Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.O=S(Cl)Cl.[F:20][C:21]([F:31])([F:30])[S:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(Cl)Cl>[N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([S:22][C:21]([F:31])([F:20])[F:30])=[CH:24][CH:25]=2)=[O:12])[CH:6]=[N:1][CH:2]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) and SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-((trifluoromethyl)thio)aniline (106 mg, 0.55 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in EtOAc (10 mL), filtered through a 10 μm Isolute® fritted cartridge and the filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by preparative HPLC to afford the title compound. LC-MS (Condition 4) tR=1.19 min, m/z=375.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.67-7.78 (m, 3H) 7.93-8.02 (m, 2H) 8.04-8.10 (m, 2H) 8.38 (t, J=1.83 Hz, 1H) 9.21-9.29 (m, 3H) 10.63 (s, 1H).
Reaction SMILES: FC(F)(F)C([O:5][C:6]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][C:16]([Cl:21])=[C:15](Cl)[N:14]=2)[CH2:8][CH2:7]1)=O.[B:25]1([OH:35])[C:29]2[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=2[CH2:27][O:26]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.CCOC(C)=O>[Cl:21][C:16]1[C:15]([O:34][C:32]2[CH:31]=[CH:30][C:29]3[B:25]([OH:35])[O:26][CH2:27][C:28]=3[CH:33]=2)=[N:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][C:6](=[O:5])[CH2:8][CH3:7])=[C:18]([CH:17]=1)[C:19]#[N:20]
Reactant: OB1OCc2cc(O)ccc21
Reactant: N#Cc1cc(Cl)c(Cl)nc1OCCCC1(OC(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 1-(3-(5,6-dichloro-3-cyanopyridin-2-yloxy)propyl)cyclopropyl 2,2,2-trifluoroacetate (0.87 g, 2.3 mmol) and benzo[c][1,2]oxaborole-1,5(3H)-diol (0.36 g, 2.4 mmol) in DMSO was added Cs2CO3 (0.89 g, 2.7 mmol) at room temperature and the resulting mixture was stirred at 40° C. overnight. The mixture was then poured into cold water, diluted with EtOAc, the organic phase was separated and the aqueous phase was further extracted twice with EtOAc. The combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated, the residue was purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H2O; B—CH3CN] B %:35%-62%, 23 min) to give the product D233 (105 mg) and D234 (112 mg), total yield 24%.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[CH:11][C:10]=1[NH:17][C:18](=[O:26])OC1C=CC=CC=1)(C(C)(C)C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[CH:11][C:10]=1[NH:17][C:18]([N:40]1[CH2:39][CH2:38][N:37]([C:31]2[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=2)[CH2:42][CH2:41]1)=[O:26]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)c(O[Si](C)(C)C(C)(C)C)cc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3O)CC2)c1
Reaction time: 2 h
Yield: 87 %

Procedure:
Phenyl N-[2-(t-butyldimethylsilyloxy)-4,5-dimethylphenyl]carbamate (0.17 g, 0.5 mmole) and 1-(3,5-dimethoxyphenyl)piperazine(0.13 g, 0.6 mmole) were dissolved in tetrahydrofuran(10 ml), and thereto with stirring DBU(0.09 g, 0.6 mmole) was added, and the resulting mixture was stirred for 2 hours, concentrated and chromatographed to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[I:21]N1C(=O)CCC1=O>ClCCl>[I:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:18]([CH3:20])[CH3:19])[CH:9]=1
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1.1 g, 3.8 mmol) and 10 mL of dichloromethane were combined in a round bottom flask and stirred for 10 minutes. A slurry of N-iodosuccinimide (1.0 g, 4.6 mmol) in 5 mL of dichloromethane was added and stirred at room temperature overnight. The reaction was quenched with sodium thiosulfate (20 mL, 1M in water) and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a light yellow oil (9, 1.2 g, 75%). MS (ESI) [M+H+]+=415.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([CH2:17][OH:18])[CH2:16][CH2:15]2)=[N:11][C:10]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([NH:28][C@@H:29]([CH3:34])[CH2:30][O:31][CH2:32][CH3:33])=[N:27][C:22]2=[CH:21][CH:20]=1.[CH3:35][S:36](O)(=[O:38])=[O:37]>ClCCl.CO.CO>[CH3:35][S:36]([O:18][CH2:17][C:14]1([C:12]2[NH:13][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:10]([C:19]3[N:24]=[C:23]4[O:25][C:26]([NH:28][C@@H:29]([CH3:34])[CH2:30][O:31][CH2:32][CH3:33])=[N:27][C:22]4=[CH:21][CH:20]=3)[N:11]=2)[CH2:15][CH2:16]1)(=[O:38])=[O:37]
Reactant: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(CO)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Reactant: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(COS(C)(=O)=O)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
[1-[5-(2,4-Difluorophenyl)-4-[2-[[(1S)-2-ethoxy-1-methyl-ethyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]cyclopropyl]methanol (0.56 g, 1.19 mmol) is dissolved in a 1:1 mixture of dichloromethane/methanol (12 mL total). A 0.5 M solution of methanesulfonic acid in methanol (2.37 mL) is added dropwise to the solution. The mixture is stirred at RT for 30 min and then the solvent is evaporated under reduced pressure. The residue is mixed with methanol and concentrated twice to afford the title compound (0.64 g, 96%). LC-ES/MS m/z 470.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.N1CCCC1C(O)=O.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].[C:21]([O:25][C:26](=[O:46])[CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([C:34]1[CH:43]=[C:42]2[C:37]([C:38]([Cl:45])=[CH:39][N:40]=[C:41]2Cl)=[CH:36][CH:35]=1)=[O:33])([CH3:24])([CH3:23])[CH3:22].O>CS(C)=O>[C:21]([O:25][C:26](=[O:46])[CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([C:34]1[CH:43]=[C:42]2[C:37]([C:38]([Cl:45])=[CH:39][N:40]=[C:41]2[NH:19][C:18]([NH2:20])=[NH:17])=[CH:36][CH:35]=1)=[O:33])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)C1CCCN1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
N-1(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline trifluoroacetate ##STR67## NaH (65 mg, 60% dispersion in mineral oil, 1.63 mmol) was added to a stirred solution of guanidine hydrochloride (154 mg, 1.61 mmol) in DMSO (5 mL) at 50° C. and the solution stirred for 15 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]-DL-proline t-butyl ester (253 mg, 0.64 mmol) was added and the mixture was heated at 80° C. overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with water, brine, dried over (MgSO4), and evaporated in vacuo. The residue was crystallised with CH2Cl2 -i-Pr2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline t-butyl ester (241 mg, 0.58 mmol).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>ClCCl>[CH2:30]([O:29][C:27]([O:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:28])[CH3:31]
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Oc1c(Cc2ccccc2)ccc2ccccc12
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of 2-phenylmethyl-1-naphthol (5.00 g, 0.021 mol) and triethylamine (2.53 g, 0.025 mol) in dichloromethane (65 mL) was stirred at 0°. Ethyl chloroformate (2.73 g, 0.025 mol) was added and the mixture stirred for one hour at 0°, then for two hours at room temperature. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated. The residue was flash chromatographed (5% ethyl acetate/hexane) to provide the title compound (6.50 g, 100%) as a viscous oil: NMR (CDCl3) 7.84 (t, J=8 Hz, 2H), 7.68 (d, J=7 Hz, IH), 7.50 (m, 2H), 7.25 (m, 6H), 4.30 (q, J=7 Hz, 2H), 4.IO (s, 2H), 1.36 (t, J=7 Hz, 3H); IR (neat) 1760; Mass Spec (EI) 306 (45), 262 (32), 234 (86), 215 (31); Calcd. for C20H18O3 : C-78.40 H-5.92; Found: C-78.49 H-6.06.
Reaction SMILES: O.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C@H:28]([CH2:47][O:48]CC1C=CC(OC)=CC=1)[O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:25])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C@H:28]([CH2:47][OH:48])[O:29][C:30](=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:25])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCCC(=O)O[C@@H](COCc1ccc(OC)cc1)COC(=O)CCCCCCCCCCCNC(=O)OCc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)O[C@@H](CO)COC(=O)CCCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of CH2Cl2 (50 mL) and H2O (5 mL) under air was added the diacylglycerol [7] (3.12 g, 4.00 mmol). DDQ (1.81 g, 8.00 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (20 mL), brine (20 mL) and dried over MgSO4. Flash chromatography eluting with 40-50% EtOAc in hexane gave the alcohol [8] (2.40 g, 3.62 mmol, 91%) as an off white solid: (Found: C, 70.7; H, 10.1; N, 2.1. C39H67O7N requires C, 70.7; H, 10.2; N, 2.1%); m.p. 56-58° C. [α]D20=−3.2 (c 1.02 in CHCl3); Rf=0.20 (30% EtOAc/hexane); γmax(CHCl3)/cm−1 3450, 2924, 2854, 1724, 1602, 1517, 1465, 1413, 1372, 1251, 1164; δH (400 MHz; CDCl3) 7.34-7.25 (5 H, m, Bn), 5.10-5.05 (3 H, m, CH2CHCH2, OCH2C6H5), 4.81 (1 H, bs, NH), 4.31 (1 H, dd, J 11.9, 4.4, CH2CHCH2), 4.20 (1 H, dd, J 11.9, 5.8, CH2CHCH2), 3.71 (2 H, d, J 5.8, CH2CHCH2), 3.16 (2 H, q, J 6.6, CH2NH), 2.32 (2 H, t, J 7.5, OCOCH2), 2.30 (2 H, t, J 7.8, OCOCH2), 1.63-1.59 (4 H, m, OCOCH2CH2, CH2CH2NH), 1.58-1.45 (2 H, m, CH2CH2CH2NH), 1.25 (36 H, bs, COC15H31, C11H22NH), 0.87 (3 H, t, J 6.6, CH2CH3); δC (63.5 MHz; CDCl3) 173.7, 173.4 (OCO), 156.4 (NHCO), 136.7, 128.5, 128.0, 112.6 (4×Bn), 72.1 (CH), 66.6, 62.1, 61.4 (3×CH2), 41.1 (NHCH2), 34.3, 34.1, 31.9, 30.0, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1, 26.7, 24.9, 22.7 (12×CH2), 14.1 (CH3); m/z (CI) [Found (M+Na)+ 684.4828. C39H67O7NNa requires M, 684.4816].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.C(OC(=O)C)(=O)C.O>CCOCC.C(O)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Oc1ccccc1
Agent: I
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Oc1ccccc1Oc1ccccc1
Temperature: 0 °C
Yield: 83.9 %

Procedure:
A mixture of 10 g of o-phenoxyanisol, 80 ml of hydroiodic acid (52%), 80 ml of acetic acid and 40 ml of acetic anhydride was refluxed for 1.5 hours. After being cooled, the reaction mixture was poured into ice-water to deposit a precipitate. The precipitate was dissolved in ether, and the solution was washed with an aqueous saturated sodium chloride solution, an aqueous saturated thiosulfuric acid aqueous solution and then an aqueous saturated sodium chloride solution. This ether solution was dried over anhydrous sodium sulfate, and the solvent was removed to give yellow solids. The solids were dissolved in acetic acid and stirred. The mixture was poured into cold water to deposit crystals. The crystals were washed with water and then with n-hexane, and dried at 80° C. under reduced pressure to obtain 7.8 g of o-phenoxyphenol as slightly yellow powders.
Reaction SMILES: [C:1](=O)=O.CC(C)=O.C([Li])CCC.CCCCCC.[C:19]([NH:26][C@H:27]([CH:32]=O)[CH2:28][CH:29]([CH3:31])[CH3:30])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:22]([O:21][C:19]([NH:26][CH:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:32]=[CH2:1])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C=O
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CC(CC(C)C)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of methyltriphenyl phosphonium bromide (10.97 g, 30.70 mmol) in anhydrous tetrahydrofuran (200 ml) at -78° C. (dry ice/acetone bath) under an argon atmosphere, was added n butyl lithium (19.8 ml of a 1.55M hexane solution) dropwise over the course of 5 minutes. After 10 minutes, the -78° C. bath was replaced with a 0° C. bath for one half hour, at which time the resulting orange solution was cooled again to -78° C. The solution was then added dropwise by cannula to a stirred -78° C. solution of Boc-leucinal (6.00 g, 27.91 mmol) in anhydrous tetrahydrofuran (30 ml) over the course of one-half hour. The mixture was then allowed to warm to room temperature during a 3 hour period after which water (150 ml) was added. Extraction with hexane (4×100 ml) provided a combined organic phase which was washed with brine (100 ml), dried (Na2SO4, and concentrated to give crude 3-t-butyloxycarbonylamino-5-methylhex-1-ene (6.5 g). Chromatography with ether/hexane (1/9) provided pure 3-t-butyloxycarbonyl-amino-5 methylhex-1-ene (3.71 g, 60%). Mass spectrum: EI, M+ -57=156; CI, (M+H)+ =214.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (69 mg, 0.2322 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (73 mg, 0.357 mmol), 4 N HCl in dioxane (70 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and a solid precipitated out, which was filtered off. Purified solid with normal phase chromatography to yield a white solid (33.6 mg, 31%), 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. mp 295° C.; LCMS: m/z=465.41 (M+H+), 1H NMR (400 MHz, MeOD) δ 8.76 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 7.48 (m, 1H), 7.15 (m, 1H), 6.97 (d, 1H, J=8.3 Hz), 2.95 (s, 3H), 2.34 (m, 2H), 2.12 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OC)=[O:15])=[C:12]([CH3:18])[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH3:18])[N:11]=[C:10]([CH:19]([CH3:20])[CH3:21])[C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C)c(C(=O)OC)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc(C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.5 ml (92.75 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 9.5 g (26.5 mmol) of the compound from Example 19 in 200 ml of absolute tetrahydrofuran at 0° C. and the mixture is stirred for 30 minutes at room temperature. After cooling again to 0° C., 200 ml of water are cautiously added dropwise and the mixture is extracted three times using 150 ml of ethyl acetate each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (200 g of silica gel 70-230 mesh, φ4.5 cm, using ethyl acetate/petroleum ether 2:8).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15]2)[CH2:10][CH2:9]1.CCN(CC)CC.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:36]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)(=[O:21])=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCN(C2CCNCC2)C1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(C2CCN(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 25.9 %

Procedure:
(RS)-4-(1-Piperidin-4-yl-pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid (53.8 mg, 0.1 mmol), Et3N (50.5 mg, 0.5 mmol), phenylboronic acid (36.6 mg, 0.3 mmol) and copper(II) acetate (36 mg, 0.2 mmol) were suspensed in CH2Cl2 (2 ml). After 3.5 hours stirring at room temperature, the reaction mixture was directly chromatographed over silica gel (CH2Cl2—MeOH 98:2 then 95:5) to provide (RS)-4-[1-(1-phenyl-piperidin-4-yl)-pyrrolidine-3-sulfonyl]-phenol (10 mg, 26%) as a white foam, MS: m/e=387.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:4][N:5]=[N:6][C:7]=1[Cl:8].[CH3:19][CH:20]([NH2:22])[CH3:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:9][C:10]([NH:22][CH:20]([CH3:21])[CH3:19])=[O:18])=[CH:4][N:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)N
Reactant: O=C(Nc1cnnc(Cl)c1Cl)Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cnnc(Cl)c1Cl
Yield: 10 %

Procedure:
A stirred solution of 1.0 gram (0.004 mole) of phenyl N-(5,6-dichloro-4-pyridazinyl)carbamate and 0.27 gram (0.005 mole) of 1-methylethylamine in tetrahydrofuran is heated under reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to a residue. The residue is purified by column chromatography to yield 0.1 gram of N-(5,6-dichloro-4-pyridazinyl)-N'-(1-methylethyl)urea.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:30])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: COc1ccc2c(c1)CCC(N)C(=O)N2
Product: COc1ccc2c(c1)CCC(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N2

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step D by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.86 (m,1H), 2.4-3.0 (m,5H), 3.77 (s,3H), 4.49 (m,1H), 5.25 9br s,1H), 6.68 (d,8 Hz, 1H), 6.70 (s,1H), 6.89 (d,8 Hz, 1H), 7.55 (br s,1H). FAB-MS: calculated for C21H31N3O5 405; found 428 (m+na,100%), 406 M+H,23%).
Reaction SMILES: S(O)(=O)(=O)C.[O:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H][H].[N:14]1C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C=O)C.[Pd].O.C1COCC1>[C:10]([NH2:14])(=[O:6])[CH3:9].[O:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11]
Reactant: [H][H]
Reactant: c1ccncc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Agent: O=C1NCCO1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(N)=O
Reaction time: 1 h

Procedure:
The above azide (from Example 6)(21.67 g, 61.16 mmol) dissolved in DMF (400 mL) and THF (500 mL) was degassed with nitrogen for 30 minutes whereupon 10% Pd/C (4.74 g, 4.4 mmols) was added and the reaction hydrogenated on a Parr apparatus (60 psi of hydrogen) for 14 hr. The reaction mixture was removed from the Parr apparatus and placed under a nitrogen atmosphere whereupon pyridine (5.44 mL, 67.3 mmols) and acetic anhydride (6.35 mL, 67.3 mmols) were added. After stirring for 1 hr the reaction mixture was filtered through a pad of Celite, washing thoroughly with methanol and then copious amounts of 50% MeOH/CH2Cl2 (ca. 2 L). The filtrate was evaporated to afford the crude acetamide in DMF. The mixture was slowly added to water (2 L) and the ppt collected on a filter, washed with water (5×400 mL) and dried in a vac oven (50° C.) to provide the acetamide as an analytically pure white solid (14.2 g, 63% yield). The combined filtrates were extracted with methylene chloride (5×200 mL), dried over Na2SO4 and concentrated. Water was added to the residue and the resulting ppt was filtered off and dried in a vac oven (50° C.) to afford a second crop of the acetamide as a light tan, fluffy solid (5.61 g, 25%). For the analytically pure material Mp=229-230° C., decomp. MS (M+1)=371 m/z.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)(C)C.Cl>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc2nccc(Br)c2c1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)COc1ccc2nccc(N3CCN(c4ccncc4)CC3)c2c1
Yield: 34.3 %

Procedure:
To a solution of methyl 4-bromoquinolin-6-yloxyacetate (169 mg) in isopropanol(10 ml) was added 1-(4-pyridyl)piperazine (93 mg) followed by 2 drops of saturated ethereal HCl. The resulting mixture was refluxed for 18 hours. The mixture was filtered and concentrated. Purification by flash column chromatography on silica, eluting with methanol/dichloromethane (10% to 15% v/v in 1% increments) gave methyl 4-[4-(4-pyridyl)piperazin-1-yl]quinolin-6-yloxyacetate (74 mg) as a solid: NMR(d6DMSO) δ3.2-3.4(m,4H), 3.6-3.7(m,4H), 3.75(s, 3H), 5.0(s,2H), 6.95(d,2H), 7.05(d,1H), 7.25(d,1H), 7.45(dd,1H), 7.9(d,1H), 8.25(d,2H), 8.6(d,11H); m/e 379(M+H)+.