Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH:14]([CH3:16])[CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[NH3:17]>CO>[NH2:17][CH2:2][C:3]([N:5]([CH:14]([CH3:16])[CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: N
Solvent: CO
Product: COc1ccc(N(C(=O)CN)C(C)C)cc1
Reaction time: 72 h

Procedure:
A solution of 2.86 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (10 mmol) in 100 mL methanol was saturated with ammonia at 0° and left for 3 days at ambient temperature in a sealed flask. Methanol and ammonia were removed in vacuo and the residue was dissolved in 100 mL of chloroform and washed with water (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered, concentrated in vacuo and dried under high vacuum to afford 2.7 g of the title compound as an oil. 1H NMR (300 MHz, CDCl3) d 6.96 (m, 4H), 4.99 (m, 1H), 3.84 (s, 3H), 2.97 (s, 2H), 1.58 (s, 2H), 1.05 (d, 6H, J=6.6); low resolution MS (ESI)m/e 223 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH3:22].CC1C=C(C)C(C2N=C(C3CCOCC3)NC=2C)=CC=1C(O)=O.Cl.[NH:47]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=3)[CH2:49][CH2:48]2)=[O:7])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:13][C:12]=1[CH3:22]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: Cc1cc(C)c(-c2nc(C3CCOCC3)[nH]c2C)cc1C(=O)O
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(C2CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 164, except 4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid (compound 168.1) was used in place of 2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid (compound 164.2) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) m/z (ES+) 469 (M+H)+.
Reaction SMILES: [C:1](#[N:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.C[O-].[Na+].[CH:17](OCC)=[O:18]>CCOCC>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:2]([CH:17]=[O:18])[C:1]#[N:13])[CH:12]=[CH:11][C:8]=1[O:9][CH3:10]
Reactant: CCOC=O
Reactant: COc1ccc(CC#N)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(C#N)C=O)cc1OC
Reaction time: 72 h
Yield: 93 %

Procedure:
To the mixture of homoveratronitrile (17.7 g, 0.1 mol) and sodium methoxide (7.7 g, 0.11 mol) in ether (300 mL) was added the solution of ethyl formate (8.2 mL) in ether (100 mL). The mixture was stirred vigorously for 3 days. The precipitated solid was filtered, washed with ether. The solid was dissolved in water (100 mL). After adding 10% acetic acid to pH=3, the resulting precipitation was collected by filtration, washed with water and dried to afford 2-(3,4-Dimethoxy-phenyl)-3-oxo-propionitrile as white solid (19 g, 93%). LC-MS m/e calcd for C11H11NO3 (MH+) 206, found 206.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:25][CH3:26])=[CH:6][C:7]([O:23][CH3:24])=[C:8]([CH:22]=1)[C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[CH:15]2)=S)([CH3:3])[CH3:2].[NH2:27][NH2:28].C(N(C(C)C)CC)(C)C.[CH:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45](Cl)Cl)=[CH:40][CH:39]=1>O1CCOCC1>[CH:1]([C:4]1[C:5]([O:25][CH3:26])=[CH:6][C:7]([O:23][CH3:24])=[C:8]([C:9]2[N:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[CH:16]=[CH:15]4)[C:45]([NH:44][C:41]3[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=3)=[N:27][N:28]=2)[CH:22]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(C(C)C)cc1C(=S)Nc1ccc2c(ccn2C)c1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccccc2)n1-c1ccc2c(ccn2C)c1
Temperature: 100 °C

Procedure:
A flask was charged with 5-isopropyl-2,4-dimethoxy-N-(1-methyl-1H-indol-5-yl)-thiobenzamide (123 mg; 0.33 mmol), dioxane (2 mL), and hydrazine (0.5 mL). The reaction was heated to 100° C. for one hour, and the solvent was removed by evaporation. To the solid cake was added ethyl acetate (10 mL) and 10% aqueous potassium carbonate (1 mL), and it was shaken until the solid was completely dissolved. The organic layer was isolated, and dried with sodium sulfate. To the crude intermediate in the organic layer was added diisopropylethylamine (86 mg, 0.66 mmol) and phenylisocyanide dichloride (88 mg; 1.5 eq.). The reaction was stirred overnight, and washed with saturated aqueous ammonium chloride, dried with sodium sulfate, and the product was purified by column chromatography to give [5-(5-Isopropyl-2,4-dimethoxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (64 mg).
Reaction SMILES: C[CH2:2][OH:3].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:35]=[C:15]3[N:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]5[CH2:34][CH2:33]5)[CH:21]=4)[N:14]3[N:13]=2)=[CH:8][N:7]=1)#[N:5].C[Si](Cl)(C)C.C([O-])(O)=[O:42].[Na+]>>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:35]=[C:15]3[N:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH:32]5[CH2:33][CH2:34]5)[CH:21]=4)[N:14]3[N:13]=2)=[CH:8][N:7]=1)=[O:42].[CH:32]1([CH2:31][O:30][C:22]2[CH:21]=[C:20]([C:19]3[N:14]4[N:13]=[C:12]([C:9]5[CH:10]=[CH:11][C:6]([C:4]([NH2:5])=[O:3])=[N:7][CH:8]=5)[N:35]=[C:15]4[N:16]=[CH:17][CH:18]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH:27]([F:29])[F:28])[CH2:33][CH2:34]1
Reactant: N#Cc1ccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)cn1
Reactant: CCO
Reactant: O=C([O-])O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)cn1
Product: NC(=O)c1ccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)cn1
Temperature: 50 °C
Yield: 40 %
Yield: 24 %

Procedure:
In EtOH (13 ml, 220 mmol), dissolved was 2-(2-cyano-pyridin-5-yl)-7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 123) (0.12 g, 0.28 mmol), and TMSCl (14 ml, 110 mmol) was slowly added dropwise thereto, and the mixture was stirred at 50° C. To the reaction mixture, NaHCO3(aq) was added, and the mixture was extracted three times with CH2Cl. The extract was washed twice with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to remove solvent. The mixture was purified via silica gel column chromatography (CH2Cl2/MeOH, 100/1) to obtain the desired compound, 5-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carboxylic acid methyl ester (Compound 138) (0.05 g, 40%) and 5-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]pyridine-2-carboxamide (Compound 139) (0.03 g, 24%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14]1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][C:14]1[O:13][C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2ccoc2c1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(CCCCBr)oc2c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
n-Butyllithium solution (2.29 M in hexane, 44 ml., 0.1 mole) is added to a solution of diisopropylamine (10.1 g., 0.1 mole) in tetrahydrofuran (150 ml.) and hexamethylphosphoramide (15 ml.). The resulting solution is treated with benzofuran-6-carboxylic acid (8.1 g., 0.05 mole) and then with 1,4-dibromobutane (10.8 g., 0.05 mole) at 0° C. The mixture is stirred at 0° C. for 6 hours. It is then quenched with water, acidified with hydrochloric acid and extracted with ethyl acetate. Evaporation of the solvent gives 2-(4-bromobutyl)benzofuran-6-carboxylic acid.
Reaction SMILES: [CH:1]([OH:6])([OH:5])[CH2:2][CH2:3][CH3:4].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>>[CH2:10]([OH:11])[CH2:9][CH:8]([OH:12])[CH3:7].[C:1]([O-:6])(=[O:5])[CH2:2][C:3]([CH3:4])=[O:11]
Reactant: C=C1CC(=O)O1
Reactant: CCCC(O)O
Product: CC(=O)CC(=O)[O-]
Product: CC(O)CCO

Procedure:
5 mmol of triethylamine are mixed with 1 mol of 1,3-butanediol. The mixture is kept on ice and stirred while 1 mol of diketene is added dropwise over 1.5 hours. Stirring is continued for 5 to 7 hours at 0° C., then for 15 hours at room temperature. The reaction is monitored occasionally by proton NMR and after 15 hours, it is complete. This procedure yields a mixture of butanediol-acetoacetate and butanediol-diacetoacetate in proportion 77:23 (assayed by gas chromatography). Butanediol-diacetoacetate can be obtained as a main product by reacting 1 mol of butanediol with 2 mol of diketene.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].Cl.N1C=CC=CC=1>[OH-].[Na+]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCc3cccc(OC)c3)c3ccccc3nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1ncc2c(NCc3cccc(O)c3)c3ccccc3nc21
Temperature: 200 °C

Procedure:
A mixture of 1-ethyl-N-(3-methoxyphenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (3.8 g, 0.0114 mol) and pyridine hydrochloride (10 g) was heated at about 200° C. for 3 hours. The reaction mixture was cooled and then 10% NaOH (70 mL) was added. The mixture was washed with ether (2×30 mL) and then the aqueous layer was acidified with acetic acid to a pH of about 5. The solid which formed was collected by filtration and dried in vacuo to afford 2.5-3 g of 1-ethyl-N-(3-hydroxyphenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as an off-white solid, m.p. 273°-275° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)=[O:17])=[CH:12][N:11]=1
Reactant: CN1CCNCC1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxyl}pyrazine-2-carboxylic acid (40.4 mg, 0.089 mmol) synthesized in Example (63a) was dissolved in tetrahydrofuran (5 mL), and 1-methylpiperazine (30 μL, 0.27 mmol), HATU (67.9 mg, 0.18 mmol) and N,N-diisopropylethylamine (93 μL, 0.54 mmol) were added, followed by stirring at room temperature for 12 hours under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, and extraction was carried out with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=0%-5%) to afford the desired compound (47 mg, yield 98%) as a pale yellow solid.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH3:7][O:8][C:9](=[O:13])[CH2:10][CH2:11][SH:12].[CH2:14]([O:16][C:17]([C:19]1[C:20](Cl)=[N:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)=[O:18])[CH3:15].CCCCCC>CN(C=O)C.O>[CH2:14]([O:16][C:17]([C:19]1[C:20]([S:12][CH2:11][CH2:10][C:9]([O:8][CH2:7][CH3:1])=[O:13])=[N:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCS
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
336 mg (3.0 mmol) potassium tert-butylate were added to a solution of 360 mg (3.0 mmol) 3-mercaptopropionic acid methyl ester in DMF (8 ml) at 0° C. and the mixture was stirred for 30 min at 0° C. Then 953 mg (3.0 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester were added and the reaction solution was heated slowly to 50° C. and stirred for 16 h at this temperature. After cooling to RT the mixture was diluted with water and extracted with EE. The organic phase was dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 625 mg (1.5 mmol, 50%) 2-(3-ethoxy-3-oxopropylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][C:29]([F:32])([F:31])[F:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([F:32])([F:31])[F:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: FC(F)(F)CI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(OCC(F)(F)F)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 27.4 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (53 mg, 0.38 mmol) and 2-iodo-1,1,1-trifluoroethane (28 μL, 0.28 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) afforded 9 mg (27%) of 3-(2-pyridyl)-5-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.27 (s, 1H), 8.24 (d, 1H), 8.08 (s,1H), 7.92 (t, 1H), 7.50 (m, 2H), 4.53 (q, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:28][CH:27]=[CH2:26])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.8 g, 2.5 mmol) in dimethylformamide (10 mL). Add sodium hydride (0.13 g, 60% in oil, 3.25 mmol). After about 30 minutes, when the gas evolution ceases, add allyl bromide (0.35 mL 4.0 mmol). Heat to 75° C. After 4 hours, dilute with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(allyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.83 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia). Combine 1-t-butoxycarbonyl-4-(1-(allyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.9 g, 2.5 mmol) and ethanol (10 mL). Add aqueous hydriodic acid (10 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound.
Reaction SMILES: Br[C:2]#[N:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1>CO.O>[NH2:3][C:2]1[O:13][C:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)=[N:14][N:15]=1
Reactant: NNC(=O)Cc1ccc(O)cc1
Reactant: N#CBr
Solvent: O
Solvent: CO
Product: Nc1nnc(Cc2ccc(O)cc2)o1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Solid BrCN 6.059 g (57.2 mmol) was added in one portion into ice-cooled slurry of (4-hydroxy-phenyl)-acetic acid hydrazide 8.642 g (52.0 mmol) and KHCO3 6.510 g (65 mmol) in MeOH (100 mL). The mixture was stirred at 0-5° C. for 1 hour, the ice bath allowed to melt and stirred at room temperature overnight (18 hr). The reaction mixture was diluted with water (100 mL), stirred for 1 hour, the precipitate was collected by filtration, washed with water and dried on high vacuum. A second fraction precipitated after concentrating and cooling the supernatants.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>C(O)C.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Cl)c1
Reactant: C=O
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)c(Cl)c1

Procedure:
2-Phenylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (34.0g) was dissolved in ethanol (300 ml) and paraformaldehyde (6.0g) in water (600 ml) added. The mixture was refluxed 4 hours, cooled and worked up as in Example 2(c) to yield 20 g m.p. 206°
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N(Br)C(=O)C1.[C:17]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]2)=[CH:21][CH:20]=1)#[N:18]>O1CCOCC1.O>[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[S:32][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][N:31]=3)[CH2:26][CH2:25]2)=[CH:33][CH:34]=1)#[N:18]
Reactant: N#Cc1ccc(CN2CCN(C(N)=S)CC2)cc1
Reactant: CO/C=C/C(=O)OC
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(Cc3ccc(C#N)cc3)CC2)s1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of (E)-methyl 3-methoxyacrylate (290 mg, 280 mL, 2.51 mmol) in 1:1 mixture of dioxane/water (4 mL) was treated with NBS (507 mg, 2.85 mmol) at 0° C. and stirred for 1 hour. The mixture was transferred to a flask containing the thioamide 337 (593 mg, 2.28 mmol) at room temperature and the resulting mixture was refluxed for 1.5 hours. It was cooled down, quenched by adding saturated NH4Cl solution (5 mL) and concentrated. Obtained material was partitioned between EtOAc and water. Organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using 60% EtOAc in hexanes as an eluent, to afford the title compound 338 (602 mg, 77% yield). MS: calc: 342.1; found: 343.1 (M+H)
Reaction SMILES: [H-].[Na+].C(P([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CC)C.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O.O>CCCCCC.O1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1/[CH:16]=[CH:8]/[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CCP(CC)CC(=O)OC(C)(C)C
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Sodium hydride (60% oil, 0.6 g, 15.7 mmol) was washed with hexane and suspended in tetrahydrofuran (5 ml). To the mixture, a solution of tert-butyl diethylphosphinoacetate (2.5 g, 9.8 mmol) in tetrahydrofuran (2 ml) was added under ice cooling condition. The reaction mixture was stirred at room temperature for 30 minutes, cooled under ice cooling condition. A solution of 2-formylpyridine (1.0 g, 9.3 mmol) in tetrahydrofuran (3.0 ml) was added to the mixture, and the mixture was stirred at 0° C. for 1.5 hrs. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel (60 g) column chromatography, and eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (1.5 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[O:10][C:9](=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>CN(C)C=O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]([NH:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][C:8]=2[C:9]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[O:23])=[O:10])=[CH:14][CH:15]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
A mixture of 6-nitro-2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.21 g, 3.73 mmol) and p-anisidine (551 mg, 4.47 mmol) in N,N-dimethylformamide (5 mL) was heated at 80° C. for 2.5 h. After cooling to room temperature, the reaction mixture was poured into an ice/water mixture and extracted twice with methylene chloride. The combined organic layers were washed with water, dried (sodium sulfate), and filtered. From the resulting solution crystallized 706 mg (42%) of the title product as a light brown solid. The mother liquor was chromatographed (silica gel, 20% diethyl ether/80% hexanes to 40% diethyl ether/60% hexanes) to give 242 mg (14%) of additional product; mp 210-11° C.