Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]([OH:27])[CH2:14][CH2:15][CH2:16]C2C=CC(OC)=C(OC)C=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].CI.[CH2:30]1COCC1>O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]([O:27][CH3:30])[CH2:14][CH2:15][CH3:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C1CCOC1
Reactant: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCC(OC)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 60% dispersion of NaH in mineral oil (32.7 g, 1.3625 mole) was added portionwise over 40 minutes to a mechanically stirred solution of 1,4-bis (3,4-dimethoxyphenyl)butane-1-ol (292 g, 0.843 mole), MeI (125.4 g, 0.883 mole, 55 cc), and dry THF (1.5 1) at 22°-33° C. maintained by intermittent cooling. Additional MeI (22.8 g, 0.16 mole, 10 cc) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with H2O (15 cc), stirred for 1 hour, and filtered. The filtrate was evaporated in vacuo to a syrup; the syrup was treated with CH2Cl2 (1 1) and H2O (500 cc) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1×500 cc). The combined organic phase was washed with H2O (3×400 cc), dried (Na ) and evaporated in vacuo to a yellow syrup; yield: 293 g (96%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: CCCCO
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(OCCCC)c1cc(C)ccc1[N+](=O)[O-]
Yield: 199.5 %

Procedure:
Dissolve 5-methyl-2-nitrobenzaldehyde (7.84 g, 47.52 mmol), 1-butanol (10.55 g, 142.6 mmol) and toluene-4-sulfonic acid (0.5 g) in toluene (200 mL). Heat to reflux, and remove the water using a Dean-Stark apparatus. Heat for 3 hours. Add water, and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter, concentrate under reduced pressure, and purify by flash chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to give 14 g (99%) of the title compound as colorless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br.[NH:12]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2
Reactant: O=C1CCCc2ccccc2N1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccccc2N1Cc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a stirred mixture of 0.1 g (4 mmole) sodium hydride and 0.75 g (3.0 mmole) 3-bromobenzyl bromide in 5 mL dimethylformamide was added 0.438 g (2.72 mmole) solid 1,3,4,5-tetrahydro-benzo[b]azepin-2-one. The mixture was cooled in a water bath, then it was stirred at 23° for 1 hr. The solvent was removed under reduced pressure and the residue was partitioned between 30 mL ethyl acetate and 5 mL water. The organic phase was washed with 5 mL water, 5 mL saturated sodium chloride, dried (mgSO4) and concentrated under reduced pressure. The residue was recrystallized from hexane to provide the title compound, 0.658 g, m.p. 81-82°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)[C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:13][O:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[N:11]=1)[C:6]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:8]
Reactant: COc1cc(C(=O)O)cc(OC)n1
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc(OC)nc(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 2,6-Dimethoxy-isonicotinic acid and D-leucine methyl ester. 1H NMR (500 MHz, CDCl3): δ 0.92 (d, 3H, J=7.27 Hz), 0.93 (d, 3H, J=7.26 Hz), 1.41-1.58 (m, 8H), 3.95 (s, 3H), 4.08 (s, 3H), 4.15 (m, 1H), 6.43 (d, 1H, J=8.32 Hz), 7.47 (m, broad, 1H), 8.41 (d, 1H, J=8.34 Hz). MS (M+H; 311).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH:8]([S:17]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:19])=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([CH:23]1[CH2:24][CH2:25][N:20]([S:17]([CH:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:6]([OH:33])=[O:5])(=[O:19])=[O:18])[CH2:21][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CC(CCc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(CCc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
3-(4-Benzy-piperidine-1-sulfonyl)-5-phenyl-pentanoic acid tert-butyl ester (1.04 g, 2.2 mmol) was taken up in DCM (5 mL) with stirring and cooled to 0° C. TFA (5 mL) was added slowly and the resulting solution placed in the fridge overnight. Solvents evaporated under reduced pressure to give the title compound as a yellow oil (913 mg, Quant). 1H-NMR δ(MeOD) 7.56-7.11 (10H, m), 3.66-3.56 (3H, m), 2.90-2.59 (6H, m), 2.51 (2H, d, J=6.7 Hz), 2.20 (1H, m), 1.90 (1H, m), 1.62-1.47 (3, m) and 1.25-1.11 (2H, m). 13C-NMR δ(MeOD) 174.5, 142.6, 141.7, 130.6, 130.1, 130.0, 129.7, 127.7, 127.4, 58.7, 47.6, 44.2, 39.2, 35.5, 33.9, 33.7, 33.0. IR Vmax (ATR) 2915, 1709, 1451, 1304, 1133, 1041, 937, 746, 698. ESMS=(M+1) 416.0, (M−1) 414.0.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C:7](=O)[C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[S:4]1(=[O:19])=[O:18])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:3]1[CH:8]=[C:7]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[S:4]1(=[O:19])=[O:18])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:2]
Reactant: CCN1CC(=O)c2ccc3ccccc3c2S1(=O)=O
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCN1C=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 24 h
Yield: 50.1 %

Procedure:
A mixture of 2 gm (7.3 millimols) of 2-ethyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide, 1.04 gm (14.6 millimols) of pyrrolidine, 200 mgm p-toluenesulfonic acid and 100 mlof benzene was refluxed for 24 hours in a vessel equipped with a water trap. Subsequently, another 1.04 gm (14.6 millimols) of pyrrolidine and 200 mgm of p-toluenesulfonic acid were added, and the reaction mixture wasrefluxed for 24 hours more. After cooling, the reaction mixture was evaporated, and the residue was extracted with ether several times. The combined ether extracts were washed twice with water, dried and evaporated. Recrystallization of the residue from methanol yielded 1.2 g (50% of theory) of the desired enamine, m.p. 115°-117° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C@@H:14]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C@@H:14]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1[C@H](Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1OC[C@H](Cc2ccccc2)N1[C@H](Cc1ccc(O)cc1)Oc1ccccc1

Procedure:
A solution of (S)-4-benzyl-3-[(1S)-2-(4-benzyloxyphenyl)-1-phenoxyethyl]-2-oxazolidinone (1.8 g) in ethyl acetate (50 ml) containing 10% palladium on carbon (1.8 g) was hydrogenated at 40 psi overnight. The catalyst was filtered, the solution concentrated and the product purified by flash chromatography (hexanes/ethyl acetate, 3:2) as an oil (0.81 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][CH:16]=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]([OH:43])[C:16]([NH:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[CH:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:17])=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C#CCOc1ccc(CCNC=O)cc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide (34 g, 0.14 mol) and triethylamine (34 g, 0.34 mol) are dissolved in dichloromethane (120 ml). Bis(trichloromethyl) carbonate (triphosgene, 16 g, 55 mmol) in dichloromethane (80 ml) is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of titanium tetrachloride (28 g, 0.15 mol) in dichloromethane (150 ml) is added and the mixture is stirred for 2 hours at −40° C. 4-Chlorobenzaldehyde (20 g, 0.14 mol) in dichloromethane (70 ml) is added dropwise and the mixture is stirred for 17 hours at room temperature. The mixture is hydrolyzed with 5N HCl (80 ml), stirred 30 minutes at room temperature and washed with water. After evaporation of the organic layer the residue is submitted to flash-chromatography (ethyl acetate/hexane) to give 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy -phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.54 (t, 1H, CO≡CH), 2.72 (t, 2H, CH2CH2), 3.53 (t, 2H, CH2CH2), 3.84 (s, 3H, OCH3), 4.78 (m, 2H, OCH2), 4.98 (s, 1H, CHOH), 6.07 (bs, 1H, NH), 6.53–7.38 (m, 7H, CH arom.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:19])=[O:6]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 25 °C

Procedure:
3-Bromo-4-methylbenzoic acid (5 g, 23.25 mmol) was suspended in CH2Cl2 (100 mL) and stirred under argon at room temperature. Oxalyl chloride (5.9 g, 46.5 mmol) was added followed by DMF (20 μL). Gas evolution began, and the mixture was stirred for 2 days during which time complete solution occurred. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (20 mL). This was stirred for thirty min. The phases were separated and the organic washed 1× with brine dried over anhydrous Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc/hexane and dried under vacuum to afford the title compound as a white crystalline solid. LC-MS m/z 213.8 (M+H)+, 1.41 min (ret time); mp 178-179° C.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[CH3:21][NH:22][C:23]([NH:25][CH3:26])=[O:24]>C(O)CO.O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:22]([CH3:21])[C:23](=[O:24])[N:25]([CH3:26])[C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: CNC(=O)NC
Solvent: OCCO
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(OC)cc3)n(C)c(=O)n2C)cc1
Temperature: 180 °C
Yield: 68.5 %

Procedure:
A mixture of 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone (1 g, 3.6 mmol) and 1,3-dimethylurea (1.29 g, 14.7 mmol) in ethylene glycol (10 mL) was refluxed at 180° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc in hexanes to afford 4,5-bis(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.8 g, 67%) as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[O:11][S:12]([CH3:15])(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])CS.[O-]CC.[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[O:11][S:12][CH2:15][C:25]([O:29][CH2:30][CH3:31])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OS(C)(=O)=O
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSOC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
1-O-benzyl-3-O-t-butyldimethylsilyl-2-O-mesylglycerol (0.83 g) was dissolved in N,N-dimethylformamide (5 ml), and ethyl thioglycolate (0.34 ml) and sodium ethoxide (sodium 0.07 g/ethanol 5 ml) were added thereto, and the mixture stirred at 80° C. for 6 hours. After removing the solvent by evaporation under reduced pressure, water was added to the residue and the solution was extracted with ethyl ether (20 ml×3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1.[OH:42]O>CC(O)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([OH:42])=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:28][CH2:29]5)[C:23]([F:26])([F:24])[F:25])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cc3c(cc2-c2cnc(N)nc2)[nH]c2c(C(N)=O)cnc(N[C@H](C4CC4)C(F)(F)F)c23)OC1(C)C
Reactant: OO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)c(O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 7-(2-aminopyrimidin-5-yl)-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (218 mg, 0.38 mmol) in AcOH (7.7 mL) was added hydrogen peroxide (30%, 0.20 mL, 1.9 mmol) at 0° C. The reaction was left to stir at room temperature for 3 h, diluted with EtOAc, and washed with water. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 11.38 (s, 1H); 9.25 (s, 1H); 8.42 (s, 2H); 7.97 (s, 1H); 7.90 (br s, 1H); 7.75 (s, 1H); 7.60 (s, 1H); 7.22 (br s, 1H); 6.63 (m, 2H); 4.86 (m, 1H); 1.45 (m, 1H); 0.72 (m, 1H); 0.60 (m, 1H); 0.53 (m, 1H); 0.36 (m, 1H). LRMS (APCI) calc'd for (C21H18F3N7O2) [M+H]+, 458.1. found 458.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH3:7])=[C:2]=[S:3].[CH:8]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH2:4]([NH:1][C:2]([NH:15][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:3])[CH2:5][CH2:6][CH3:7]
Reactant: NC1CCCCCC1
Reactant: CCCCN=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=S)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution prepared by dissolving 1-isothiocyanatobutane (3.0 ml, 26.0 mmol) in dichloromethane (5 ml) was slowly added to a solution prepared by dissolving 1-cycloheptylamine (3.3 ml, 26.0 mmol) in dichloromethane (20 ml) at 0° C. for 15 minutes. Triethylamine (7.3 ml, 52.1 mmol) was added to the mixed reaction solution and stirred at room temperature for 2 hours. After confirming completion of the reaction, distilled water (10 ml) was added to the reaction solution, and 1N of an HCl aqueous solution was added to neutralize. After separating an organic layer, a aqueous layer was extracted over dichloromethane (3×20 ml), and the organic layer was dried on sodium sulfate anhydrous, filtered and concentrated. The concentrated organic layer was purified by flash column chromatography (hexane:ethylacetate=3:1), thereby obtaining a target compound as a yellow liquid (4.1 g, 68%). The compound was used in the subsequent reaction.
Reaction SMILES: [OH:1]CC(C)(C)C=O.[CH3:8][O:9][CH2:10][C:11]([CH3:18])([CH3:17])[CH:12](Br)[C:13]([OH:15])=[O:14]>>[CH3:8][O:9][CH2:10][C:11]([CH3:18])([CH3:17])[CH:12]([OH:1])[C:13]([OH:15])=[O:14]
Reactant: CC(C)(C=O)CO
Reactant: COCC(C)(C)C(Br)C(=O)O
Product: COCC(C)(C)C(O)C(=O)O

Procedure:
4-methoxy-3,3-dimethyl-2-hydroxy butyric acid is prepared by conventional methods from 3-hydroxy-2,2-dimethyl-propionaldehyde and from that compound the ethyl ester of 4-methoxy-3,3-dimethyl-2-bromo-butyric acid is obtained.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[S:19][NH2:20])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].O.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[S:19]([NH2:20])=[O:27])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CCO
Solvent: O
Product: NS(=O)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Yield: 31.7 %

Procedure:
To an ice cooled stirred solution of 10 (1.5 g, 5 mmol) in ethanol:H2O (525 mL, 20:1, v/v), m-chloroperoxybenzoic acid (1 g, 1 eq.) in ethanol (50 mL) was added dropwise during 20 min. After 4 h the separated crystals were filtered off, the filtrate was evaporated to dryness, triturated with methanol, filtered, washed with methanol and dried at room temperature to yield 11, (0.5 g, 31% yield), m.p. >120° C. The filtrate was evaporated and purified by chromatography as described for 6 to yield another crop of 11, (0.25 g, 15%: overall yield 46%). IR (KBr): 1060 (vs, br, S=O), 1330 (s, S=O), 3000-3600 (NH2, OH) cm-1 : UV: λmax (pH 1) 272 nm (ε 3,000): λmax (pH 7) 275 nm (ε7,100): λ max (pH 11) 272 nm (ε 1,700): 1H NMR (DMSO-d6): δ 6.46 (d, 1, J =5.16 Hz, C1'H), 6.71 (s, 2, SONH2, exchanged with D2O), 8.83 (s, 1, C2H), 9.06 (s, 1, C8H), and other sugar protons. Anal. Calcd for C10H13N5O5S·0.3H2O (321.32): C, 37.38: H, 4.24: N, 21,80: S, 9.97. Found: C, 37.03: H, 4.19: N, 21.42: S, 10.37.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][CH:13]([CH:14]=[CH2:15])[CH:4]([CH:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH:7]=O)[O:3]1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1([CH3:17])[O:16][CH:13]([CH:14]=[CH2:15])[CH:4]([CH:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH:7]=[N:19][OH:20])[O:3]1
Reactant: NO
Reactant: C=CC1OC(C)(C)OC1C(CC=O)OCOC
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC1OC(C)(C)OC1C(CC=NO)OCOC
Reaction time: 8 h
Yield: 91.7 %

Procedure:
The above 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal (91.9 mg) was dissolved in 1 ml of pyridine, and 45 mg of hydroxylamine hydrochloride was added at room temperature, and stirring was conducted at room temperature for 8 hours. The reaction mixture was diluted with diethyl ether. The diluted reaction mixture was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 89.5 mg of 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal oxime having the following properties (yield 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])OC)=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1)=[O:14].[CH:38]([NH:40][NH2:41])=O.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:41][N:40]=[CH:38][N:11]=2)=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:19][CH:20]=1
Reactant: COC(=N)c1ccc(C)c(NC(=O)c2ccc(Nc3nc(-c4ccccc4)c4ccccc4n3)cc2)c1
Reactant: NNC=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(-c2ncn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 150 °C
Yield: 21.9 %

Procedure:
A mixture of methyl 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzenecarboximidoate (50 mg, 0.10 mmol), formylhydrazine (30 mg, 0.5 mmol) and Hunig's base (17 μL, 0.20 mmol) in ethanol (2 mL) was heated to 150° C. in a sealed tube overnight. The reaction was cooled to rt and concentrated on a rotary evaporator. The residue was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(1H-1,2,4-triazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (10.9 mg, 22%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.84-9.82 (m, 2H), 8.62 (s, 1H), 8.19 (d, 2H), 8.06-7.99 (m, 3H), 7.90-7.78 (m, 5H), 7.66-7.63 (m, 3H), 7.42 (ddd, 1H), 7.36 (d, 1H), 2.36 (s, 3H). MS (EI) for C30H23N7O: 498.2 (MH+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:44])[C:13]2=[N:14][N:15]([CH2:17][C:18]3[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=3)[N:16]=[C:11]3[C:12]2=[C:6]([CH2:7][S:8][N:9]=[C:10]3[N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:5]1=[O:43].CO>O>[NH2:28][C:10]1[C:11]2[C:12]3[C:13](=[N:14][N:15]([CH2:17][C:18]4[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=4)[N:16]=2)[C:4]([F:44])([F:3])[CH:5]([OH:43])[C:6]=3[CH2:7][S:8][N:9]=1
Reactant: COc1c(C)cnc(CN2N=C3C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC4=C3C(=N2)C(F)(F)C4=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C)cnc(CN2N=C3C(N)=NSCC4=C3C(=N2)C(F)(F)C4O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
Sodium borohydride (6 mg) was added to a mixture composed of the above di-tert-butyl {9,9-difluoro-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (41 mg) and methanol (2 ml) under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (8.7 mg, 42% in total from Example 110) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: O=S1(=O)CCCO1
Solvent: CO
Product: O=S(=O)(O)CCCN1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-bromophenyl)-4-piperidinol (2.51 g, 9.8 mmol) in MeOH (25 mL) was added 1,3-propane sultone (1.28 g, 10.7 mmol). The mixture was stirred at reflux for 2 h. Only a small amount of compound precipitated. The resulting suspension was cooled to room temperature with stirring and a solution of 50% MeOH/Acetone was added to precipitate a maximum of compound. The solid was collected by filtration, washed with 50% MeOH/Acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound G, 2.11 g (57%).