=[CH:19][C:20]=1[OH:21])=O.[NH2:24][CH2:25][CH2:26][SH:27].CCCCCC.C(OCC)(=O)C.C(Cl)Cl.C(OCC)(=O)C.CC(C)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:27][CH2:26][CH2:25][N:24]=[C:13]([C:15]2[C:16](=[O:23])[O:17][C:18]([CH3:22])=[CH:19][C:20]=2[OH:21])[CH2:12]1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(C)oc2=O)c(OC)c1
Reactant: NCCS
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NCCS2)c(OC)c1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
The crude reaction mixture prepared in Step 5.1 was diluted with absolute ethanol (5 mL). 2-Aminoethanethiol (2.31 g, 30 mmol fresh dry material) was added and the mixture heated to 75° C. The reaction was monitored by TLC (silica gel, hexane-ethyl acetate (1:1 v/v) and methylene chloride-ethyl acetate-acetone (5:5:1 v/v)) and analytical HPLC. After 1.5 hours (>90% completion) the reaction was allowed to cool to room temperature to form a yellow crystalline solid. The solid material was collected by filtration and washed with ethanol-diethyl ether (1:1 v/v) and then hexane. Product was purified by column chromatography and then crystallization (methylene chloride-ethanol) to provide 3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one (6.81 g, 61%). LCMS: MH+375.6. Elemental Analysis: Calc: C 60.78, H 5.64, N 3.73 Found: 60.73, H 5.66, N 3.73. 1H NMR (CDCl3-TMS): d 14.3 (bs, 1H), 7.23 (m, 1H), 6.46 (m, 2H), 5.69 (s, 1H), 4.76 (d, 1H, J=13 Hz), 4.47 (d, 1H, J=11 Hz), 4.17 (m, 1H), 4.00 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.52 (t, 1H, J=11.5 Hz), 3.00 (t, 1H, J=11.5 Hz), 2.78 (dd, 1H, J=11.5,5 Hz), 2.09 (s, 3H). 1H NMR (DMSO-d6): d 13.7 (bs, 1H), 7.23 (dd, 1H, J=9, 3 Hz), 6.5 (m, 2H), 5.7 (s, 1H), 4.37 (d, 1H, J=13 Hz), 4.28 (d, 1H, J=10 Hz), 4.08 (m, 2H), 3.73 (s, 6H), 3.61 (t, 1H, J=11 Hz), 2.79 (m, 2H), 2.03 (s, 3H). 13C NMR JEOL, (DMSO-d6): d 183.84, 178.36, 163.42, 162.89, 160.32, 157.33, 128.28, 123.29, 107.76, 105.46, 99.16, 95.78, 56.26, 55.77, 46.0, 38.90, 34.19, 29.07, 19.68.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])=[O:10])=[S:2]
Reactant: CC(C)(C)[Si](OC(=O)c1cccc(O)c1)(c1ccccc1)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(=O)c1cccc(OC(=S)Cl)c1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 130 ml of thiophosgene in 250 ml of dry diethyl ether at -78° C. was added dropwise a mixture of 72 g of diphenyl- (2-methylprop-2-yl)silyl 3-hydroxybenzoate and 29 ml of triethylamine in 200 ml of dry diethyl ether. The mixture was stirred at -78° C. for 30 minutes, at room temperature for 120 minutes, and then partitioned between diethyl ether and water. The organic layer was washed with cold water and with brine, and was dried over anhydrous calcium chloride. Evaporation in vacuo, and repeated addition of dry diethyl ether and re-evaporation in vacuo afforded 86.5 g of the title compound as a viscous orange oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1(/[CH:13]=[CH:14]\[C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>C1COCC1.O.C(OCC)C>[NH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[CH:13]\[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:20][N:19]=1
Reactant: N#Cc1ccc(/C=C\C2CCCCC2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(/C=C\C2CCCCC2)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 130.2 %

Procedure:
Under a nitrogen atmosphere, add lithium aluminum hydride (965 mg, 25.4 mmol) to THF (20 mL) at 0° C. Add a solution of (Z)-5-(2-cyclohexylvinyl)-pyridine-2-carbonitrile (1.8 g, 1.74 mmol) in THF (5 mL) and stir at 0° C. for 1 h and to room temperature overnight. Cool the mixture to 0° C. and carefully add water (0.95 mL). Add diethyl ether (125 mL), 3N aqueous NaOH (0.95 mL), and water (2.85 mL) and stir for 1 h at room temperature. Filter the solid residue and concentrate in vacuo to obtain the title compound as a colorless oil (0.49 g, 30%). MS (APCI+) m/z: 217 (M+H)+.