Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:15](O)[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si:25]([CH3:39])([CH3:38])[O:26][C:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=1[O:33][Si](C)(C)C.B(F)(F)F.CCOCC>ClCCl.CCOCC>[CH2:1]([N:8]1[C@@H:15]([C:27]2([O:26][Si:25]([CH3:39])([CH3:38])[CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][C:28]2=[O:33])[C@H:14]2[N:10]([C@H:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:12][CH2:13]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CS[C@@H](c3ccccc3)N12
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C[Si](C)(C)OC1([C@H]2[C@@H]3CS[C@@H](c4ccccc4)N3C(=O)N2Cc2ccccc2)CCCCC1=O
Temperature: 0 °C
Yield: 76 %

Procedure:
To a solution of compound 6-benzyl-7-hydroxy-3-phenyl-(3S, 7aR)-perhydroimidazo[1,5-C][1,3]thiazol-5-one of formula (6) (0.326 parts, 1 mmol) in dichloromethane (10 parts) was added 1,2-bistrimethylsilyloxy cyclohexene (0.516 parts, 2 mmol). Then the solution was cooled to 0° C. and Lewis acid for example BF3.Et2O (0.142 parts, 1 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 10 mints. and the reaction mixture was quenched with saturated ammonium chloride (10 parts). Then the organic layer was separated, concentrated and column purification with ethylacetate:pet.ether (15:85) as eluent provided compound 6-benzyl-7-(1-trimethylsilyloxy-2-oxocyclohexyl)-3-phenyl-(3S, 7R, 7aR)-perhydroimidazo[1,5-C][1,3]thiazole-5-one of formula (7e) (viscous liquid, 0.376 parts, 0.76 mmol) in 76% yield. And with ethyl acetate:pet.ether (25:75) as eluent provided the compound 6-benzyl-7-(1-hydroxy-2-oxocyclohexyi)-3-phenyl-(3S, 7R, 7aR)-perhydroimidazo[1,5-C][1,3]thiazole-5-one of formula (7e′) (highly viscous liquid, 0.093 parts. 0.22 mmol) in 22% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[NH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][N:19]([C:25](=[O:26])[N:24]([CH3:28])[CH3:23])[N:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cn[nH]c1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)n1cc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 0.33 g of 8-chloro-6-(2-chlorophenyl) 1H,4H-pyrazolo[4,3-d](2)benzazepine in 10 ml of methylene chloride, the mixture of 0.16 g of dimethylcarbamoyl chloride and 0.15 g of pyridine is added and the whole stirred for 2 hours at room temperature. The mixture is diluted with methylene chloride, washed with ice-cold aqueous sodium carbonate, dried and evaporated under reduced pressure. The residue is chromatographed on silica gel and eluted with benzene-methanol(95:5), to yield the 8-chloro-6-(2-chlorophenyl)-2-dimethylcarbamoyl-2H,4H-pyrazolo[4,3-d](2)benzazepine melting at 175°-176°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH2:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH3:38].[OH-].[Na+]>C1COCC1>[ClH:36].[ClH:36].[CH2:37]([N:39]1[CH2:44][CH2:43][N:42]([C:18]([C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)[CH:13]=3)[CH:16]=2)=[O:20])[CH2:41][CH2:40]1)[CH3:38]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2cc(Oc3cccc(C(=O)O)c3)ccn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)c2cccc(Oc3ccnc(Nc4nc(C)cs4)c3)c2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A 3 dram vial was charged with 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol) and THF (2 mL), and the reaction mixture was cooled to 0° C. Ethyl carbonochloridate (0.03359 mL, 0.3513 mmol) was added and the reaction mixture was stirred at 0° C. for 30 minutes. 1-Ethylpiperazine (0.1164 mL, 0.9164 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 1 hour, and then 2N NaOH was added. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified using prepacked silica gel column with 5% methanol in DCM as eluent to afford the desired product (0.085 g, 56.05% yield) as off white solid. Mass spectrum (esi) m/z=424 (100) (M+H-2HCl).
Reaction SMILES: C1(C2C=CC=CC=2N[N:10]=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.I[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClCCl>O>[C:36]1([N:11]2[N:10]=[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=[N:12]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Ic1ccccc1
Reactant: c1ccc(NN=NNc2ccccc2-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-n2nc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
2-phenylazoaniline (3.47 g, 17.6 mmol) prepared above was placed in a 100-mL 1-neck round bottomed flask. Acetic acid (20 mL) and iodobenzene diacetate (6.23 g, 19.4 mmol) were added, in that order, resulting in an exotherm. The reaction was allowed to proceed for 1 hour during which time the mixture cooled to room temperature. Dichloromethane and water were added to the reaction mixture. The organic layer was separated and dried over MgSO4. The solution was filtered and concentrated using a rotary evaporator. The residue was purified on a silica gel column using dichloromethane as eluent. The fractions containing the desired product were combined and solvent removed. The solid was dried in a vacuum oven for 2 h. Yield: 34%.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Product: C[C@@H](NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) by reacting 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester with D-alanine at the reflux condition for 5 days. MS-(−)-ion: M−1=351.1.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH3:9][C:10]([CH3:57])([CH:55]=[CH2:56])[CH2:11][C:12]1[N:13]=[C:14]([CH2:36][C:37]([C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][N:49]=3)=[CH:44][CH:43]=2)([OH:41])[CH:38]([F:40])[F:39])[N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1.CC(C)=O.[OH2:62]>[Os](=O)(=O)(=O)=O>[F:39][CH:38]([F:40])[C:37]([C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][N:49]=2)=[CH:46][CH:47]=1)([OH:41])[CH2:36][C:14]1[N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[C:12]([CH2:11][C:10]([CH3:57])([CH3:9])[CH:55]([OH:5])[CH2:56][OH:62])[N:13]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CC(C)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1)C(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NMO (214 mg, 1.8 mmol) followed by osmium tetroxide (2.5 wt % in n-butanol) (cat.) were added to a solution of 3-[4-(2,2-dimethylbut-3-en-1-yl)-1-trityl-1H-imidazol-2-yl]-1,1-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]propan-2-ol (600 mg, 0.91 mmol) in acetone/water (2:1) (12 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 4-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-3,3-dimethylbutane-1,2-diol.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:27])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)Cc3ccc(O)cc3)cc2)C1
Reactant: CC(C)CBr
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)Cc3ccc(OCC(C)C)cc3)cc2)C1

Procedure:
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide was reacted with isobutyl bromide by method H. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS(ESI): 424 (M+H+).
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[F:57][C:58]([F:67])([F:66])[C:59]1[CH:64]=[CH:63][N:62]=[CH:61][C:60]=1[NH2:65].CC([O-])(C)C.[Na+]>>[CH3:54][N:44]1[C:45]2[C:50](=[CH:49][C:48]([NH:65][C:60]3[CH:61]=[N:62][CH:63]=[CH:64][C:59]=3[C:58]([F:67])([F:57])[F:66])=[CH:47][C:46]=2[C:52]#[N:53])[C@@H:42]2[CH2:41][NH:40][CH2:56][CH2:55][C@H:43]12
Reactant: Nc1cnccc1C(F)(F)F
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as a yellow solid (50 mg, 26%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 4-trifluoromethyl-pyridin-3-ylamine (141 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 374 (base, M+H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[C:9](=[O:12])([O-:11])[O-].[Na+].[Na+].[CH2:15](Cl)Cl.BrBr>CO>[CH3:1][S:2][CH2:3][C:4]1([O:5][CH3:6])[CH:8]=[CH:7][CH:9]([O:12][CH3:15])[O:11]1
Reactant: CSCc1ccco1
Reactant: ClCCl
Reactant: O=C([O-])[O-]
Agent: BrBr
Agent: [Na+]
Solvent: CO
Product: COC1C=CC(CSC)(OC)O1
Temperature: -20 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A mixture of 2-methylthiomethyl furan (23.3 g, 0.182 mole), anhydrous sodium carbonate (32.16 g, 0.303 mole), methylene chloride (40 mL) and absolute methanol (40 mL) was cooled to -20° C. under nitrogen atmosphere. A solution of bromine (24.32 g, 0.152 mole) in 60 mL absolute methanol was added over a period of one hour. The reaction mixture was stirred for another 4 hours and filtered by suction. The filtrate was stirred with anhydrous potassium carbonate (10 g--1 hour) and filtered. The solvents were removed on the rotatory evaporator and methylene chloride (100 mL) was added. The organic solution was dried over anhydrous sodium sulfate, filtered and the solvent was removed on the rotatory evaporator. The residue was distilled under reduced pressure to give 16.51 g (57%) of pure product, bp 66°-68° C. (0.4 mm Hg), nD =1.4860.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:8]2[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1.[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CN(C=O)C>[O:3]=[C:4]1[C:8]2[N:9]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1COCC[Si](C)(C)C)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To sodium hydride (60% dispersion in mineral oil) (0.46 g, 11.4 mmol, 1.1 equiv) in anhydrous DMF (10 mL) under a nitrogen atmosphere at 0° C. was added dropwise a solution ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (2.0 g, 10 mmol, 1 equiv) in anhydrous DMF (15 mL). After stirring for 30 min at 0° C., SEM-Cl (2.1 g, 12.4 mmol, 1.2 equiv) was then added dropwise over 5 min and the mixture warmed to rt overnight. The reaction was quenched by pouring the reaction contents into a beaker of ice water. It was extracted with EtOAc (4×50 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-30% EtOAc/heptane) to afford 2.9 g of ethyl 6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (86% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.84 (s, 1H), 5.87 (s, 2H), 4.35 (q, J=7.13 Hz, 2H), 3.57 (dd, J=8.59, 7.71 Hz, 2H), 2.82-2.92 (m, 4H), 1.38 (t, J=7.14 Hz, 3H), 0.85-0.92 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])=[CH:4][CH:3]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[O:6][C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH3:17]
Reactant: C=COC(C)=O
Reactant: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
trans-2-(4-Bromophenoxy)cyclohexanol (5.305 g, 19.56 mmol) was dissolved in ethyl acetate (196 mL) and treated with vinyl acetate (3.37 g, 39.1 mmol), followed by lipase enzyme from Candida antarctica (Novozyme 435, Sigma L4777, lipase immobilized on acrylic resin, 5.3 g). The reaction was capped and stirred for 18 hours, then filtered through Celite® and rinsed with ethyl acetate (500 mL). Concentration of the filtrate in vacuo provided a pale yellow oil, which was purified via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to afford (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate, the less polar product, as a colorless oil. Yield: 2.047 g, 6.54 mmol, 33%. Data for (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate: 1H NMR (400 MHz, CDCl3) δ 1.32-1.59 (m, 4H), 1.71-1.80 (m, 2H), 1.95 (s, 3H), 2.02-2.14 (m, 2H), 4.17 (ddd, J=9.6, 8.1, 4.4 Hz, 1H), 4.96 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.1 Hz, 2H). Enantiomeric alcohol (1S,2S)-2-(4-bromophenoxy)cyclohexanol, the more polar product, was obtained as a white solid (3.57 g). Data for (1S,2S)-2-(4-bromophenoxy)cyclohexanol: 1H NMR (400 MHz, CDCl3) δ 1.26-1.46 (m, 4H), 1.74-1.79 (m, 2H), 2.08-2.15 (m, 2H), 2.50 (br s, 1H), 3.72 (ddd, J=10.6, 8.5, 4.6 Hz, 1H), 3.96 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H). The absolute configurations of these compounds were assigned on the basis of an X-ray crystal structure of the enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide (see step 7 below).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10].O.[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1.O>C1C=CC=CC=1.CC(C)=O>[CH3:15][C:14]1([CH3:19])[O:10][CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:11][O:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(CO)CCCCCCBr
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCC(CCCCCCBr)CO1

Procedure:
24.2 g of crude 2-(6-bromohexyl)-1,3-propanediol was dissolved in a mixture of 200 mL of benzene, 30 mL acetone, and 0.4 g toluene-4-sulfonic acid monohydrate (Fluka, puriss.) in a 1 L 1-necked round flask. While magnetically stirring and refluxing 1.4 mL of water was separated and collected in a Dean-Stark trap during 22 h. The solvents were removed by rotary evaporation under reduced pressure and the residue vacuum distilled to recover 14.65 g of 2,2-dimethyl-5-(6-bromohexyl)-m-dioxane with b.p. 96°-97° C./0.06 mbar.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]([C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:15]([CH:16]=O)[C:14]=1[OH:25])([CH3:12])([CH3:11])[CH3:10].[OH2:26]>C(O)C>[C:9]([C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:15]([CH2:16][NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][CH2:16][C:15]2[C:18](=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=[C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])[CH:14]=2)[OH:26])[C:14]=1[OH:25])([CH3:12])([CH3:11])[CH3:10]
Reactant: O
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CCO
Product: CC(C)(C)c1cc(CNC2CCCCC2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Yield: 94 %

Procedure:
Rac-trans-1,2-diaminocyclohexane (6.09 g, 53 mmol) was dissolved in 300 ml of ethanol and placed in a three-necked flask fitted with a mechanical stirrer. 3,5-Di-tert-butylsalicylaldehyde (25.0 g, 107 mmol) was then added. The mixture was subsequently refluxed for one hour, forming a red suspention. After cooling, about 100 ml of water were added dropwise while stirring. The precipitate formed was filtered off and washed with a small portion of 95% strength ethanol, giving 29.8 g of crude product. This was purified by recrystallizing it once from 350 ml of ethanol. This gave 27.18 g of pure product as a yellow powder. The yield was 94%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1cccc(Nc2ccccc2)c1N
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (R)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (404 mg, 2.11 mmol) and the mixture was stirred at RT for 2 h. After this period of time, additional amounts of (R)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 20 h and then additional amounts (R)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(R)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (456 mg, 64%). LCMS: RT 3.69 min [M+H]+ 370.2
Reaction SMILES: [NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([N:28]2[CH2:29][CH:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=3)[CH2:27]2)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: FC(F)(F)Oc1ccc(C2CNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CC(c3ccc(OC(F)(F)F)cc3)C2)n1)C(N)=O
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (compound 37-6) (243 mg, 1 mmol), 3-(4-(trifluoromethoxy)phenyl)azetidine (1 mmol), and K2CO3 (138 mg, 1 mmol) was dissolved in DMF (3 mL), stirred at 80° C. for 14 hr, and then cooled to room temperature. The mixture was extracted with EtOAc (2×20 mL) and dried over MgSO4. After the removal of ethyl acetate via rotary evaporation the residue was subjected to flash chromatography using DCM/MeOH as the eluent to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(3-(4-(trifluoromethoxy)phenyl)azetidin-1-yl)pyrimidine-4-carboxamide (Cpd. No. 101) as a white solid (150 mg). 1H NMR (CD3OD) δ 7.12 (m, 2H), 6.80 (m, 2H), 6.42 (s, 1H), 5.05 (m, 1H), 3.90-4.45 (m, 5H), 1.35 (d, 3H). LC/MS: m/z=425 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:18]=[C:19]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])[CH:20]=[CH:21][C:22]=3[N:23]([CH3:25])[CH3:24])=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CO>[ClH:1].[CH3:24][N:23]([CH3:25])[C:22]1[CH:21]=[CH:20][C:19]([S:26]([NH:29][CH3:30])(=[O:28])=[O:27])=[CH:18][C:17]=1[NH:16][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:7][CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: CNS(=O)(=O)c1ccc(N(C)C)c(Nc2ncnc3cc(OCCCCl)ccc23)c1
Reactant: C1COCCN1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(N(C)C)c(Nc2ncnc3cc(OCCCN4CCOCC4)ccc23)c1
Product: Cl
Temperature: 90 °C
Reaction time: 72 h
Yield: 55.4 %

Procedure:
A mixture of 3-({7-[(3-chloropropyl)oxy]-4-quinazolinyl}amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (50 mg, 0.111 mmol) and morpholine (0.048 mL, 0.556 mmol) in MeOH (1 mL) was stirred at 90° C. for 3 days before being cooled and concentrated. The residue was triturated with Et2O-EtOAc and the resulting solid was collected by filtration, washed with Et2O, and dried to give 4-(dimethylamino)-N-methyl-3-[(7-{[3-(4-morpholinyl)propyl]oxy}-4-quinazolinyl)amino]benzenesulfonamide hydrochloride (33 mg, 48%) as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[CH:5].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:2]([N:16]1[CH2:15][CH2:14][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:18][CH2:17]1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 69.3 %

Procedure:
A solution of 4-bromo-1-butyne (0.500 g, 3.76 mmol) in acetonitrile (20 mL) was added with 1-tert-butoxycarbonylpiperazine (0.700 g, 3.76 mmol) and potassium carbonate (0.779 g, 5.64 mmol), and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(but-3-ynyl)piperazine-1-carboxylate (0.621 g, 69%).