Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under cooling with ice, 1-benzhydrylazetidin-3-ol (718 mg) in tetrahydrofuran (8 mL) was added dropwise to a suspension of 60% sodium hydride (144 mg) in N,N-dimethylformamide (8 mL), and the resultant mixture was stirred for 20 minutes. Methyl iodide (0.23 mL) was added to the reaction mixture, followed by stirring at room temperature overnight. The reaction mixture was partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (680 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.4 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (1.4 g) and triethylamine (1.0 g) in dichloromethane (40 ml) were added tridecanoyl chloride (2.0 g) and dimethylaminopyridine (0.2 g). The solution was stirred at room temperature for about 20 hours and thereto was added dilute aqueous hydrochloric acid solution. The organic layer was separated by a funnel and distilled to remove the solvent. The residue was washed with n-hexane and dried to obtain the titled compound (about 1.8 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15])[CH2:6][CH2:5]2.C(Cl)Cl.[O:30]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(C#N)(C)=O.O>[OH:30][C:7]([CH3:25])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:26])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccn1)O2
Reactant: O=[N+]([O-])[O-]
Agent: CC(=O)C#N
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCc2ccccn2)=C(C)C1=O
Yield: 83.9 %

Procedure:
6-Hydroxy-2,5,7,8-tetramethyl-N-(2-(pyridin-2-yl)ethyl)chroman-2-carboxamide (97.7 mg, 0.276 mmol) was dissolved in 3 mL AcCN and 2 mL CH2Cl2 and cooled to 0° C. prior to treatment with 332.5 mg CAN (0.606 mmol) in 2 mL H2O. The reaction was quenched by the addition of 5 mL EtOAc and 4 mL 1.0 M NaHCO3 followed by extraction of the aqueous layer 3×5 mL EtOAc. The combined organics were back extracted 3×3 mL saturated NaCl, dried over Na2SO4 and concentrated. Flash chromatography yielded 85.8 mg of 2-hydroxy-2-methyl-N-(2-(pyridin-2-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [ClH:1].O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(O)(C)C>[ClH:1].[CH2:15]([NH:33][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.45 g of D-glucosamine hydrochloride are dissolved in 30 ml of isopropanol and 10 ml of water at 60° C., and 12.1 g of stearylamine are added. The resulting clear solution is stirred for a further 10 min and then cooled to room temperature. The product which has crystallized out is filtered off with suction and washed first with ethanol/water (5:2, v/v), then with ethanol and finally with ether. The residue is dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[CH2:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31]Cl)[CH3:21].C(N(CC)CC)C.[I-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:31][C:23]3[N:22]([CH2:20][CH3:21])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:7]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CCn1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCn1c(CNc2ccc(S(=O)(=O)Nc3nc(C)cc(C)n3)cc2)nc2ccccc21

Procedure:
32.4 mg (0,12 mmol) sulfamethazine and 36 mg (0.18 mmol) 1-ethyl-2-chloromethylbenzimidazole were dissolved in 4 ml methanol. 64 μl (0.44 mmol) triethylamine and catalytic amount of sodium iodide were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to provide white crystals of the title compound, 10 mg (20%). 1H NMR (DMSO-d6, 500 MHz): 7.68 (2H, m), 7.60 (1H, m), 7.52 (1H, m), 7.22 (1H, m), 7.17 (1H, m), 7.00 (1H, br, s), 6.78 (3H, m), 6.60 (1H, br, s), 4.60 (2H, m), 4.30 (2H, q, 7.2 Hz), 2.18 (6H, s), 1.28 (3H, t, 7.2 Hz); MS (ESI+): m/z 437 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][CH2:33][S:32]1(=[O:37])=[O:36]>>[O:36]=[S:32]1(=[O:37])[CH2:33][CH2:34][CH2:35][N:31]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=S1(=O)CCCN1c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3N3CCCS3(=O)=O)cc2F)cn1

Procedure:
Title compound was prepared using methods analogous to those described in Example 384 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-(2-bromophenyl)isothiazolidine 1,1-dioxide. MS (ESI): mass calcd. for C19H17FN4O2S, 384.11; m/z found, 385.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=1.4, 2H), 7.78-7.71 (m, 1H), 7.69-7.58 (m, 1H), 7.50-7.32 (m, 4H), 7.29-7.20 (m, 1H), 5.21 (s, 2H), 3.77 (t, J=6.8, 1H), 3.43-3.17 (m, 2H), 2.67-2.47 (m, 1H), 2.42-2.17 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([CH2:26][OH:25])[CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1cccc(CO)c1
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cccc(CO)c3)nc21
Temperature: 180 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.500 g (4.10 mmol) of 3-(hydroxymethyl)aniline was heated in a 180° C. oil bath for 10 minutes. At ca. 120° C., 2 mL of glacial acetic acid were added to dissolve the gum. Water (20 mL) was added to precipitate a solid. The mixture was filtered. The cake was washed well with water and dried; wt 0.130 g. Purification was effected by silica gel chromatography eluting with chloroform and then with ethyl acetate to obtain the fraction containing the pure product. The ethyl acetate eluent was concentrated to 1 mL volume. The crystals that separated one inducement were filtered and washed with 0.5 mL of ethyl acetate and then 1 mL of ether; wt 0.059 g; mp 215°-217° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]([S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>C(C(C)=O)C>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[CH:12][C:3]([CH2:2][O:14][C:15]3[CH:16]=[C:17]([CH:21]([S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:18]=[CH:19][CH:20]=3)=[N:4]2)=[CH:9][CH:8]=1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(O)c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A mixture of 2-bromomethyl-7-chloroquinoline (2.5 g) (Step 2), phenol (Step 1) (3.4 g) and K2CO3 (3 g) was heated at reflux for 4 hours in methyl ethyl ketone (100 ml). The reaction mixture was cooled and ether (100 ml) was added. The suspension was filtered and evaporated. Flash chromatography of the residue using 30% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[O:10][C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:7]=2[O:6]1)=[NH:4].C[O-].[Na+].[C:31](=O)(OCC)[O:32]CC>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:7]2[O:6][CH:5]([C:3]3[NH:4][C:31](=[O:32])[O:1][N:2]=3)[O:10][C:9]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:8]=2[CH:23]=1
Reactant: CCOC(=O)OCC
Reactant: N=C(NO)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(C2Oc3ccc(Cl)cc3C(C3CCCCC3)(C3CCCCC3)O2)no1
Temperature: 25 °C

Procedure:
To a solution of 500 mg N-hydroxy-6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxamidine in 3.7 ml ethanol was added 0.7 ml of a sodium methoxide solution (30% in methanol) and then 0.617 ml diethyl carbonate. The mixture was refluxed for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in 3.4 ml water and 1M aqueous HCl was added until pH7 was reached. The obtained precipitate was filtered, washed with water, dissolved in EtOAc and dried with MgSO4. Then the solvent was removed in vacuo and the crude product purified by preparative HPLC (C18 reverse phase column, elution with water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 257 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46](Cl)=[N:45][CH:44]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.O>[C:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])=[CH:22][CH:21]=3)=[N:45][CH:44]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Nc1ccccc1)OCc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(COC(=O)Nc3ccccc3)s2)cc1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with (2-chloro-1,3-thiazol-5-yl)methyl N-phenylcarbamate (136 mg, 0.5 mmol). The crude residue stirred in ethyl acetate/water for 16 hours before being filtered, and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and purified by flash chromatography on silica, eluting with methanol/dichloromethane (0-30%) to give the title compound; Mass Spectrum: M+H+-Boc 489.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42]C(=O)OC(C)(C)C)[CH2:37]1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-c2csc3c(/C=C/CN4CCCC(N)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 19.6 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (100 mg, 0.207 mmol) and tert-butyl piperidin-3-ylcarbamate (124 mg, 0.621 mmol), were reacted according to General Procedure B. The crude product (137 mg, 0.206 mmol) was dissolved in methanol (1 mL) and treated with 6.0 M hydrochloric acid in 1,4 dioxane (0.514 mL, 2.06 mmol) and heated to 55 degrees Celsius for 20 hours. The mixture was cooled to room temperature then 1M sodium carbonate solution (5 mL) was added and product was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified via HPLC preparation to furnish the title compound as an ivory powder (23.0 mg, 0.0406 mmol): LCMS (Conditions a): MH−=565 RT=3.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (1H), 7.91 (2H), 7.65 (1H), 7.28 (3H), 7.10 (3H), 7.01 (1H), 6.64 (1H), 6.15 (1H), 5.59 (1H), 3.71 (3H), 3.85 (3H), 3.52 (1H), 3.14 (2H), 2.89 (1H), 2.78 (1H), 2.62 (1H), 2.16 (1H), 2.03 (1H), 1.66 (1H), 1.42 (1H), 1.15 (1H).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:2][NH2:3])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCl)c1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CNN)c1
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
While a solution of hydrazine monohydrate (1.32 g, 26.4 m mol) in ethanol (20 ml) was heated under reflux, a solution of 3-tert-butoxycarbonylaminobenzyl chloride (1.06 g, 4.4 m mol) in ethanol (10 ml) was added dropwise thereto over a period of 5 minutes. After this mixture was further refluxed for 0.5 hour, the solvent was distilled off under reduced pressure. The resulting oily residue was extracted with ether (2×20 ml). After the extract was concentrated under reduced pressure, the resulting residue was subjected to chromatography on silica gel (50 g) using chloroform-methanol (10:1), so that the desired compound (0.91 g, 87%) was obtained as an oily material.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:2]2[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1

Procedure:
One mole of cyanuric chloride was treated with one mole of phenylmagnesium bromide in Step I to form 6-phenyl-2,4-dichloro-s-triazine. This reaction is described in detail in a paper by Hirt, et al., Helvetica Chimica Acta 33, pages 1365-9 (1950). In Step II, the product of the reaction of Step I (0.025 mole) was dissolved in chloroform (35 ml) and stirred in an oil bath at 50° C. To this solution was added dropwise with stirring a solution of sodium hydroxide (0.05 mole), 3-ethynylphenol (0.05 mole), and water (25 ml) during one hour. The reaction was continued overnight and yielded an organic phase which was subsequently separated and dried over sodium sulfate. Removal of solvent under reduced pressure gave a solid product 6-phenyl-2,4-bis(3-ethynylphenoxy)-s-triazine, mp 139°-144° C., which thermally cured at 260° C. to a heat stable polymer.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(N)CN>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:6]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1Cc2[nH]c3ccc(F)cc3c2C1
Reactant: Fc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: NCCN
Solvent: O
Product: CCOC(=O)N1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1

Procedure:
A mixture of 6.6 g. (0.028 mole) of 7-fluoro-2-carbethoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 8.86 g. (0.031 mole) of cuprous bromide, 3.28 g. (0.031 mole) of sodium carbonate and 17.2 g. (0.098 mole) of p-bromofluorobenzene in 75 ml. of N-methyl-2-pyrrolidione is heated to reflux for 4 hrs. The reaction mixture is cooled and poured into ice and water containing 40 ml. of ethylene diamine. The mixture is extracted with benzene, and the benzene extracts subsequently back-washed with water and a saturated brine solution and dried over magnesium sulfate. Removal of the solvent in vacuo provides a gum which on trituration with hexane provides 5.8 g. of product as a brown solid, m.p. 143°-145° C.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[C:10]#[C:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:11]1[C:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1)[CH3:13]
Reactant: CCC#CC(=O)OCC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccccc12

Procedure:
A solution of 1-aminopyridinium iodide (10 g, 40 mmol) [Aldrich 441503], ethyl 2-pentynoate (5.7 g, 45 mmol) [Aldrich 632112] and potassium carbonate (12.0 g, 90 mmol) were stirred in N,N-dimethylformamide (200 mL) at 20° C. for 16 h. The mixture was poured into water to give a tan suspension. The solid was filtered and washed with water to give the desired to compound (5.0 g, 57%). LCMS for C12H15N2O2 (M+H)+: m/z=219.1. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (m, 1H), 8.00 (m, 1H), 7.52 (m, 1H), 7.05 (m, 1H), 4.28 (m, 2H), 3.00 (m, 2H), 1.33 (m, 3H), 1.24 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH:35]=[CH:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Reactant: C1=CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CC=CC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of 3-pyrroline, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][NH:9][CH2:10][CH:11]=2)=[CH:3][CH:2]=1.[CH2:13](I)I>C1C=CC=CC=1.[Cu]>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([C:7]23[CH2:13][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2=CCNC2)cc1
Reactant: ICI
Agent: [Cu]
Solvent: c1ccccc1
Product: Cc1ccc(C23CNCC2C3)cc1

Procedure:
A mixture of 3-(p-tolyl)-3-pyrroline, methylene iodide, and powdered copper in a molar ration of 1:2:4 is heated in benzene for about 50 hours. Filtration and evaporation of the solution gives 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]2=[CH:2][NH:32][C:29]1[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C1Nc2ccc(F)cc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3ccc(F)cc32)n[nH]1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-methyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one (0.050 gms.) is reacted with 0.055 gms. of 5-methyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (1.5 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)c1nccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1nccc(N(CC(=O)N(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3,4-Dichloro-N-(2-isopropyl-pyrimidin-4-yl)-benzenesulfonamide (80 mg, example 14) was dissolved in DMF (1 mL) and treated with cesium carbonate (113 mg). To the mixture was added 2-chloro-N,N-dimethylacetamide (37 mg) and the resulting suspension was allowed to stir at room temperature for 48 hours and then at 80° C. for 24 hours. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using DCM/MeOH/NH4OH 9:1:0.1 as an eluant. The desired product was obtained as a colorless glass (28 mg). MS (ESI): 431.3 (MH+).