Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24]>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH2:9]1)=[O:24])[CH:27]=[CH2:28]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Reactant: C=CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of 1-benzyl-3-t-butyldimethylsilyloxymethylpyrrolidine (60.10 g) and allyl chloroformate (25.27 ml) in toluene (600 ml) was heated at 60° C for one hour. The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (500 g), and eluted with a mixture of ethyl acetate and hexane (1:9-3:7, V/V) to give 1-allyloxycarbonyl-3-t-butyldimethylsilyloxymethylpyrrolidine (30.00 g).
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][CH:16]=[O:17])[C:3]([NH:5][C:6]1[S:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:4].Cl>O>[CH:11]1([C:8]2[S:7][C:6]([N:5]3[CH:16]([OH:17])[CH2:15][CH2:14][N:2]([CH3:1])[C:3]3=[O:4])=[N:10][N:9]=2)[CH2:12][CH2:13]1
Reactant: CN(CCC=O)C(=O)Nc1nnc(C2CC2)s1
Agent: Cl
Solvent: O
Product: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15]([NH:17]N)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:19])(=[O:5])=[O:4]>[Ni]>[CH3:1][N:2]([CH3:20])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:19])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)NN)cc21
Agent: [Ni]
Product: CN(C)S(=O)(=O)n1c(N)nc2ccc(C(N)=O)cc21

Procedure:
The procedure of method B above was repeated with 2.5 g. of 1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylic acid hydrazide and 10 g. of Raney nickel to yield 1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxamide, m.p. about 206°-208° C. A second crop was obtained from the mother liquors.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Br[CH2:15][CH2:16]Br>CN(C)C=O>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]2[NH:4][CH2:15][CH2:16][O:1][C:2]=2[CH:8]=1)([O-:11])=[O:10]
Reactant: BrCCBr
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2

Procedure:
Following Intermediate Method 4, the reaction of 2-hydroxy-4-nitroaniline with sodium hydride and 1,2-dibromoethane in N,N-dimethylformamide produces 2,3-dihydro-7-nitro-1,4-benzoxazine, (XIX). The reaction of (XIX) with sodium hydride and 2-iodopropane in N,N-dimethylformamide yields 2,3-dihydro-4-(1-methylethyl)-7-nitro-1,4-benzoxazine, (XX). Hydrogenation of (XX) with platinum oxide yielded (XXI). ##STR31##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Br:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[C:15]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[N:17][CH:18]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cncc(Br)c1
Product: N#Cc1cc(C=O)ccc1Oc1cncc(Br)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 5-bromopyridin-3-ol.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[C:41]([NH:1][C@@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH2:33])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N
Product: CC(=O)N[C@H]1[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Yield: 13 %

Procedure:
Method 4 was followed using tert-butyl ((1R,2R,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexyl)carbamate and acetic anhydride to give N-(4-((1R,3R,4R,5S)-4-acetamido-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 13% yield. LC/MS (m/z)=498.3 (MH+), Rt=0.58 min.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:44]([CH2:48][C:49](Cl)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:49](=[O:50])[CH2:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[C:8]2[CH2:28][C:29]([CH2:34][CH3:35])([CH2:36][CH3:37])[C:30]([O:32][CH3:33])=[O:31])=[CH:38][CH:39]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCC(CC)(Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold solution (0° C.) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-diethylpropanoate (from Step D) (177 mg, 0.33 mmol) in CH2Cl2 (3 mL) was added AlCl3 (220 mg, 1.65 mmol) followed by t-butylacetyl chloride (82 μL, 0.66 mmol). The reaction was stirred at 0° C. for 20 minutes and then quenched with 30 mL of 0.5N Na, K tartrate solution, and extracted with 3×30 mL of EtOAc. The organic layers were combined and dried over MgSO4. Filtration and concentration gave an oily residue which was purified by flash chromatography (eluant: EtOAc-hexane 17:83) to give the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
tert-Butyl piperazine-1-carboxylate (45.8 mmol, 8.53 g) and 4-(3-(cyclopropylmethyl)ureido)benzoic acid (45.8 mmol, 10.73 g) were mixed in dichloromethane (200 mL) and triethylamine (103 mmol, 14.36 ml, 10.43 g) added followed by 1-propanephosphonic acid cyclic anhydride (68.7 mmol, 40.7 mL, 43.7 g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour and then was poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound (17.13 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22](O)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1.[NH4+:26].[OH-]>ClCCl>[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22]([NH2:26])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 50 °C
Yield: 69.8 %

Procedure:
Oxalyl chloride (0.04 g, 0.3 mmol) was slowly added to a solution of 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture was warmed to 50° C. for 4 h and then cooled to 25° C. The solution was condensed in vacuum and then slowly added to 28% NH4OH (10 mL) and a solids precipitated out immediately. The mixture was warmed to 50° C. and stirred for another 2 h. Water (20 mL) was added to the reaction mixture and the slurry was cooled to 25° C. The product was filtered and the cake was washed with water, dried to afford 0.44 g 2-p-tolylbenzo[d]oxazole-4-carboxamide solid (Yield: 69.8%). 1H-NMR (300 MHz, DMSO-d6): 2.46 (s, 3H), 6.01 (s, 1H), 7.34-1.36 (d, J=5.7 Hz, 2H), 7.43-7.47 (t, J=6.0 Hz, 1H), 7.71-7.73 (d, J=6.0 Hz, 1H), 8.15-8.18 (m, 3H), 9.02 (s, 1H). MS (ESI) m/e 253 [M+H]+.
Reaction SMILES: [Na].[N:2]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[N:3]1.[CH2:12]([OH:14])[CH3:13]>>[N:2]1([C:7]2([C:10](=[NH:11])[O:14][CH2:12][CH3:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: CCO
Reactant: N#CC1(n2cccn2)CC1
Agent: [Na]
Product: CCOC(=N)C1(n2cccn2)CC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Sodium metal (12 mg, 0.52 mmol) was added to anhydrous ethanol (3 mL) at room temperature and the mixture was stirred for 15 min. 1-(1H-pyrazol-1-yl)cyclopropanecarbonitrile (0.1 g, 0.75 mmol) dissolved in ethanol (2 mL) was added and the reaction mixture was heated to 70° C. for 90 min. The resulting solution was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(OCC(=O)O)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1cccc(OCC(=O)O)c1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
To a 100 mL recovery flask was added 3-aminophenoxyacetic acid 2 (2.00 g, 12.0 mmol, 1.0 eq.) and a stirbar. Acetic acid (5 mL), conc. HCl (2 mL) and H2O (3 mL) were added to the flask. The reaction mixture was cooled to 0° C. upon which a solution of NaNO2 (0.908 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added over a period of 20 sec. The mixture was stirred for 5 minutes. A solution of NaN3 (0.855 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added slowly to the reaction mixture upon which the mixture foamed. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 1 h. A light brown solid precipitates out of solution. The suspension was filtered and washed with cold H2O to yield a light-brown solid (1.48 g). Upon drying, the more precipitate formed in the filtrate. The precipitate was refiltered to yield more product (0.17 g). Total yield: 1.65 g, 71%. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 192.1 (M−H)−1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 7.31-7.27 (t, 1H), 6.73-7.69 (m, 2H), 6.59-6.58 (m, 1H), 4.62 (s, 2H) ppm.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.[N:16]([O-])=O.[Na+]>O.Cl>[NH:4]([C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[NH2:16]
Reactant: COc1ccc(C(=O)O)c(NC(C)=O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(NN)c1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
A suspension of 2-acetylamino-4-methoxy-benzoic acid (15 g, 73.7 mmol) in water (75 mL) was cooled to −5° C. and conc HCl (150 mL) was added followed by cooling to −5°. To this mixture was added a solution of NaNO2 (5.43 g, 77.4 mmol) in water (50 mL) that had been cooled to −5°; this solution was added at such a rate so as to maintain the temperature of the reaction mixture between −5° and 0° C. The reaction mixture was stirred for 10 min and the clear solution was added to a solution of stannous chloride (41.9 g, 221 mmol) in conc HCl (150 mL) that had been cooled to −20° C. This addition was conducted so as to maintain a temperature of −20° to −10° C. for the reaction mixture, followed by stirring the mixture for 1.5 h at −20° C. The solid that formed was collected by filtration, washed with chilled EtOH, and dried to give an off-white solid (10.8 g): APCl/LCMS m/z 183 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:32]=[CH:31][C:16]([CH2:17][CH2:18][N:19]([CH3:30])[C:20](=O)OCC4C=CC=CC=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C=O.[H][H]>CO.[Pd]>[CH3:30][N:19]([CH3:20])[CH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)=[CH:32][CH:31]=1
Reactant: CN(CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Solvent: CO
Product: CN(C)CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Yield: 46.8 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)phenethyl(methyl)carbamate (30 mg, 0.069 mmol), paraformaldehyde (4 mg, 0.14 mmol), and 10% Pd/C (10 mg) in methanol (10 ml) was stirred at room temperature over 1 atm of hydrogen for 4 h. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by prep-HPLC to obtain 2-(4-(2-(dimethylamino)ethyl)phenyl)benzo[d]oxazole-7-carboxamide (10 mg, yield 48%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.34 (s, 6H), 2.62-2.66 (m, 2H), 2.89-2.93 (m, 2H), 7.46-7.52 (m, 3 H), 7.88-7.91 (m, 2H), 8.224-8.26 (d, J=8.4 Hz, 2H). LC-MS (ESI) m/z: 310 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:40])([CH3:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)[N:17]=[C:16]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[N:15]=2)=[C:9]([F:37])[CH:8]=1.[CH3:41][N:42]([CH3:48])[C:43](=[O:47])[C:44](O)=[O:45].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2([NH:20][C:18]3[N:17]=[C:16]([O:31][CH2:32][C:33]([F:35])([F:36])[F:34])[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][C:3]([CH3:40])([CH3:39])[CH2:2][NH:1][C:44](=[O:45])[C:43]([N:42]([CH3:48])[CH3:41])=[O:47])=[O:38])=[CH:8][C:9]=4[F:37])[N:19]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)NCC(C)(C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (20 mg, 0.034 mmol) and 2-(dimethylamino)-2-oxoacetic acid (4.83 mg, 0.041 mmol) in DMF (1 mL) were added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (16.5 mg, 0.052 mmol) and iPr2NEt (0.012 ml, 0.069 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamide (13.8 mg, 56%) as product. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.03 (6H, s), 1.31-1.53 (4H, m), 3.06 (3H, s), 3.10-3.21 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.39 (3H, s), 4.75 (2H, m), 7.14-7.29 (3H, m), 7.33-7.48 (1H, m), 7.70-7.81 (1H, m), 7.92-8.04 (1H, m), 8.07-8.15 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Br)(Br)([Br:31])=O>CN(C)C=O>[Br:31][C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: O=P(Br)(Br)Br
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)c1ccccc1
Product: Clc1ccc(-n2nc3c(c2Br)CCCC3)cc1
Temperature: 25 °C

Procedure:
To 5.0 parts of 2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one [from Example 1(c)] with 3.0 parts of N,N-diethylaniline and 5.0 parts of dimethylformamide under nitrogen atmosphere was added 6.3 parts of phosphorous oxybromide. The mixture was heated to 130°-170° for 2 hours. After cooling to room temperature, the reaction mixture was extracted with 100 parts of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. Recrystallization from methanol/water gave 2.7 parts of product, m.p. 101°-102°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=S)=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH3:27]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[NH:27])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(COc2cccnc2NC(=S)Nc2ccccc2)cc1
Product: COc1ccc(COc2cccnc2NC(=N)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.51 g, 0.0069 mol), N-[3-(4-methoxybenzyloxy)pyrid-2-yl]-N'-phenylthiourea (2.14 g, 0.0058 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.27 g (62%), m.p. 141°-143 ° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[CH2:14]([NH2:24])[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:24][CH2:14][C:15]2[CH:23]=[CH:22][C:21]3[O:20][CH2:19][O:18][C:17]=3[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 96.9 %

Procedure:
A mixture comprising 3.6 g of 2,4,6-trichloroquinazoline, 2.4 g of piperonylamine, 1.6 g of triethylamine and 50 ml of isopropyl alcohol was heated under reflux for 1.5 hours and hot-filtered to give 5.2 g of the title compound as a filter cake.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[C:34](=[O:36])[CH3:35])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(C)cc([N+](=O)[O-])cc12

Procedure:
A stirred mixture of 4-[(3-bromophenyl)amino]-8-methyl-6-nitro-quinoline-3-carbonitrile (15.3 g, 40 mmol), 0.37 g (3 mmol) of dimethylaminopyridine, 40 ml of acetic anhydride, and 80 ml of pyridine was refluxed for 3 h and concentrated at 50° C. under vacuum. The residue was stirred with methylene chloride and 0.1 N HCl. After filtration through Celite, the organic layer was washed with water, dried and concentrated. The residue was subjected to chromatography on silica gel with 1% acetic acid in methylene chloride to give 11.2 g of an amber glass, NMR (CDCl3) d 2.29 (N-acetyl group).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:38]1[O:39][C:40]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:41]=2[N:42]=1.O>CS(C)=O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][C:41]=3[N:42]=2)[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc2oc(Cl)nc2c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2oc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.9 %

Procedure:
To a solution of 185 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2.00 mL of DMSO was added 18 mg of sodium hydride (55% dispersion) at room temperature, followed by stirring for 10 minutes. 89 mg of methyl 2-chloro-1,3-benzoxazole-5-carboxylate was added thereto, followed by stirring at 100° C. overnight. 55 mg of methyl 2-chloro-1,3-benzoxazole-5-carboxylate was further added thereto, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate and chloroform-methanol) to obtain 33 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylate as a colorless resinous compound. ESI+: 638
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:15][C:16](=[O:18])[CH3:17])([CH2:13][OH:14])[CH2:11][OH:12])=[CH:4][CH:3]=1.CO[C:21](OC)([CH3:23])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][O:12][C:21]([CH3:23])([CH3:22])[O:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(CO)(CO)CCc1ccc(Br)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)NC1(CCc2ccc(Br)cc2)COC(C)(C)OC1
Yield: 87.3 %

Procedure:
A solution of N-[3-(4-bromophenyl)-1,1-bis(hydroxymethyl)propyl]acetamide (42.2 g) of Reference Example 4, acetone dimethyl acetal (41.9 g) and a catalytic amount of p-toluenesulfonic acid in acetone (200 mL) was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure, and the residual crude crystals were suspended in aqueous sodium hydrogen carbonate solution and collected by filtration to give the title compound (41.5 g) as white crystals.