Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:7]=1[F:13])=[O:4].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(OCC)C.[Cu](I)I>[NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:8][C:7]=1[F:13])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#C[Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
A solution of (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (1.00 g, 2.51 mmol) in triethylamine (1.5 mL, 10.8 mmol) was thoroughly degassed with argon, bis-dichlorotriphenylphosphine palladium(II) (20.3 mg, 0.05 mmol) added followed by copper iodide (9.8 mg, 0.05 mmol) and trimethylsilylacetylene (277 mg, 2.77 mmol) and the mixture stirred under argon at ambient temperature for 3 hours. Additional triethylamine (1.5 mL, 10.8 mmol) was added to form a stirrable reaction mixture and stirring continued for an additional 20 hours. The reaction mixture was diluted with diethyl ether and a small amount of Celite added prior to filtration through Celite. The Celite was eluted with diethyl ether (4×20 mL) and the combined organic filtrates concentrated in vacuo. The resulting green oil was dissolved in a small amount of diethyl ether and diluted with hexanes (10 mL) to induce crystallization. The product was isolated by filtration, washed with hexanes and dried in vacuo to afford (2S,3S)-2-amino-N-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-3-phenyl-butyramide as a grey solid (610 mg, 66%). A second crop of product was obtained by reprocessing of the mother liquors from the initial crystallization (168 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:23])([F:14])[F:24])=[CH:21][N:20]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(C(F)(F)F)cn1

Procedure:
A 1.1 g. portion of 2,6-dichlorobenzoyl isocyanate and 0.8 g. of 5-trifluoromethyl-2-aminopyridine were mixed in 50 ml. of ethyl acetate at ambient temperature and stirred for 18 hours. The solvent was then evaporated and the product was recrystallized from ethanol to obtain 0.2 g. of the product named above, m.p. 228°-230° C. Elemental analysis showed:
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48](OCC)=[O:49])=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[CH3:61][O:62][NH:63][CH3:64]>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:49])=[C:33]2[S:53]([N:63]([O:62][CH3:61])[CH3:64])(=[O:54])=[O:55]
Reactant: CNOC
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CON(C)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-methoxy-N-methylamine hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 362.13 [M+H]+.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[CH3:6][S:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[NH4+:26]>ClCCl>[CH3:6][S:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([S:2]([NH2:26])(=[O:5])=[O:3])=[CH:21][CH:20]=1
Reactant: O=S(=O)(O)Cl
Reactant: [NH4+]
Reactant: CSc1onc(-c2ccccc2)c1-c1ccccc1
Agent: [OH-]
Solvent: ClCCl
Product: CSc1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Reaction time: 3 h
Yield: 30 %

Procedure:
To stirred chlorosulfonic acid (3.0 mL, 45.06 mmol) at room temperature was carefully added solid 5-methylthio-3,4-diphenylisoxazole (Step 2) (0.915 g, 3.42 mmol). After 3 hours at room temperature, the reaction was poured over crushed ice. The resulting suspension was layered with dichloromethane and excess concentrated ammonium hydroxide and was stirred vigorously for 3 hours. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic phases were combined, washed with aqueous KHSO4 solution (0.25N), aqueous NaHCO3 solution, and brine, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was crystallized by dissolution in dichloromethane followed by the addition of isooctane until slight turbidity was seen. The resulting suspension was vacuum filtered yielding 4-[5-methylthio-3-phenylisoxazol-4-yl]benzenesulfonamide (0.355 g, 30%) as fine needles: mp 135°-137° C. 1H NMR (CDCl3 /300 MHz) 7.90 (d, 2H, J=8.5 Hz), 7.47-7.31 (m, 7 H), 4.81 (s, 2H), 2.69 (s, 3H). FABLRMS m/z 347 (M+H). FABHRMS m/z 347.0497(M+H, C16H15N2O3S2 requires 347.0524). Anal. Calc'd for C16H14N2O3S2.1.69 wt % H2O: C, 54.54; H, 4.19; N, 7.95. Found: C, 54.53; H, 4.04; N, 7.87.
Reaction SMILES: [CH2:1]([N:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]2([CH2:20][CH2:19][C:18](=O)[C:17]3[C:9]2=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=3)[C:7]1=[O:28])[CH2:2][CH2:3][CH2:4][CH3:5].C(N1C2C(=CC=CC=2)C2(C3C(=CC4OCOC=4C=3)C(=O)C2)C1=O)CCCC>>[CH2:1]([N:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]2([CH2:20][CH2:19][CH2:18][C:17]3[C:9]2=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=3)[C:7]1=[O:28])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Product: CCCCCN1C(=O)C2(CCCc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 23, and making non-critical variations using 1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione to replace 1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione, the title compound was obtained (69%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.25 (td, 1H), 7.08-6.94 (m, 2H), 6.90 (d, 1H), 6.60 (s, 1H), 5.89 (s, 1H), 5.81-5.76 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.77 (m, 2H), 2.38-2.24 (m, 1H), 2.17-2.06 (m, 1H), 2.02-1.83 (m, 2H), 1.78-1.65 (m, 2H), 1.42-1.29 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.3, 146.7, 146.1, 142.4, 137.3, 131.6, 127.8, 127.8, 124.1, 122.5, 109.0, 108.3, 107.3, 100.7, 52.0, 40.0, 34.0, 29.4, 29.1, 27.1, 22.4, 18.8, 14.0; MS (ES+) m/z 364.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.C(Cl)(C)(C)C.[Cl-:14].[Al+3].[Cl-:16].[Cl-]>C(Cl)Cl>[Cl:14][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([Cl:16])([CH3:8])[CH2:4][CH2:3]1
Reactant: CC1CCC(C)CC1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Solvent: CC(C)(C)Cl
Product: CC1(Cl)CCC(C)(Cl)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,4-dimethylcyclohexane (10 g, 89.1 mmol) and tert-butyl chloride (32.6 g, 348 mmol) in 45 mL of anhydrous methylene chloride in a 3-neck round-bottom flask under argon at 0° C., was slowly added aluminum chloride (1.24 g, 8.91 mmol). The resulting mixture was stirred at 0° C. for 1.5 hours then quenched with ice, and the product was extracted with CH2Cl2. The organic layer was separated and washed with water, and brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by Kugelrohr distillation to yield the title compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(Cl)CCl.C1C=[CH:30][C:31]2[N:36](O)[N:35]=[N:34]C=2C=1.C1C[O:41]CC1>>[N:36]([CH2:31][C:30]([NH:1][C@H:2]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:41])=[N+:35]=[N-:34]
Reactant: On1nnc2ccccc21
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](N)CSCc1cccc(OC2CCCCO2)c1
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](CSCc1cccc(OC2CCCCO2)c1)NC(=O)CN=[N+]=[N-]
Reaction time: 12 h
Yield: 89 %

Procedure:
To a 500 mL round bottom flask containing 131 (5.9 g, 17.38 mmol) and azido acid (2.13 g, 20.8 mmol) in THF (174 mL) was treated with EDC (5.33 g, 27.81 mmol), HOBt (3.75 g, 27.81 mmol) and TEA (12.2 mL, 86.9 mmol) at room temperature and was stirred for 12 h. The reaction was concentrated on silica and was purified over silica gel using EtOAc:Hexanes (1:1) as an eluent to afford 132 (6.5 g, 89%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[OH-].[Na+].[C:15](OC(=O)C)(=O)C.S(OC)(OC)(=O)=O>O.C(O)=O>[CH3:15][NH:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8]([OH:11])(=[O:9])=[O:10])[NH2:1]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O=CO
Solvent: O
Product: CNc1cc(N)ccc1S(=O)(=O)O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
94 g of 1,3-diaminobenzene-4-sulfonic acid in 430 ml of water and 70 g of formic acid were boiled under reflux for 3 hours. Then, at 20° C., 100 ml of water were added and the pH was adjusted to 6.5 with caustic soda solution. 70 g of acetic anhydride were then added, the pH being kept between 5.5 and 6.5 with caustic soda solution. The pH was then adjusted to 12.5 with caustic soda solution, and 75 g of dimethyl sulfate were added. After 30 minutes, 110 g of 50% w/w caustic soda solution were added, and the mixture was boiled under reflux at 100° C. for 3 hours. 150 ml of water were then distilled off and the pH was adjusted to 1 with hydrochloric acid. At 20° C., the precipitated 3-(N-methylamino)aniline-4-sulfonic acid was isolated by filtration.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]=[CH:3][CH2:4][OH:5].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:5][CH2:4][CH:3]=[CH:2][CH2:1][O:6][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:13][CH:12]=1
Reactant: OCC=CCO
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC=CCOCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 69.5 %

Procedure:
To a solution of 2-buten-1,4-diol (4.9 g, 60 mmol) in dry dimethylformamide (120 ml) was added sodium hydride (60% dispersion in oil; 5.28 g, 132 mmol) and the mixture was stirred at room temperature for 100 minutes. To this solution was added 4-methoxybenzyl chloride (17.9 ml, 132 mmol) in dimethylformamide (30 ml) dropwise over 45 minutes and the mixture was stirred for a further 40 minutes. The mixture was partitioned between ether (150 ml) and water (150 ml). The organic layer was further washed with water (150 ml), dried (magnesium sulphate) and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with hexane-acetone (4:1, 3:1) to afford 1,4-bis(4-methoxybenzyloxy)but-2-ene as a clear colourless liquid (13.7 g, 70%). IR: υmax (film) 2840, 1615, 1515 and 1250 cm-1. 1H NMR: δH (CDCl3) 3.80 (6H, s, 2×CH3), 4.02 (4H, d, J=4.5 Hz, 2×CHCH2), 4.43 (4H, s, 2×ArCH2), 5.79 (2H, t, J=4.5 Hz, 2×CH), 6.88 (4H, d, J=9 Hz, ArH) and 7.27 (4H, d, J=9 Hz, ArH).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH3:19])=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]2[CH:9]=[C:8]1[C:20](=[O:37])[NH:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:23]([F:26])([F:25])[F:24])[CH3:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH:1]1([NH:4][C:16]([C:14]2[CH:15]=[C:10]3[CH:9]=[C:8]([C:20]([NH:21][CH:22]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=4)[C:23]([F:24])([F:25])[F:26])=[O:37])[N:7]([CH2:5][CH3:6])[C:11]3=[N:12][C:13]=2[CH3:19])=[O:17])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)O)c(C)nc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3CC3)c(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cyclopropylamine (0.0217 g, 0.380 mmol) was dissolved in N,N-dimethylformamide (2.3 ml) and 1-ethyl-6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.150 g, 0.317 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (0.120 g, 0.317 mmol) and 4-methylmorpholine (0.105 ml, 0.951 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulphate, adsorbed on silica gel and chromatographed with cyclohexane/ethyl acetate (1:1). This gave 0.033 mg (18% of theory) of N5-cyclopropyl-1-ethyl-6-methyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2,5-dicarboxamide. HPLC-MS: log P=3.52; mass (m/z): 513.1 (M+H)+; 1HNMR (D6-DMSO): δ 0.57 (m, 2H), 0.71 (m, 2H), 1.20 (t, 3H), 2.89 (s, 3H), 3.32 (s, 3H), 4.02 (q, 1H), 4.59 (q, 2H), 6.29-6.33 (m, 1H), 7.35 (s, 1H), 7.70-7.83 (m, 2H), 7.95 (s, 1H), 8.06 (m, 1H), 8.21 (s, 1H), 8.41 (d, 1H), 9.78 (d, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[OH:25][CH2:26][CH2:27][SH:28]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:28][CH2:27][CH2:26][OH:25])=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: OCCS
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(SCCO)s2)c(C(=O)C2CCCC2)c1
Yield: 28.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(2-hydroxy-ethylsulfanyl)-thiazol-2-yl]-urea (114 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-hydroxy-ethanethiol (158 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: N[C@H]1CC[C@H](CO)CC1
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CO)CC1)C1CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (1.16 g, 3.75 mmol) was reacted with (trans-4-aminocyclohexyl)methanol (726 mg, 5.61 mmol) to afford the desired product (1.23 g, 81%) as a white solid. ESI MS m/z 403 [C20H23BrN2O2+H]+
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[N:7]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:2]1([O:1][C:13]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[O:14])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1ccnc1
Product: O=C(On1ccnc1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxyimidazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by preparative HPLC (water-acetonitrile-0.1% TFA) (36%, crystals).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].CS([C:18]1[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)(=O)=O.O>CN(C)C=O>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:20]=[N:19][C:18]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[N:23][CH:22]=1
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxypiperidine (6.18 g, 61 mmol), and potassium carbonate (11.0 g, 80 mmol) in N,N dimethylformamide (150 mL) was added 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (12.3 g, 54 mmol) and stirred at room temperature for 18 h. To the reaction mixture was added 300 mL of water and the heterogeneous mixture was stirred for an additional 10 minutes. The white solid was filtered and washed with water to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[NH2:15][C:16]1[C:21]([NH2:22])=[C:20]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:19]([Cl:34])=[CH:18][N:17]=1.C([O-])(=O)C.[NH4+]>>[Cl:34][C:19]1[C:20]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[C:21]2[N:22]=[C:7]([C:6]3[S:5][C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[N:3][C:2]=3[Cl:1])[NH:15][C:16]2=[N:17][CH:18]=1
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 10.5 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (65 mg, 0.28 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.26 mmol), and Ammonium acetate (98 mg, 1.3 mmol) were reacted to produce 13.87 mg (11%) of the title compound. (300 MHz, DMSO-d6) 12.79 (s, 1H), 7.95 (s, 1H), 7.77 (s, 2H), 7.25 (s, 2H), 6.40-6.30 (m, 2H), 4.98 (t, J=17 Hz, 8.5 Hz, 1H), 3.72 (m, 4H), 3.27 (m, 4H), 3.48 (m, 4H), 2.87 (s, 1H), 2.75 (s, 1H), 2.57 (d, J=8 Hz, 1H), 2.19 (d, J=8 Hz, 1H), 1.36 (d, J=8 Hz, 1H). MS=507 (M+H), HPLC: 2.35 min. (G Method)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=3[CH:20]=2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To t-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g), 4-ethoxyphenyl borate (2.35 g), 1M potassium carbonate solution (25 ml) and ethanol (25 ml) was added toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphine palladium (0.55 g), and the mixture was ref luxed under argon atmosphere overnight. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give t-butyl 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g) as yellow crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[N:21][CH:22]=2)=[CH:13][CH:12]=1>ClCCl>[Cl:3][CH2:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2ccc(Cl)cc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cncc(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
543 mg (0.333 ml, 4.56 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 500 mg (2.28 mmol) [5-(4-Chloro-phenyl)-pyridin-3-yl]-methanol in 30 ml dichloromethane and stirred for 2 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (444 mg, 75%) used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 90 %

Procedure:
A solution of the product from Step 2 (2.82 g, 11.2 mmol) in phosphorous oxychloride (20 mL) was heated at 100° C. for 16 h. The reaction was concentrated and azeotroped once with methylene chloride. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution then saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated to provide 7-(benzyloxy)-4-chloroquinazoline (2.72 g, 90%) as a yellow solid. MS 271.2 (ES+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]CC)=O)[C:8]([C:19]([O:21]CC)=O)=[C:7]2[OH:24])([O-:3])=[O:2].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[OH:16][C:14]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[C:7](=[O:24])[C:8]=2[C:19](=[O:21])[N:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Solvent: CCO
Product: O=c1c2cc([N+](=O)[O-])ccc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of diethyl 6-nitro-4-hydroxy-quinoline-2,3-dicarboxylate (1.670 g, 5.00 mM) in ethanol (30 mL) was added phenylhydrazine (3.44 mL, 35.00 mM) to give a deep red solution. The solution was heated to reflux for 1 hour and concentrated to about 15 mL. Continued heating gave a thick suspension which was diluted with ethanol (5 mL) and refluxed for 16 additional hours. The mixture was cooled to room temperature and filtered to give the phenylhydrazine salt of the title compound as a tan solid. This material was refluxed in glacial acetic acid (25 mL) for 2 hours and cooled to room temperature. Filtration gave the title compound (1.01 g, 58%) as a tan powder, mp 368° C. (decomp.); MS(CI): 351 (M+H).