Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].CCOC(C)=O.CCCCCC>CN(C=O)C>[CH3:15][Si:16]([CH3:18])([CH3:17])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 0 °C

Procedure:
Tert-butyl 4-oxopiperidine-1-carboxylate, 1.1 (250 g, 1.256 mol) was taken in dry DMF (150 mL) under N2 atmosphere and added TEA (230 g, 2.27 mmol) at room temperature. The reaction mixture was cooled to 0° C., added trimethylsilyl chloride (178 g, 1.64 mol) drop wise for 30 minutes. After addition completed the reaction mixture heated at 80° C. for 16 h. The reaction was monitored by TLC (20% EtOAc/hexane), and allowed to cool the reaction mixture to room temperature, poured into ice water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, brine solution, dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5-10% EtOAc-Hexane) to afford tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2 (300 g, 87.79%). 1HNMR (CDCl3, 400 MHz): δ 4.78 (s, 1H), 3.87-3.80 (m, 2H), 3.55 (t, 2H), 2.15-2.05 (m, 2H), 1.45 (s, 9H), 0.19 (s, 9H).
Reaction SMILES: B(Cl)(Cl)Cl.C(OC([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30]CC3C=CC=CC=3)=[N:20][NH:21][CH:22]=2)[CH2:14][CH2:13]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]([N:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)=[CH:22][NH:21][N:20]=2)=[C:24]([OH:30])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccc(F)cc2OCc2ccccc2)CC1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(F)ccc1-c1n[nH]cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
Boron trichloride (1.0 M in DCM; 0.829 mL, 0.829 mmol) was added to a solution of 4-[3-(2-benzyloxy-4-fluoro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.166 mmol) in DCM (7.5 mL). A brown precipitate formed. The mixture was stirred at room temperature for 1 hour and then poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo. The product was purified by preparative HPLC to give 3-(4-fluoro-2-hydroxyphenyl)4(piperazin-1-yl)-1H-pyrazole (13 mg, 30%) as an off-white solid; δH (MeOH-d4) 7.96 (1H, br s), 7.72 (1H, s), 6.71-6.64 (2H, m), 3.36-3.33 (4H, m), 3.13-3.10 (4H, m), 2.65 (1H, s); LCMS retention time 1.46 min, M+H+ 263.2.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[CH2:4]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=1)[CH2:3][CH2:2][CH3:1]
Reactant: O=[N+]([O-])O
Reactant: CCCCc1ccc(O)cc1
Solvent: O
Product: CCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.0 g of 4-n-butylphenol in 14 ml of water was added dropwise 3.7 ml of 70% nitric acid while cooling with ice and the temperature of the mixture was raised to room temperature and the reaction was carried out for 40 minutes. After 500 ml of water was added thereto, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was subjected to silica-gel column-chromatography [eluent: ethyl acetate] to give 6.20 g of 4-n-butyl-2-nitrophenol.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[I-].[Na+].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O>[C:19]1(=[O:29])[N:23]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]3)[C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc2[nH]c(=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A suspension of 6-(3-chloropropoxy)carbostyril (170 g) and sodium iodide (129.5 g) in dimethylformamide (1.7 liter) is heated with stirring at 60° C. for one hour. To the mixture is added potassium phthalimide (159 g), and the mixture is heated with stirring at 70° C. for 6 hours. After the mixture is allowed to cool, the precipitated crystals are collected by filtration, and washed with water. The mixture is further washed successively with ethanol and diethyl ether, and dried to give 6-(3-phthalimidopropoxy)carbostyril (222 g) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=4)=[O:28])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:11]4[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH:2]=[O:1])=[O:7])[CH:12]=4)[CH:18]=3)=[CH:21][CH:22]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCO)c[nH]4)c3)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a stirred solution of N-(3-hydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (1.0 g, 2.06 mmol) in 20 ml of anhydrous DMF was added Dess-Martin periodinane (1.22 g, 2.88 mmol). The mixture was stirred at room temperature under nitrogen for 80 minutes and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as light brown solid, which was used in the next step without further purification. Yield: 1.0 g, 100%.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C(OC(=O)[C@H](C(C)C)N)(C)(C)C.C([O:53][C:54](=[O:61])[C@H:55]([CH2:57][CH:58]([CH3:60])[CH3:59])[NH2:56])(C)(C)C>>[CH3:59][CH:58]([CH3:60])[CH2:57][C@H:55]([NH:56][S:33]([C:20]1[CH:21]=[CH:22][C:23]2[O:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:31][C:32]=2[CH:19]=1)(=[O:35])=[O:34])[C:54]([OH:61])=[O:53]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-leucine-t-butyl ester, (S)-4-methyl-2-(phenoxathiine-2-sulfonylamino)-pentanoic acid is obtained; mp 120-130° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[CH3:1][CH:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: CCC(C)CCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(C)CCC(=O)Cl

Procedure:
The acid from step A2 is converted into the acid chloride by interaction with thionyl chloride according to a standard method. After removal of the excess of thionyl chloride, the residual acid chloride is used in step C2 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.C([OH:26])C.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>O>[C:28]1([CH3:38])[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[C:28]1([CH3:38])[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[NH2:9][CH2:10][C:11]1[N:12]([C:13]2[S:17][C:16]([CH2:18][CH3:19])=[CH:15][C:14]=2[C:8](=[O:26])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:20]([CH3:23])=[N:21][N:22]=1
Reactant: CCO
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (702 g) was suspended in a mixed solvent (4.9 l) of ethanol and water (9:1), and p-toluenesulfonic acid monohydrate (1165 g) was added. The mixture was stirred at 80° C. for 1.5 hours. The mixture was concentrated to about 2.5 l by evaporating the solvent under reduced pressure, and ethyl acetate (4 l) was added. The reaction mixture was filtered to give crystals, and the crystals were washed with ethyl acetate and ethanol and dried to give 1214 g of 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>ClCCl>[CH3:41][S:42]([O:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.7 g) in dichloromethane (100 ml) were added methanesulfonyl chloride (1.44 ml) and triethylamine (3.06 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue The residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (40:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.39 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:39]=[C:38]4[C:33]([CH:34]=[CH:35][CH:36]=[CH:37]4)=[C:23]4[CH:24]=[C:25](O)[CH:26]=[C:27]([N:28]([CH3:31])[C:29]=2[CH:30]=1)[C:22]=34>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[N:39]=[C:38]4[C:33]([CH:34]=[CH:35][CH:36]=[CH:37]4)=[C:23]4[CH:24]=[C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[C:27]([N:28]([CH3:31])[C:29]=2[CH:30]=1)[C:22]=34
Reactant: CN1c2cc(Cl)ccc2-c2nc3ccccc3c3cc(O)cc1c23
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN1c2cc(Cl)ccc2-c2nc3ccccc3c3cc(OS(=O)(=O)C(F)(F)F)cc1c23
Yield: 81 %

Procedure:
The general procedure (Method L) applied to trifluoromethanesulphonic acid anhydride (0.05 ml, 0.3 mmol, 1 eq), 10-chloro-6-hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine, 37 (100 mg, 0.3 mmol) in DCM (50 mL) gave the title compound as a yellow solid, (114 mg, 0.25 mmol, 81%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Yield: 99 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9]C(OC(C)(C)C)=O)[C:7](=[O:17])[NH:6]1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:9][C@H:8]1[C:7](=[O:17])[NH:6][C@H:5]1[CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CN=[N+]=[N-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1N

Procedure:
cis-2-Azidomethyl-3-t-butoxycarbonylamino-4-oxoazetidine (ca. 1 g) is dissolved in 2 ml of methylene chloride and the solution is cooled to 0° and treated with 0.5 ml of trifluoroacetic acid for 30 minutes at 0°. The solution is washed with 5% aqueous sodium bicarbonate and extracted with dilute hydrochloric acid. The aqueous phase is neutralized and extracted with ethyl acetate. Evaporation of the solvent gives the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:4][CH2:3]1.[N:19]#[C:20]Br.[OH-].[K+].CC(C)=O>O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:20]2[NH2:19])[CH2:6][CH2:7]1
Reactant: N#CBr
Reactant: CN1CCN(CCCNc2ccccc2N)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCN(CCCn2c(N)nc3ccccc32)CC1
Yield: 32.5 %

Procedure:
To a stirred solution of N-[3-(4-methyl-1-piperazinyl)propyl]-o-phenylendiamine (334.8 g., 1.35 mole) in water (1400 ml.) under nitrogen, was added cyanogen bromide (200 g., 1.89 mole) at a rate sufficient to maintain the reaction temperature at 50°-65° C. The addition took place over a 2 hour period. The reaction mixture was then cooled and the pH adjusted to 10 by the dropwise addition of 50% KOH. The basic aqueous layer was extracted from chloroform (5 × 500 ml.). The organic layers were combined, dried (MgSO4), and evaporated in vacuo to give a dark brown semi-solid. Slurrying with acetone (300 ml.) gave on filtration and washing with acetone 120.1 g., (32.5% yield) of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-aminobenzimidazole as a pale yellow solid, m.p. 195°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:20]#[C:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C#Cc1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 μmol, 0.05 equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol) 5-Bromo-pyridine-2-carboxylic acid methyl ester and 3-fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.), triphenylphosphine (91 mg, 347 μmol, 0.03 equiv.) and copper(I)iodide (66 mg, 347 μmol, 0.03 equiv.) were added and the mixture was stirred for 20 hours at 80° C. The reaction mixture was cooled and evaporated to dryness with Isolute® sorbent. The crude product was purified by flash chromatography on silica gel (70 g) eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95 g, 66% yield) was obtained as a light yellow solid, MS: m/e=256.3 (M+H+).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[C:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:1]
Reactant: COc1ccc(COC(=O)Cc2cccc(CC(N)=O)c2)cc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)Cc2cccc(CC#N)c2)cc1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of 1.31 g of 4-methoxybenzyl [3-(2-amino-2-oxoethyl)phenyl]acetate in pyridine (20 mL) was added 718 mg of methane sulfonyl chloride under ice-cooling, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.25 g of 4-methoxybenzyl [3-(cyanomethyl)phenyl]acetate as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:13]([C:18]#[N:19])(=[O:17])[O:14][CH2:15][CH3:16].Cl>CC(O)=O>[F:12][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][CH:10]=1)[N:1]=[C:18]([C:13]([O:14][CH2:15][CH3:16])=[O:17])[NH:19][C:4]2=[O:6]
Reactant: CCOC(=O)C#N
Reactant: COC(=O)c1cc(F)ccc1N
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Temperature: 70 °C
Yield: 85.8 %

Procedure:
A stirred mixture of methyl 2-amino-5-fluorobenzoate (1 g, 5.92 mmol) and ethyl carbonocyanidate (1.17 g, 11.8 mmol) in HOAc (8 mL) was treated with a 12 N aq solution of hydrochloric acid (0.8 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the solvent was removed under reduced pressure. The residue was suspended in water and treated with a saturated aq solution of NaHCO3 until pH=7. The solid was filtered, washed with water/diethyl ether and dried under reduced pressure to afford ethyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.2 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 7.76-7.95 (m, 3H), 4.39 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H); LC-MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]#[C:3][CH3:4].F[B-](F)(F)F.[CH3:18][O+](C)C>>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:18])=[N:11]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCC1CCCCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: CC#CCC1CCCCC(OC)=N1

Procedure:
The product of EXAMPLE 256 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:20][CH:19]=2)[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(CC2C=CC(N3C=CC=N3)=CC=2)NS(C2C=CC=CN=2)(=O)=O)N=1)(C)(C)C>>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[S:33]([CH:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[N:28]=2)=[CH:20][CH:19]=1)[C:11]1[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:49])=[O:5])[CH:14]=[CH:13][CH:12]=1)(=[O:34])=[O:35]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nc(C(F)(F)F)cs3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2ccccn2)n1
Product: O=C(O)CNc1cccc(C(NCc2ccc(-c3nc(C(F)(F)F)cs3)cc2)S(=O)(=O)c2ccccn2)n1
Yield: 85.1 %

Procedure:
Reaction and post-treatment were carried out in the same manlier as in Example 21-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(4-trifluoromethylthiazol-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (440 mg, 0.611 mmol) obtained in Example 25-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate to afford the title compound (293 mg) as a white solid. (Yield: 85%)
Reaction SMILES: [C:1]([C:5]1[C:10]([Br:11])=[C:9]([I:12])[CH:8]=[C:7]([Si](C)(C)C)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:5]1[C:10]([Br:11])=[C:9]([I:12])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc([Si](C)(C)C)cc(I)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nccc(I)c1Br

Procedure:
A solution of 14.8 g (36 mmol) of 2-tert-butyl-3-bromo-4-iodo-6-trimethylsilylpyridine and 14.0 g (40 mmol) of tetrabutylammonium fluoride trihydrate in 150 ml of THF is heated under reflux for 5 min. After cooling and removal of the THF in vacuo, the residue is taken up in 200 ml of dichloromethane, the org. phase is washed five times with 100 ml of water each time and dried over sodium sulfate. After removal of the dichloromethane in vacuo, the residue is recrystallised from ethanol. Yield: 9.2 g (27 mmol), 75%. Purity: >95% according to 1H-NMR.