Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:13][CH2:14][C:15]2([OH:28])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:3]1.FC(F)(F)C(O)=[O:32].[ClH:36]>ClCCl.O1CCOCC1>[Cl-:36].[NH2+:18]1[CH2:17][CH2:16][C:15]2([O:28][C:5]3[C:10]4[C:11]([C:2](=[O:1])[C:3](=[O:32])[C:4]=3[S:13][CH2:14]2)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccccc32)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CC[NH2+]CC1)O2
Product: [Cl-]
Temperature: 25 °C
Reaction time: 30 h
Yield: 58 %

Procedure:
To a solution of tert-butyl 4-{[(3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate (3.8 g, 0.942 mmol) in 50 ml dichloromethane which was cooled to 0° C. was added trifluoroacetic acid (200 ml). The reaction mixture was stirred at room temperature for 30 hours and the solvent removed under reduced pressure. The mixture was dissolved in dichloromethane (150 ml) and poured over a 0° C. mixture of saturated sodium carbonate (500 ml) and water (200 ml). Methanol (500 ml) was then added to the reaction mixture and allowed to stir overnight. The mixture was extracted with dichloromethane (4×400 ml). The organic extracts were combined and washed with a mixture of 2.0M sodium carbonate and brine (5×500 ml). The organic layer was separated, dried with Na2SO4, and concentrated under reduced pressure to give a purple solid. To a stirred solution of the purple solid in dichloromethane (100 ml), 4.0 M HCl in dioxane (20 ml) was added dropwise. The precipitate was filtered, washed with dichloromethane and ether, and recrystallized from ethanol to give a purple crystalline solid (1.84 g, 58%). M.p.=229-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.19 (br. s, 2H), 7.90-7.86 (m, 1H), 7.84-7.80 (m, 1H), 7.76-7.71 (m, 1H), 7.58-7.53 (m, 1H), 3.33-3.25 (m, 2H), 3.16-3.07 (m, 4H), 2.22-2.15 (m, 2H), 2.20-1.50 (m, 2H); LCMS: 302 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:3]([C:23]([O:25]C)=O)=[N:4][C:5]([N:12]([CH3:22])[S:13]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)(=[O:15])=[O:14])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[C:30]([S:36][CH3:37])[CH:29]=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:23]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[C:5]([N:12]([CH3:22])[S:13]([C:16]3[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=3)(=[O:14])=[O:15])[N:4]=2)=[O:25])=[C:30]([S:36][CH3:37])[CH:29]=1
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)c2cn(C)cn2)c2cccnc2c1O
Reactant: CSc1cc(F)ccc1CN
Solvent: Cc1ccccc1
Product: CSc1cc(F)ccc1CNC(=O)c1nc(N(C)S(=O)(=O)c2cn(C)cn2)c2cccnc2c1O

Procedure:
A solution of methyl 8-hydroxy-5-{methyl[(1-methyl-1H-imidazol-4-yl) sulfonyl]amino}-1,6-naphthyridine-7-carboxylate. (0.14 g, 0.371 mmol) and 1-[4-fluoro-2-(methylthio)phenyl]methanamine (0.102 g, 0.594 mmol) in toluene (1 mL) were heated at 130 C in a sealed tube for 72 hr. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC (Waters PrepPak Column, C18 eluting with 5-95% acetonitrile/water (0.1% TFA) at 100 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH:33][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Nc1cnn(CCN2CCCC2)c1
Reactant: FC(F)(F)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: FC(F)(F)c1ccc(-c2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1

Procedure:
[1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.100 g, 0.33 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.078 g, 0.43 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (78 mg, 52%). MP=205-207° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.35 (s, 1H), 8.76 (d, J=6.44 Hz, 1H), 8.38 (d, J=8.00 Hz, 2H), 7.08-7.93 (m, 3H), 7.84 (s, 1H), 7.47 (s, 1H), 7.11 (t, J=7.08 Hz, 1H), 4.17 (t, J=6.37 Hz, 2H), 2.80 (t, J=6.24 Hz, 2H), 2.45 (s, 4H), 1.64 (s, 4H). MS=442 (MH)+.
Reaction SMILES: [NH2:1][C:2](=[N:16][O:17][C:18]([O:20]CC(CC)CCCC)=O)[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[O:20]=[C:18]1[O:17][N:16]=[C:2]([C@@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:1]1
Reactant: CCCCC(CC)COC(=O)ON=C(N)[C@@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1noc(=O)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
A mixture of tert-butyl [(1S,2R)-2-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}cyclopentyl]carbamate (492 mg) and xylene (10 ml) was stirred at an outside temperature of 140° C. for 4 hours. The reaction mixture was left to be cooled, ethyl acetate (40 ml) was added, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol-chloroform) to obtain tert-butyl [(1S,2R)-2-(5-oxo -4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopentyl]carbamate (328 mg) as a pale yellow solid.
Reaction SMILES: [N+](C1C=CC(CP(=O)(OCC)OCC)=CC=1)([O-])=O.N1C=CC=C(C=O)C=1.[N+:27]([C:30]1[CH:43]=[CH:42][C:33]([CH:34]=[CH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1)([O-])=O>>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([NH2:27])=[CH:43][CH:42]=2)[CH:37]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccnc2)cc1
Agent: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: O=Cc1cccnc1
Product: Nc1ccc(CCc2cccnc2)cc1

Procedure:
Anilines with other sidechains will be readily prepared by a person having ordinary skill in the art having regard to that skill and this disclosure, and will be usable in the syntheses of Reaction Scheme 4. For example, diethyl (4-nitrobenzyl)phosphonate was reacted in a Wittig reaction with pyridin-3-carboxaldehyde and the resulting 3-(4-nitrostyryl)pyridine hydrogenated to give 4-[2-(pyridin-3-yl)ethyl]benzenamine, used to synthesize compound 99A, and the anilines used to synthesize compounds 97A and 98A were similarly prepared; 4-nitrobenzaldehyde was reacted with glyoxal and ammonia to give 2-(4-nitrophenyl)-1H-imidazole, which was N-methylated with methyl iodide and then reduced with stannous chloride to give 4-(1-methyl-1H-imidazol-2-yl)benzenamine, used to synthesize compound 106A; 2-fluoro-4-nitrobenzoic acid was converted to the corresponding benzoyl chloride with oxalyl chloride, then reacted with 3-(morpholin-4-yl)propan-1-amine and reduced to give 4-amino-2-fluoro-N-[3-(morpholin-4-yl)propyl]benzamide, used to synthesize compound 50A; and 4-nitrobenzenesulfonyl chloride was reacted with 2-(morpholin-4-yl)ethan-1-amine and then reduced with stannous chloride to give 4-amino-N[2-(morpholin-4-yl)ethyl]benzenesulfonamide, used to synthesize compound 128A.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[O:13])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]([CH:18]([CH3:19])[CH3:20])=[C:6]([O:8][C:9]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:11]([CH:12]3[O:24][CH2:23][CH2:22][O:13]3)[CH:10]=2)[N:7]=1
Reactant: OCCO
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of 3-(2,6-dichloro-5-isopropyl-pyrimidin-4-yloxy)-5-methyl-benzaldehyde (1.71 g, 5.25 mmol), ethylene glycol (0.88 ml, 15.75 mmol), and p-toluenesulfonic acid (263 mg, 0.26 mmol) in toluene (20 ml) was refluxed for 3 hr., using a reflux condenser equipped with a Dean-Stark trap. After cooling to room temperature, the mixture was diluted with EA, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 1.79 g (92%) of a colorless syrup. 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 3.99-4.16 (4H, m), 5.82 (1H, s), 6.92 (1H, s), 7.03 (1H, s), 7.21 (1H, s).
Reaction SMILES: CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([OH:33])=O)=[CH:28][C:23]=2[O:22][CH2:21]1.Cl.Cl.[CH2:36]([N:43]1[C:52]2[C:47](=[CH:48][C:49]([Cl:53])=[CH:50][CH:51]=2)[CH2:46][CH:45]([NH2:54])[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCCl>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([NH:54][CH:45]3[CH2:46][C:47]4[C:52](=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=4)[N:43]([CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:44]3)=[O:33])=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Reactant: NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(CCc1ccc2c(c1)OCO2)NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.8 %

Procedure:
Typical procedure: To a suspension of PS-DIC 110 mg/well (Argonaut, 1.38 mmol/g loading) in DCE (0.5 mL) at room temperature was added HOBt (5 mg in 100 μL DMF), followed by 3-(benzo[d][1,3]dioxol-5-yl)propanoic acid (75 μmol). To this was added 1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-amine, dihydrochloride (14 mg, 50 μmol), prepared as described in Example 19C, in 1,2-dichloroethane (0.5 mL). The reaction mixture was shaken at RT for 24 h, contents were filtered into a synthesis tube rack (STR) and the solvent was dried in a speed vac. The resulting residue was chromatographed using preparative HPLC (conditions: Xterra MS-C18 (30×50 mm); eluted with 10% to 100% B, 6 min gradient. (A=100% water with 0.1% TFA and B=acetonitrile with 0.1% TFA); flow rate at 30 mL/min; UV detection at 220 nm) to give the title compound, 3-(benzo[d][1,3]dioxol-5-yl)-N-(1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)propanamide, (2.2 mg, 8%). HPLC (method C): retention time=1.6 min, MS (ES): m/z 449 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([S:30](Cl)(=[O:32])=[O:31])[CH:28]=2)[C:23]([Cl:34])=[CH:22][N:21]=1>C(Cl)Cl>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([S:30]([NH:1][C:2]3([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)(=[O:32])=[O:31])[CH:28]=2)[C:23]([Cl:34])=[CH:22][N:21]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: COC(=O)C1(N)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCCC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
A mixture of methyl 1-aminocyclohexanecarboxylate (325 mg, 1.68 mmol), NEt3 (0.49 mL, 3.5 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (415 mg, 1.40 mmol) in CH2Cl2 (30 mL) was stirred at 23° C. for 16 h. The mixture was diluted with CH2Cl2, washed with dilute HCl (2 M), saturated aqueous NaHCO3, brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexane-EtOAc (80:20 to 70:30) as eluant, followed by trituration with i-Pr2O, to give to give methyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-cyclohexanecarboxylate (132 mg, 0.32 mmol) as a white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[CH2:20]=[O:21]>>[OH:21][CH2:20][N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:11]1=[O:19]
Reactant: O=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2
Reactant: C=O
Product: O=c1n(CO)c2cccnc2n1-c1ccc2c(c1)OCO2

Procedure:
A mixture of 500 mg. of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-one and 30 ml. of 37% formaldehyde was heated on the steam bath for 1.5 hours. The hot solution was treated with decolorizing carbon, filtered, and the filtrate was treated with 2 ml. of 2.5 N sodium hydroxide and 30 ml. of water. The precipitate was collected: 400 mg. of 1,3-dihydro-1-hydroxymethyl-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-one, m.p. 268° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][NH:15]2>>[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][N:15]2[C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ccc2c(c1Cl)CCN2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2c1ccc(Cl)c2Cl

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 4,5-dichloroindoline (D32) to give (E16) (0.5 g, 25%) m.p. >240° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[Cl-:9].[Al+3].[Cl-:11].[Cl-].ClCl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:9][C:4]1[CH:3]=[C:2]([C:6](=[O:8])[CH3:7])[S:1][C:5]=1[Cl:11]
Reactant: [Cl-]
Reactant: CC(=O)c1cccs1
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Cl)c(Cl)s1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 108.9 %

Procedure:
To a solution of 1-Thiophen-2-yl-ethanone (5.0 grams, 40.0 mmole) in chloroform (50 ml) at 20° C. was added portionwise aluminum chloride (15.9 grams, 119.0 mmole). The mixture was stirred at 20° C. for 10 minutes and 1 M Cl2 in carbon tetrachloride (120 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes and diluted with methylene chloride (300 ml) and washed with 1 N sodium hydroxide and water and dried over magnesium sulfate and concentrated to give a solid (8.5 g). MW 195.07; MS (m/e) 196 (M++1).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Cl>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH2:33][O:32][CH3:31])=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: COCOc1ccccc1CCl
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COCOc1ccccc1COc1cc2c(cc1-c1cc(C=CC(=O)O)ccc1OC)C(C)(C)CCC2(C)C
Yield: 98.5 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.26 g (6.73 mmol) of 2-methoxymethoxybenzyl chloride obtained above, 3.2 g (94%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH:11]1[CH2:14][CH2:13][CH2:12]1>>[N:11]1([C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:14][CH2:13][CH2:12]1
Reactant: C1CNC1
Reactant: N#Cc1cccnc1F
Agent: Cl
Product: N#Cc1cccnc1N1CCC1
Yield: 82 %

Procedure:
Prepared in 82% yield from 3-cyano-2-fluoropyridine and azetidine hydrochloride according to the procedure described for Example 178A. MS (ESI+) m/z 160.0 (M+H)+; 1H NMR (DMSO-d6) δ 2.28-2.38 (m, 2H), 4.19-4.25 (m, 4H), 6.73 (Dd, J=7.6, 4.9 HZ, 1H), 7.92 (dd, J=7.7, 1.8 Hz, 1H), 8.30 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:6](=[O:29])[N:5]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:4]=1[CH3:40])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=[O:23])[C:6](=[O:29])[N:5]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=2)[C:4]=1[CH3:40])#[N:2]
Reactant: CC1=C(C#N)[C@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The reaction was carried out under argon. tert-Butyl [(6R)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetate (350 mg, 609 μmol; Example 7) was initially charged in dichloromethane (60 ml), and trifluoroacetic acid (20 ml) was added. The mixture was stirred at RT for 90 min. The volatile components were then removed on a rotary evaporator. The residue was taken up in toluene (50 ml) and again concentrated under reduced pressure. This procedure was repeated once more. The crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a colorless solid (290 mg, 92% of theory).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:12][C:8]1[C:7]2[NH:13][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(OCCCBr)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2c1NCCCO2
Temperature: 70 °C
Yield: 68.9 %

Procedure:
To 2-(3-bromo-propoxy)-6-methyl-phenylamine (4.8 g, 20 mmol) in acetonitrile (200 mL) was added potassium carbonate (13.8 g, 100 mmol). The mixture was heated at 70° C. for 24 hrs, followed by the filtration to remove solids. After evaporation, the mixture was repartitioned with ethyl acetate (250 mL) and water (150 mL). The organic layer was then washed with brine (150 mL) and dried over MgSO4. Evaporation followed by purification by silica gel column chromatography eluting with hexane/ethyl acetate (11/1 to 4/1) yielded 1-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene 2-3 as a pale yellow oil (2.25 g). MS: 164.0 (M+H)+; tR=1.191 min (method 1). NMR (CDCl3), 6, 6.789-6.858 (2H, m), 6.664 (1H, t), 4.158 (2H, t), 3.343 (2H, t), 2.198 (3H, s), 1.191-2.067 (2H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Yield: 106.1 %

Procedure:
0.5 g (0.00216 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene, treated with 0.5 g (0.0027 mol) of 4-nitro-benzoyl chloride and boiled at reflux for 6 hrs. The suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetatelhexane (1:3) as the eluent. 0.78 g (85%) of 1-benzyl-piperidin-4-yl 4-nitro-benzoate was obtained as yellow crystals; m.p. 87°-89°.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[CH:3]2[CH2:1][CH3:2]
Reactant: CCC1C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, and brine, dried (MgSO4) and evaporated to afford the crude product (9.2 g, 96%). A sample was recrystallized from EtOAc/hexane to obtain the title compound, m.p. 130-132° C.; 1H-NMR (DMSO-d6) δ 0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43 (s, 1H); MS (−ESI) m/z 238/240 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:8][C:7]=2[CH:17]=1)#[CH:2].Br[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH:25]=2)[N:20]=1>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]4[O:10][C:9]([CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)=[N:8][C:7]=4[CH:17]=2)[CH:28]=[CH:27]3)=[CH:34][CH:33]=1
Reactant: C#Cc1ccc2oc(CN3CCCC3)nc2c1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Product: Clc1ccc(-c2ccc3nc(C#Cc4ccc5oc(CN6CCCC6)nc5c4)ccc3c2)cc1

Procedure:
Prepared analogously to Example 18d from 5-ethynyl-2-pyrrolidin-1-ylmethyl-benzoxazole and 2-bromo-6-(4-chloro-phenyl)-quinoline.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[O:19]([C:21]#[N:22])[K].C(OCC)(=O)C>CC(O)=O.O>[O:16]1[CH2:17][CH2:18][CH:13]([O:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]3[C:2]=2[N:1]=[C:21]([OH:19])[N:22]=[C:4]3[OH:6])[CH2:14][CH2:15]1
Reactant: N#CO[K]
Reactant: COC(=O)c1cccc(OC2CCOCC2)c1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(O)c2cccc(OC3CCOCC3)c2n1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To a solution of methyl 2-amino-3-(tetrahydro-2H-pyran-4-yloxy)benzoate (18 g, 0.071 mol) in AcOH (180 mL) was added a solution of KOCN (11.47 g, 142 mmol) in water (22 mL) at 60° C. Then the mixture was heated at 80° C. for 40 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. Then the mixture was concentrated in vacuo. The residue was diluted with water (200 mL). The precipitate was filtered to give the title compound (9 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO): δ 11.354 (s, 1H), 10.491 (s, 1H), 7.539 (d, 1H), 7.455 (d, 1H), 7.191 (t, 1H), 4.732 (m, 1H), 4.006 (m, 2H), 3.535 (m, 3H), 2.023 (m, 2H), 1.842 (m, 2H)