Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1.[I-].[Na+].Cl[CH2:45][CH2:46][CH2:47][O:48][C:49]1[CH:58]=[CH:57][CH:56]=[CH:55][C:50]=1[C:51]([O:53][CH3:54])=[O:52]>C(#N)C>[CH3:54][O:53][C:51]([C:50]1[CH:55]=[CH:56][CH:57]=[CH:58][C:49]=1[O:48][CH2:47][CH2:46][CH2:45][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)=[O:11])[CH2:7][CH2:8]1)=[O:52]
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: COC(=O)c1ccccc1OCCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccccc1OCCCN1CCC(NC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Yield: 76.8 %

Procedure:
To a solution of 0.80 g (2.14 mmol.) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride, 1.5 ml (10.76 mmol.) of triethylamine and 0.65 g (4.27 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) in acetonitrile (20 ml) were added, at room temperature, 0.38 g of sodium iodide and 0.59 g (2.58 mmol.) of methyl 2-(3-chloro-1-propoxy)benzoate. The mixture was heated under reflux for 3 days under nitrogen atmosphere. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by concentration. The concentrate was purified by means of a column chromatography (methanol/ethyl acetate 30-50%), followed by distilling off the solvent under reduced pressure to afford the object compound (0.81 g, 77%) as a reddish amorphous product.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1.C([N:37](CC)[CH:38]([CH3:40])[CH3:39])(C)C.C1CC=CCC=1.C1(N)CC1.C([Mg]Cl)(C)C>[Pd].O1CCCC1>[Br:8][C:6]1[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH:24]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:37][CH:38]2[CH2:40][CH2:39]2)=[O:14])[CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCNC(c2ccccc2)C1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: [Pd]
Agent: CC(C)[Mg]Cl
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Br)nc(N2CCN(C)CC2c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 115 mg), 1-methyl-3-phenyl-piperazine (77 mg), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 30 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated under atmosphere of nitrogen within a microwave for 2.5 h at 120° C. An additional portion of palladium on carbon (50 mg) in tetrahydrofuran (1 mL) was added and the mixture was heated for 1 h at 120° C. After cooling, cyclopropylamine (0.3 mL) was added followed by dropwise addition of a solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 2.5 mL). The mixture was stirred for 10 min. and quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded N-cyclopropyl-4-methyl-3-(4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′-[1,2′]bipyrazinyl-4′-yl)-benzamide (49 mg) and 3-(6′-Bromo-4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-N-cyclopropyl-4-methyl-benzamide (8 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>CS(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CCNC3=O)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (0.99 g) prepared according to the method described in J. Med. Chem., Vol. 39, 4583-4591 (1996) was dissolved in dimethyl sulfoxide (2.5 ml). N-t-Butoxycarbonylpiperazine (3.4 g) was added to the solution, and the mixture was stirred at 120° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one (0.495 g, 24.9%).
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCS(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 6.9 g. 3-n-butylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which subsequently solidified. This solid product was recrystallized from petroleum ether to give 1-dipropylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, m.p. 39° - 40° C. Elemental analysis satisfactory.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-])(=[O:3])[CH3:2].S(OC)(OC)(=O)=O.[C-:20]#[N:21].[K+]>CS(C)=O>[C:1]([NH:4][CH2:5][C:6]1[N:7]=[C:8]([C:20]#[N:21])[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc[n+]1[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: COS(=O)(=O)OC
Product: CC(=O)NCc1cccc(C#N)n1
Reaction time: 3 h
Yield: 15.2 %

Procedure:
A mixture of 2-acetylaminomethylpyridine N-oxide (1.00 g) and dimethyl sulfate (0.63 ml) was stirred for three hours. Dimethyl sulfoxide (6 ml) and potassium cyanide (392 mg) were added to the mixture and the solution was stirred for two hours at ambient temperature. Additional potassium cyanide (392 mg) was added to the mixture and which was further stirred for two hours. After the solvent was removed by concentration, the residue was mixed with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) by eluting with a mixture of ethyl acetate and methanol (20:1) to give 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30](=[O:31])[CH2:29][Cl:28])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCN3C(=O)CCl)CC1
Reaction time: 4 h

Procedure:
A solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole (0.55 g, 2 mmol), triethylamine (0.56 mL, 4 mmol) in dichloromethane (8 mL) was added chloroacetyl chloride (0.2 mL, 2.6 mmol) at 0° C. The solution was stirred from 0° C. to room temperature for 4 hrs. The solution was diluted with dichloromethane and washed with 5% aqueous citric acid, aqueous sodium biocarbonate, and water, dried over MgSO4, and concentrated. The residue was purified with silica gel column eluted with ethyl acetate in hexane to give product (0.37 g, yield: 52%). ESI-MS: 350.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]([CH3:38])([CH3:37])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[C:21]3=[N:22]C(SC)=[N:24][CH:25]=[C:20]3[CH2:19][N:18]([C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[C:17]2=[O:36])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:48])C=1.[CH3:51][S:52]([CH3:54])=[O:53].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]([CH3:38])([CH3:37])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[C:21]3=[N:22][C:51]([S:52]([CH3:54])(=[O:48])=[O:53])=[N:24][CH:25]=[C:20]3[CH2:19][N:18]([C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[C:17]2=[O:36])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(n1)N(c1cccc(CC(C)(C)NC(=O)OC(C)(C)C)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(Cc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 350 mg (0.6 mmol) of (2-[3-[3-(2,6-dichlorophenyl)-7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester in 10 ml of dichloromethane was treated with 400 mg (1.2 mmol) of 3-chloroperbenzoic acid (50% w/w water) and the mixture stirred for 3 hours. Dimethyl sulfoxide (0.5 ml) was added. After a further 10 minutes 10 ml of saturated aqueous sodium bicarbonate was added. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 370 mg (100%) of (2-[3-[3-(2,6-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester as a white solid. [Mass spectrum (ESI) MH+ =620].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:21]([O:25][C:26]([N:28]1[C:32]([NH2:33])=[CH:31][CH:30]=[N:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C(#N)C>[C:21]([O:25][C:26]([N:28]1[C:32]([NH:33][C:13](=[O:15])/[C:12](/[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16]/[O:17][CH:18]([CH3:20])[CH3:19])=[CH:31][CH:30]=[N:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)n1nccc1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)O/N=C(/C(=O)Nc1ccnn1C(=O)OC(C)(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 20 %

Procedure:
The estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid and (prepared as in Example 6, 99 mg, 0.31 mmol), 5-amino-pyrazole-1-carboxylic acid tert-butyl ester (625 mg, 0.34 mmol) and N,N-diisopropylethylamine (162 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-5-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-acetylamino]-pyrazole-1-carboxylic acid tert-butyl ester (30 mg, 20%) as a tan solid after lyophilization from aqueous acetonitrile: H1-NMR (400 MHz, CDCl3) δ=1.41 (6H, d, J=6.3 Hz), 1.72 (9H, s), 3.30 (3H, s), 4.66 (1H, m), 6.85 (1H, d, J=1.8 Hz), 7.60 (2H, m), 7.70 (1H, d, J=1.5 Hz), 8.20 (1H, d, J=8.0 Hz), 11.64 (1H, s).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](#N)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Br.C1C[O:32]CC1>CCCCCC.O>[C:21]1([C:20](=[O:32])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: Cc1ccncc1
Reactant: N#Cc1ccccc1
Agent: Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(Cc1ccncc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of diisopropylamine (22 mL, 15.03 mmol) in THF (200 mL) under argon atmosphere was cooled to −78° C. BuLi (96 mL of a 1.6 M solution in hexane, 153.0 mmol) was added dropwise. After 1 h, a solution of 4-methylpyridine (15.00 g, 161.1 mmol) in THF (75 mL) was added and allowed to warm to 0° C. At this temperature it was stirred for 30 minutes. It was cooled to −78° C. and benzonitrile (18.27 g, 177.2 mmol) in THF (75 mL) was added and stirred at −78° C. for 2 h. It was stirred at room temperature overnight. Water (225 mL) was added, it was cooled with a water-ice bath and adjusted to pH 1 with 48% HBr. The organic phase was separated. The aqueous phase was heated to reflux for 2 h, allowed to cool and extracted with diethyl ether. The aqueous phase was taken to neutral pH with 1 N NaOH and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 28.53 g of title compound (yield: 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:30]1[C:31]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=2)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=1>>[CH3:18][N:17]([CH3:19])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:30]4[C:31]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=5)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=4)=[C:3]3[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(N(C)C)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with {4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}dimethylamine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 634.6
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]([N:29]=C=O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([NH:29][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:13])[C@H:8]([C:18]([NH:47][C:43]2[CH:44]=[CH:45][C:46]3[N:34]([CH2:32][CH3:33])[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)NC(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=524.4.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)(=O)=O)=CC=1>CN(C)C=O>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccn2)cc1
Reactant: Oc1ccc(Cn2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCCOc2ccc(Cn3cccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 72 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethyl-formamide (5 ml) solution of 300 mg of 4-(1-pyrazolyl)methylphenol under stirring over 10 minutes. After stirring at room temperature for 1 hour, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 505 mg of 2-(2-pyridyloxy)ethyl p-toluenesulfonate was added dropwise over 30 minutes. The mixture was stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted twice with 30 ml of ethyl acetate. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 208 mg of 4-(1-pyrazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether (compound 1). Yield, 41%.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(=O)(=O)(O)[OH:21].[OH2:25]>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:21])=[O:25])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(O)O
Reactant: CCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O
Product: CCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
50 Gram of 4-n-pentyl-4'-cyanobiphenyl and 500 g of 70 weight % sulfuric acid were introduced into 2 l three neck flask, and heated on a mantle heater, with stirring under reflux for 2.5 hours. The resulting reaction mixture was water-cooled and then 500 ml of water was added, followed by separating a solid product with a glass filter, water-washing and recrystallizing with glacial acetic acid to give 45.7 g of 4-n-pentyl-biphenyl-4'-carboxylic acid((II), R=C5H11) which was a colorless crystal having a molecular formula of C18H20O2 (composition: C 80.6%, H 7.5%, O 11.9% as calculated values and C 80.3%, H 7.6%, O 12.1% as observed values) and a melting point of 177° C, and formed a smectic liquid crystal at temperatures exceeding the melting point.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (tert-butyl)(phenylsulfonyl)amine (17.43 g, 81.83 mmol) in 180 ml dry THF in an ice bath was added nBuLi (66 ml, 2.5M in hexanes) via addition funnel. Then triisopropyl borate (33 ml, 143.06 mmol) was added via addition funnel. The mixture was warmed to room temperature and allowed to stir for 4 hr. The reaction mixture was then cooled in an ice bath before HCL (82 ml, 3M) was added dropwise. This was allowed to stir at room temperature for 3 hr. The mixture was then put in the freezer over the weekend. The reaction was then warmed to room temperature and extracted with ether. The aqueous layers were washed twice more with ether. The combined organic layers were washed three times with 5M NaOH aqueous solution. The combined basic layers were acidified to pH=1 with 6M HCL solution. These acidified layers were then extracted three times with ether. These ether layers were then dried over MgSO4, filtered, then concentrated in vacuo to about 50 ml solution. To this solution was added hexanes and a minimal amount of ethyl acetate. A white precipitate is observed and the mixture in stored in the freezer to allow for crystallization. The white solid is then filtered and collected (14.65 g, 57 mml, 70%) ES-MS(M+H)+=258.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH:17]1[C:22]([NH:23][NH2:24])=[CH:21][CH:20]=[C:19]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:18]=1.Cl>CO>[NH2:28][S:25]([C:19]1[CH:18]=[CH:17][C:22]([N:23]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:24]2)=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A 100 mL round-bottomed flask equipped with magnetic stirrer and nitrogen inlet was charged with methyl 4-[4-(chloro)phenyl]-2,4-dioxobutanoate from Step 1 (5.0 g, 20.78 mmol), 4-sulfonamidophenylhydrazine hydrochloride (5.11 g, 22.86 mmol) and methanol (50 mL). The reaction vessel was heated to reflux and held for 16 hours. A precipitate formed overnight. The suspension was cooled to 0° C., held for 0.5 hour, filtered and washed with cold water to provide, after air-drying, 7.91 g (91%) of crude product. Recrystallized 3.50 g from boiling ethanol to yield 3.14 g (97% of pure methyl (1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate: mp 227° C.; 1H NMR (CDCl3/300 MHz); 7.91 (d, J=8.86 Hz, 2H), 7.44 (d, J=8.86 Hz, 2H), 7.33 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 7.03 (s, 1H), 3.96 (s, 3H). Mass Spectrum, MH+=392. Anal. Calc'd for C17H14N3O4ClS: C, 52.11; H, 3.60; N, 10.72; Cl, 9.05; S, 5.18. Found: C, 52.07; H, 3.57; N, 10.70; Cl, 9.11; S, 8.27.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C1COCC1.[CH3:24][NH2:25]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:25][CH3:24])=[CH:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 (2.0 g) was dissolved in 50 mL toluene and 50 mL THF followed by the addition of 20 mL of 40% methylamine in H2O. The reaction mixture was stirred at room temp under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL methanol and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temp under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g 35 (53% yield). MS (Q1) 300 (M+).