Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH:13]([CH:17]1[CH2:19][CH2:18]1)[CH:14]1[CH2:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:20]#[N:21].[Na+]>CS(C)=O>[CH:17]1([CH:13]([CH:14]2[CH2:15][CH2:16]2)[CH2:12][C:20]#[N:21])[CH2:18][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OCC(C2CC2)C2CC2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC(C1CC1)C1CC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
209 g of 2,2-dicyclopropylethanol tosylate (prepared from 2,2-dicyclopropylethanol and para-toluenesulfonyl chloride) in solution in 45 ml of DMSO, are slowly added to 40 g of sodium cyanide in 45 ml of dimethyl sulfoxide (DMSO), with stirring and at 95° C. The heating is continued for one hour. After filtration of the precipitate and washing with ethyl ether, the filtrates are pooled, washed with a saturated solution of sodium chloride, dried and evaporated. The expected product is obtained after distillation under vacuum.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Li+].Cl.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16]>CN(C)C=O>[N:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: [O-][n+]1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccccc1-n1ccnc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A 0.76 g portion of imidazole was added to 7 ml of N,N-dimethylformamide and mixed with 0.2 g of 90% lithium hydride under ice-cooling and then the mixture was stirred for 40 minutes. Next, 2.17 g of 2-bromopyridine N-oxide hydrochloride was gradually added thereto, the mixture was stirred at room temperature for about 1 hour and further heated at 80° C. for about 1 hour, and then the solvent was evaporated and the thus obtained mixture was subjected to a silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (10:0.9:0.1, v/v/v) to obtain 1.21 g of the title compound as light yellow crystals.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]([CH3:23])[C:19]2=[O:22])=[CH:14][CH:13]=1>C1CCCCC1>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH:3]=[O:4])=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]([CH3:23])[C:19]2=[O:22])=[CH:14][CH:13]=1
Reactant: Cn1c(-c2ccccc2)cc2ccc(Cl)cc2c1=O
Reactant: CN(C)C=O
Solvent: C1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccccc2)c(C=O)c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 ml of dry N,N-dimethylformamide are cooled to 0° C., under an argon atmosphere, 12 ml (128 mmol) of phosphorus oxychloride are added dropwise and the mixture is stirred at room temperature for 1 h. 13.7 g (51 mmol) of 7-chloro-2-methyl-3-phenylisoquinol-1(2 H)-one are added and the mixture is gradually heated to 110° C. and is maintained at this temperature for 4 h. It is cooled to room temperature, the solvent is evaporated under reduced pressure, 200 ml of diethyl ether and ice are added to the residue, 1N sodium hydroxide is added, the organic phase is separated and the aqueous phase is extracted with 200 ml of dichloromethane. The two organic phases are combined, dried over sodium sulphate and filtered and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of cyclohexane and dichloromethane ranging from 80/20 to 50/50 and then with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30. After recrystallizing from cyclohexane, 7.68 g (26 mmol) of white solid are obtained. Melting point: 172°-173° C.
Reaction SMILES: [C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH2:26])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH:26][C:35](=[O:36])[O:37][CH3:38])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-amine (Intermediate 4), (110 mg, 0.322 mmol) in dichloromethane (10 mL) was added two equivalent of triethyl amine (0.090 mL, 0.644 mmol), followed by methyl chloroformate (0.037 mL, 0.483 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-ylcarbamate, (179), (20 mg). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H)
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].N[C@H]1CCCC[C@H]1O>C(O)(C)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Nc1ccc(B(O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N[C@H]1CCCC[C@H]1O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (1 g, 3.53 mmol), 4-aminophenylboronic acid (630 mg, 4.59 mmol), NiI2 (66 mg, 0.212 mmol), NaHMDS (1.94 g, 10.6 mmol), (1R,2S)-2-aminocyclohexanol (24 mg, 0.212 mmol) in isopropanol (8 mL) was stirred at 150° C. in microwave for 2 h. It was then evaporated and the residue was dissolved with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography to give 298a (360 mg, 40%). MS: [M+H]+ 249.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE XXXX, 464.57 mg, 0.901 mmol), 1,3,4-thiadiazol-2-amine (182 mg, 1.801 mmol), and cesium carbonate (880 mg, 2.70 mmol). DMF (4503 μl) was added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-7% MeOH/DCM) to give 1-(5-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (378 mg, 0.873 mmol, 97% yield) as a light-yellow foam. m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>O>[Cl:21][C:4]1[CH:5]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:7]=[C:2]([N:23]([CH2:24][CH2:25][OH:26])[CH3:22])[N:3]=1
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)CC1
Solvent: O
Product: CN(CCO)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)n1

Procedure:
A solution of tert-butyl 4-(2,6-dichloro-4-pyridyl)-5,6-dihydro-2H-pyridine-1-carboxylate (395 mg, 1.20 mmol) and 2-(methylamino)ethanol (3.5 mL, 44 mmol) in a glass vial was heated in oil bath at 100° C. for 4 h. After cooled, it was diluted with water (50 mL), extracted with EtOAc (2×50 mL). The combined EtOAc were dried over Na2SO4, filtered, concentrated in vacuo, and dried under high vacuum to give orange syrup. It was carried on without further purification. LC-MS: m/z=367 (M+H+).
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].[CH3:12][C@H:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C@@H:13]([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: C[C@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1O)c1ccccc1
Yield: 76.7 %

Procedure:
(S)-N-(2-Hydroxy-4-nitrophenyl)-N′-(methylbenzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and (S)-methyl benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (462 mg, 76%). EI-MS m/z 300(M−H)−
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:45]5[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Yield: 18.3 %

Procedure:
In the manner described in Example 30 (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (225 mg, 0.427 mmol) was reacted with 1-methanesulfonyl-piperazine (140.2 mg, 0.854 mmol) to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methyl sulfonyl)piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea (51 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.35 (m, 2H), 7.22 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 3.15 (m, 5H), 2.88 (s, 4H), 2.55 (m, 4H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 654 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[ClH:8].Cl.[NH2:10][C:11]1[CH:12]=[C:13]([C:19](=[O:40])[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][CH3:39])[CH2:24][CH2:23]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].C(N(CC)CC)C>O1CCCC1>[ClH:8].[CH2:38]([O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][C:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:1](=[O:3])[CH3:2])[CH:12]=2)=[O:40])[CH2:23][CH2:24]1)[CH3:39]
Reactant: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(N)c2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(NC(C)=O)c2)CC1
Reaction time: 12 h

Procedure:
Acetic acid anhydride (0.132 ml) was added to a solution of 1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy) ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained in Example 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (40 ml) were added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as a colorless oil (276 mg), The free base compound (270 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (277 mg) as colorless crystals having a melting point of 127 to 129° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][OH:6])#[N:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>ClCCl>[CH3:30][S:31]([O:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC#N
Reactant: CS(=O)(=O)Cl
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COS(C)(=O)=O

Procedure:
A mixture of 940 mg (2.29 mM) of 2-cyanomethyl-3-octadecylcarbamoyloxypropanol Vn2, 0.231 ml (2.98 mM) of methanesulfonyl chloride and 0.483 ml (3.44 mM) of triethylamine in 10 ml of dichloromethane is allowed to react by the same procedure as described in (52) and crude product of the titled compound Vn2a is obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[CH:31][C:30]([NH:33][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:28]=1
Reactant: COC[C@H]1CCCN1c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COC[C@H]1CCCN1c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcd for C22H21F3N4O3 (m/e) 446, obsd 447 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:29]=[CH:28][C:6]([CH:7]([C:16]2[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O.[OH-].[Na+].OO>C(O)(C)C>[CH3:30][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[C:16]3[C:17](=[CH:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[C:18](=[O:20])[O:19]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A stirred mixture of 8.1 g of 2-(4-dimethylamino-4'-methoxybenzhydryl)-5-dimethylaminobenzoic acid from part A above, 40.0 ml of water, 1.6 g of 50 percent aqueous sodium hydroxide and 2.7 ml of isopropyl alcohol was maintained at a temperature in the range of 85°-96° C. while 20.3 g of ten percent aqueous hydrogen peroxide was added over a period of approximately six hours. The reaction mixture was set aside at ambient temperature overnight. The solid was collected by filtration, washed free of alkali with water and dried in vacuo to obtain 5.5 g of 3-(4-dimethylaminophenyl)-3-(4-methoxyphenyl)-6-dimethylaminophthalide, a yellow-colored solid which melted at 156°-161° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NCCCN1CCOCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(NCCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 3-(4-morpholinyl)-1-aminopropane (3.1 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 EtOAc/MeOH) to yield the product as an orange solid (0.45 g, 23%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.C([O-])(O)=O.[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CCO>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=3)[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2,4-dichloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidine (0.12 mol) and NaHCO3 (1.95 g, 0.023 mol) in EtOH at 0° C., add piperazine-l-carboxylic acid tert-butyl ester (0.013 mol). Remove the ice bath and stir at room temperature for 16 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=2[CH2:19][CH3:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[N:10]=2
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
Potassium thiocyanate (972 mg, 10 mmol) was suspended in acetic acid (20 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (1.0 g, 2.50 mmol) in acetic acid (20 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 15 min. A solution of bromine (439 mg, 2.75 mmol) in acetic acid (14 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and washing solution were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (250 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (1.0 g, 87%) as a pale-yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1)[C:2]#[CH:3].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>O.C(O)C>[CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=[C:13]([C:12]#[N:16])[C:14]#[N:15])=[CH:8][N:9]=1)[C:2]#[CH:3]
Reactant: N#CCC#N
Reactant: C#CCOc1ncc(C=O)s1
Solvent: CCO
Solvent: O
Product: C#CCOc1ncc(C=C(C#N)C#N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
1.4 g of 2-(2-propynyloxy)-1,3-thiazole-5-carbaldehyde was dissolved in a mixture of 6 ml of water and 14 ml of ethanol, and 0.56 g of malononitrile was added dropwise. The mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the resulting cake was washed with 5 ml of ethanol two times and dried under reduced pressure to obtain 1.55 g of {[2-(2-propynyloxy)-1,3-thiazol-5-yl]methylidene}malononitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20](OC)=[O:21].CC(C)([O-])C.[K+]>COC(C)(C)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:20][OH:21]
Reactant: COC=O
Reactant: COC(=O)Cc1cc(Cl)ccc1Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (5-chloro-2-phenoxy-phenyl)-acetic acid methyl ester (167 g, 605 mmol) and methyl formate (173 mL, 2.8 mol) in t-butyl methyl ether (1 L) was cooled to −10° C. To this solution was added potassium t-butoxide (115 g, 1.03 mol) portionwise so that the temperature remained below 0° C. After 30 minutes, the reaction was quenched by addition of 4N aqueous hydrochloric acid (400 mL). The organic layer was separated and washed with water (3×350 mL) and saturated brine (350 mL). The organic fractions were combined and concentrated to dryness and used without purification. The product is 90% E as shown by NMR. 1H NMR (400 MHz, CDCl3) 3.6 (s, 3H, E methyl group; Z methyl is at 3.7), 6.8 (d, 1H), 6.9 (m, 2H), 7.0 (t, 1H), 7.2 (m, 3H), 7.3 (m, 2H), 11.8 (d, 1H, E hydroxy proton; Z hydroxy proton is at 4.7).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[O:8]=[C:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1>CO.C(Cl)Cl>[O:8]=[C:9]1[CH2:12][CH:11]([C:13]([O:15][CH3:1])=[O:14])[CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CC(C(=O)O)C1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyldiazomethane (21.0 mL of a 2 M solution in hexanes, 42.1 mmol) was added to a stirred solution of 3-oxocyclobutanecarboxylic acid (3.00 g, 26.3 mmol) in dry MeOH (11.1 mL) and dry CH2Cl2 (100 mL) at 25° C. under N2. The reaction was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford methyl 3-oxocyclobutanecarboxylate, as an oil. 1H NMR (500 MHz, CHCl3): δ 3.75 (s, 3H); 3.44-3.37 (m, 2H); 3.31-3.17 (m, 3H).