Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=O)[CH3:2].Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CO>[CH2:13]([O:20][N:21]=[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NOCc1ccccc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a suspension of 14.52 g (0.10 mol) of 3-acetylbenzonitrile in 100 ml of methanol was added 17.56 g (0.11 mol) of O-benzylhydroxyamine hydrochloride and further added dropwise 9.49 g (0.12 mol) of pyridine. The mixture was stirred at room temperature for 2.5 hours, and most of the methanol was distilled off. To the residue was added ethyl acetate and resultant mixture was washed successively with about 5% aqueous hydrochloric acid twice, an about 5% aqueous solution of sodium bicarbonate once, and water once, then dried and concentrated to obtain 24.15 g (95.0 mmol) of crude 3-(1-(benzyloxyimino)ethyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12]C(=O)OC(C)(C)C)[CH2:5]2.C(C1C=C2C(=CC=1)NC[C@@H](N[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])C2)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5]2
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Product: O=S(=O)(NC1CNc2ccc(Cl)cc2C1)c1ccccc1

Procedure:
Compound 21B was prepared from 21A by procedures analogous to those described in Example 1D and 1G.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:33]=[CH:32][CH:31]=[C:28]([C:29]5[N:34]=[N:35][NH:36][N:30]=5)[CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2cccc(-c3nn[nH]n3)c2)cc1
Reaction time: 38 h
Yield: 85 %

Procedure:
In a 250 ml two-neck flask, 60 ml of N,N-dimethyl formamide, 450 mg (1.07 mmol) of 3-(3,6-diphenyl-9H-carbazol-9-yl) benzonitrile, 208.71 mg (3.21 mmol) of sodium azide, 171.73 mg (3.21 mmol) of ammonium chloride, and a stir bar were added. The reaction was carried out at a constant temperature of 100° C. under a nitrogen atmosphere for 38 hours. After the completion of reaction, 10 ml of 10% HCl was added and a filtering was conducted. Then an extraction was conducted with ethyl acetate and water. The organic layer was drawn out and dried to obtain a light orange solid product of 3,6-diphenyl-9-(3-2H-tetraazol-5-yl-phenyl)-9H-carbazole (yield: 85%).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[F:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1C1C=CC(O)=C(C(O)=O)C=1>>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][C:37]([C:48]2[CH:47]=[CH:46][C:45]([F:44])=[CH:50][C:49]=2[F:51])=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCC

Procedure:
Ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C43H53F2NO5=701.88. found: [M+H]+=702.4.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].[C:18]([O:22][C:23]([N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>C(COC)OC.O>[F:14][C:13]1[CH:12]=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[C:26]1[N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
1.1 g of tetrakis-triphenylphosphine palladium and 4.2 g of sodium carbonate were added to a solution of 4.3 g of 3-bromo-4-fluoro-nitrobenzene and 5.0 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid in a mixture of 130 ml of dimethoxyethane and 22 ml of water, and the reaction liquid was heated overnight under reflux. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and this was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=20/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:5][CH:4]=1.[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:18]([NH:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC=O
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 43.9 %

Procedure:
To a solution of 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.3 g, 1.26 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added valeraldehyde (0.134 mL, 1.26 mmol), sodium triacetoxyborohydride (0.374 g, 1.76 mmol) and acetic acid (72 μl, 1.26 mmol). The resultant mixture was stirred for 17 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 aq. (15 mL), then extracted with CH2Cl2 (2×20 mL). The organic solution was dried (Na2SO4) and the solvent was removed in vacuo. Purification by SPE (20 g Silica column) eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (0.17 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH:17]2[CH:19]=[CH2:20])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH:17]=[CH:19][CH2:20]2)=[CH:14][CH:15]=1
Reactant: C=CC1CC1(C(=O)OC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(CO)cc2)CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the title compound of Step 2, above, (1.8 g, 5.23 mmol) in 25 ml THF was added n-Bu4NF (1.5 g, 5.75 mmol), and the resulting solution was stirred at ambient temperature for 3 hours. The mixture was poured into 50 ml 1N HCl and extracted (EtOAc, 4×30 ml). The combined extracts were dried over MgSO4, filtered and concentrated to yield 1.51 g of the title compound as an oil which was used crude in the next step.
Reaction SMILES: C(OC(=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)C.[CH3:36][O:37][C:38](=[O:66])C(C1C=CC(C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=CC=1)C.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:36][O:37][C:38](=[O:66])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:34])[C:17]=3[CH:16]=2)=[CH:11][CH:12]=1)[CH3:5]
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 164, 0.11 g, 0.37 mmol), methyl-2-(4-iodo phenyl)propionate (Reagent 1, 0.108 g, 0.37 mmol), triethyl amine (10 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by work up and flash column chromatography over silica gel (230-400 mesh) using 1%-4% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow amorphous solid (0.148 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.CCOCC>[Br:17][C:8]1[C:2]([F:1])=[CH:3][C:4]([NH2:5])=[CH:6][C:7]=1[F:9]
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Difluoroaniline (10.0 g, 77.5 mmol) is dissolved in DMF (100 mL). NBS (13.9 g, 78.0 mmol) is added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography (methylene chloride/hexanes) to give 4-bromo-3,5-difluoroaniline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[C:23]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:22]=1>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[C:23]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=3[O:19][CH3:20])=[CH:36][CH:35]=2)[CH:22]=1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: Oc1ccc(-c2ccc3c(c2)oc2ccccc23)cc1
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(-c2ccc3c(c2)oc2ccccc23)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-Dibenzofuran-3-yl-phenol following the Standard Procedure J. MS (ES) for C32H30O7 [M+NH4]+:544, [M+Na]+: 549.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.CCO>[F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)O3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of ethyl 2-fluoro-4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)chromen-6-yl]-ethynyl]-benzoate (Compound 273, 82.0 mg, 0.180 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 70.0 mg (91%) the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.93 (1H, d, J=7.8 Hz), 7.41 (1H, dd, J=2.1, 8.3 Hz), 7.37-7.25 (6H, m), 7.18 (1H, d, J=2.0 Hz), 6.91 (1H, d, J=8.3 Hz), 5.77 (1H, s), 2.69 (2H, q, J=7.6 Hz), 1.49 (6H, s), 1.24 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc2cnccc12
Product: COc1ccc(C(=O)Nc2cccc3cnccc23)cc1

Procedure:
Anisoyl chloride was reacted with 5-aminoisoquinoline according to the procedure of Example 8 to produce 5-(4-methoxybenzamido) isoquinoline. This product was then reduced according to the procedure of Example 8 to yield 5-(4-methoxybenzamido)-1,2,3,4-tetrahydroisoquinoline HCl. After purification from water it had a melting point of 289°-290° C.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:25][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][C:6]1=O)C.C(O)(=O)C.Cl.[C:32]([NH:36][NH2:37])([CH3:35])([CH3:34])[CH3:33]>C(O)C>[C:32]([N:36]1[C:6]2[CH:7]=[CH:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:13][CH2:14]3)[CH2:25][C:5]=2[CH:4]=[N:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)NN
Reactant: CN(C)C=C1CC2(C=CC1=O)CCN(C(=O)OCc1ccccc1)CC2
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)n1ncc2c1C=CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Benzyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (59.2 g, 167 mmol) was dissolved in ethanol (835 mL). To the solution was added acetic acid (20 mL, 345 mmol) and tert-butylhydrazine hydrochloride (29.1 g, 234 mmol). The reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and concentrated to an orange oil. Purification by flash column chromatography (20-40% ethyl acetate/heptanes) afforded the title compound (50 g, 79%) as a pale yellow solid. +ESI (M+H) 380.5; 1H NMR (400 MHz, CDCl3, δ): 7.26-7.40 (m, 5 H), 7.17 (s, 1 H), 6.66 (d, J=9.95 Hz, 1 H), 5.77 (d, J=10.15 Hz, 1 H), 5.12 (s, 2 H), 3.38-3.64 (m, 4 H), 2.58 (s, 2 H), 1.60 (s, 12 H), 1.50 (br. s., 1 H).
Reaction SMILES: O.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.N1[C:24]2C=CC=C[C:23]=2N=C1SCC1C(N)=NC=CC=1.ClCC=O.C(=O)(O)[O-].[Na+]>C(O)C>[N:19]1[CH:23]=[CH:24][N:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][S:11][C:3]3[NH:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:2]=3)[C:14]=12
Reactant: Nc1ncccc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: O=CCCl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2[nH]c(SCc3cccn4ccnc34)nc2c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 9.6 g (63 mmole) of 2-mercaptobenzimidazole and 7.7 g (62 mmole) of 3-hydroxymethyl-2-pyridinamine was dissolved in 60 ml of 48% aqueous hydrobromic acid and 60 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and make alkaline with potassium carbonate. The oil that separated solidified upon addition of diethyl ether to the aqueous mixture. The solid was collected by filtration, washed with portions of diethyl ether and water, and air dried to yield 12.4 g of analytically pure 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C13H12N4S.1/2H2O: C, 58.84; H, 4.93; N, 21.11; S, 12.08. Found: C, 59.06; H, 4.48; N, 20.82; S, 12.16.]A mixture of 4.0 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, 1.9 ml (ca. 18 mmole) of 50% aqueous chloroacetaldehyde, and 1.5 g (18 mmole) of sodium bicarbonate in 25 ml of ethanol was stirred at room temperature. After three days the mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue from the filtrate with a mixture of water and dichloromethane induced crystallization. The solid was collected, washed sequentially with water and dichloromethane, and air dried to yield 3.0 g of the title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: FC1C=C(C2C(C)=C(O)C(=O)N(CC(C)C)N=2)C=CC=1C.[C:22]([C:25]1[C:26](=[O:44])[N:27]([CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([F:39])[CH:32]=2)[CH:30]=1)(O)=[O:23]>>[CH:41]1([CH2:40][N:27]2[C:26](=[O:44])[C:25]([CH2:22][OH:23])=[CH:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([F:39])[CH:32]=3)=[N:28]2)[CH2:43][CH2:42]1
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CC3)n2)cc1F
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(O)c2C)cc1F
Product: COc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1F

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow fine-needles (yield: 21.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[S:25][C:19]4[N:20]=[CH:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[CH3:26])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:34][C:35]([N:37]([CH2:43][CH3:44])[CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[S:25][C:19]4[N:20]=[CH:21][N:22]([CH2:34][C:35]([N:37]([CH2:43][CH3:44])[CH2:38][C:39]([F:40])([F:41])[F:42])=[O:36])[C:23](=[O:24])[C:18]=4[C:17]=3[CH3:26])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC(F)(F)F)C(=O)CCl
Reactant: Cc1c(C(=O)N2CCN(c3cccc(Cl)c3)CC2)sc2nc[nH]c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC(F)(F)F)C(=O)Cn1cnc2sc(C(=O)N3CCN(c4cccc(Cl)c4)CC3)c(C)c2c1=O
Yield: 20.8 %

Procedure:
To a suspension of 6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (0.1 g, 0.26 mmol) in CH3CN (5 mL) was added K2CO3 (36 mg, 0.26 mmol), KI (43 mg, 0.26 mmol), and 2-chloro-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide, (52 mg, 0.26 mmol). The reaction mixture was refluxed overnight and then quenched with H2O (20 mL). The resultant precipitate was filtered and dried to provide a crude solid which was purified by flash chromatography (Et2O:DCM, 1:1) providing 30 mg of pure 2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3 (4H)-yl)-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide, (yield: 21%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:4]=[N:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26].Cl>CN(C)C=O.O>[CH3:26][O:25][CH:24]([O:27][CH3:28])[CH2:23][CH2:22][N:11]1[CH:12]=[C:7]([C:5]2[CH:4]=[N:3][S:2][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cnsc2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cnsc2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.44 %

Procedure:
5-(4-isothiazolyl)-2,4(1H,3H)-pyrimidinedione hydrochloride (Prep23, 300 mg, 1.036 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 ml) to give a pale yellow suspension. K2CO3 (215 mg, 1.554 mmol) was added ant the reaction mixture was stirred at room temperature for 1 h. 3-bromo-1,1-bis(methyloxy)propane (0.173 ml, 1.140 mmol) was added. Mixture was stirred at room temperature for 3 days, then diluted with water, acidified with diluted HCl until pH ˜5, and extracted with EtOAc. The organic phase was washed with water (3 times), brine, dried over Na2SO4, filtered and the solvent evaporated. The obtained residue was purified by flash chromatography eluting with cyclohexane/EtOAc 1:1. Obtained 60 mg (13.44% yield) of a 9:1 mixture of the title compound and the corresponding bis alkylated derivative.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[K+].C1(C)C=CC(S(O[CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=O)=O)=CC=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccc(-c2ccc(O)c(F)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Yield: 28.6 %

Procedure:
3'-Fluoro-4'-hydroxy-4-acetylbiphenyl (15 g), potassium hydroxide (4.0 g), ethanol (370 ml), optically active 1-methylheptyl p-toluenesulfonate (20.5 g), were heated for 5 hrs. under reflux, to obtain by usual work-up, 6.37 g of 3'-fluoro-4'-(1-methylheptyloxy)-4-acetylbiphenyl, m.p. 67.6°~68.5° C.