Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[C@@H](CN=[N+]=[N-])Nc1nc(Cl)ncc1F
Temperature: 70 °C

Procedure:
A mixture of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.37 g, 7.26 mmol) and sodium azide (1.89 g, 29.07 mmol) in DMF (50 mL) was heated at 70° C. for 6 hours. The reaction mixture was cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 1.2 g of the desired product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J=2.6, 1.1 Hz, 1H), 5.07 (m, 1H), 4.32-4.09 (m, 1H), 3.60 (dd, J=12.8, 3.9 Hz, 1H), 3.34 (dd, J=12.8, 7.6 Hz, 1H), 0.96 (m, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.28 minutes (M+H) 273.14.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][S:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][S:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CSCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 84.8 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methylsulfanyl-ethyl)-amide (82 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (82 mg), 2-methylthio-ethylamine (30 mg), HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 483. 1H NMR (DMSO-d6, 400 MHz): δ 8.58 (s, 1H), 8.09 (s, 1H), 7.91 (m, 1H), 7.47 (m, 2H), 7.48 (d, 1H), 7.37 (d, 1H), 3.64 (s, 3H), 3.48 (q, 2H), 2.68 (t, 2H), and 2.12 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.[OH:7][PH:8]([OH:10])=[O:9].P(Cl)(Cl)Cl>O>[NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1([P:8]([OH:10])(=[O:7])[OH:9])[P:8]([OH:10])(=[O:7])[OH:9]
Reactant: O=[PH](O)O
Reactant: O=C1CCCN1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C1(P(=O)(O)O)CCCN1
Reaction time: 8 h

Procedure:
85.0 gm of 2-pyrrolidone (1.0 mol) and 164 gm of H3PO3 (2.0 mols) were melted at 80°C. While stirring this melt, 176 ml of PCl3 (2.0 mols) were added thereto. The mixture was stirred for three additional hours and was left standing at 70°C overnight. Then, three liters of H2O were used for the hydrolysis. The solution was boiled with activated carbon; and after filtration, the reaction product was precipitated with acetone. The white substance was dissolved in water, and passed over a cation exchanger. The solution was concentrated; and the substance was separated upon the addition of ethanol. The yield of crystalline azacyclopentane-2,2-diphosphonic acid was 95 gm, or about 41% of the theory. The molecular weight of the compound was determined by titration to be 230 (calculated: 231.09).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][NH:11]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[C:4]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[O:31])[CH:3]=1.N1CCCCC1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][NH2:11])=[C:4]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[O:31])[CH:3]=1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: NCC(=O)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
A round-bottomed flask was charged with 9H-fluoren-9-ylmethyl [2-({4-bromo-2-[(2-fluorophenyl)carbonyl]phenyl}amino)-2-oxoethyl]carbamate (580 mg) and tetrahydrofuran (15 mL). The mixture was treated with piperidine (1.5 mL) then stirred at room temperature for 1.5 h. After concentrating to an oil, the residue was taken up in methylene chloride and purified by silica gel chromatography to yield N1-{4-bromo-2-[(2-fluorophenyl)carbonyl]phenyl}glycinamide (135 mg) as a white powder. H1 NMR (d6-dmso): 8.42 (d, 1H), 7.82 (dd, 1H), 7.65-7.72 (m, 1H), 7.6 (dt, 1H), 7.52 (m, 1H), 7.33-7.40 (m, 2H), 4.0-6.4 (br s, 2H), 3.20 (s, 2H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH:20]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1ccccc1C1CCCCC1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1C1CCCCC1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Cyclohexyl-benzoic acid. LC-MS (basic): tR=1.42 min; [M+H]+=463.2.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)CC(=O)Cl
Reactant: CCCCNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(Cc1ccccc1)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 6.0 g of N-benzyl-n-butylamine in 3 ml of methylene chloride containing 4.5 ml of triethylamine, under inert gas, was cooled to 0° C. and treated by the dropwise addition of 4.27 ml of iso-valerylchloride. Another 3 ml of methylene chloride was added and stirred at ambient temperature for 18 hours. The insolubles were filtered and the cake washed with methylene chloride. The combined filtrates were washed with water, brine and dried. Evaporation of the volatiles gave a brown oil which was purified by chromatography on silica gel using 1:8 ethyl acetate:-hexanes giving 7.75 g of the desired product as a yellowish oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1.[O-]CC.[Na+].[CH:55]([C:57]1[N:58]([CH3:62])[CH:59]=[CH:60][N:61]=1)=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:55]/[C:57]1[N:58]([CH3:62])[CH:59]=[CH:60][N:61]=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1
Reactant: Cn1ccnc1C=O
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(/C=C/c2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinolin-2-yl]methyltriphenylphosphonium chloride (17.4 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.62 g) and ethanol (150 ml)). Then a solution of 2-formyl-1-methylimidazole (3.7 g) in ethanol (20 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/methanol (100/1, v/v) gave ethyl (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-(1-methylimidazol-2-yl)vinyl]quinoline-3-carboxylate (8.3 g, 67%) which was then recrystallized from ethyl acetate.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][CH2:6]1.[Br:16]Br>C(Cl)Cl>[Br:16][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:15])[CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: O=C1CCOc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 75.9 %

Procedure:
Into a round bottom flask kept at 0° C., AlCl3 (0.533 g, 3.99 mmol) and, 5 mL of CH2Cl2 was added. The reaction system was put under nitrogen and stirred for about 7 minutes before adding 10 mL of a CH2Cl2 solution of 4-chromanone (0.296 g, 1.99 mmol). After the reaction mixture was stirred for 10 minutes, 10 mL of Br2 (0.352 g, 2.20 mmol) was added and, the reaction mixture was stirred at room temperature for an hour. At the end of this period of time, the reaction mixture was poured into 30 mL of ice-water and, the product was extracted 3 times from the aqueous phase with EtOAc. The resultant organic phase was washed once with brine and dried under Na2SO4. After the solvent was evaporated, the solid formed was filtered and dried to obtain 0.361 g (1.51 mmol) of the product (93% pure) in a 74% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH:16]1[O:18][CH2:17]1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(-c2cccc(OCC3CO3)c2)cc1
Reaction time: 15 h

Procedure:
4.7 g of m-phenylphenol, 15.1 g of epibromohydrin, 13.6 g of potassium carbonate and 33.3 g of 2-butanone were introduced into a three-necked flask with reflux condenser and stirrer. In addition, air was slowly passed through and the temperature was held at 70° C., and the mixture was stirred for 15 hours. After filtration, the filtrate was freed from low-boiling components in a rotary evaporator. m-Phenylphenol glycidyl ether was obtained as a clear, liquid product: 1H-NMR (CDCl3, 400 MHz): 2.78 (dd, 1H), 2.90 (t, 1H), 3.36 (m, 1H), 4.02 (dd, 1H), 4.24 (dd, 1H), 6.90 (dd, 1H), 7.15 (d, 1H), 7.20 (d, 1H), 7.35 (m, 2H), 7.40 (t, 2H), 7.55 (d, 2H).
Reaction SMILES: C[C@:2]1([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34]C)=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.O.O.O.[F-:47].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:9][C:8]([F:11])([F:10])[C@H:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:3]1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][OH:34])=[C:26]([F:47])[CH:27]=4)[N:22]=3)=[N:19][N:20]=2)[CH:17]=1
Reactant: [F-]
Reactant: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a stirred solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.37 g, 1.94 mmol) in THF (100 mL) was added tetrabutylammonium fluoride trihydrate (1.84 g, 5.83 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between saturated aqueous NH4Cl solution and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in EtOAc) to give tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.01 g, 88%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([OH:25])=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2=[O:12].[O:27]1CC[CH2:29][CH2:28]1.[H-].[Na+].C(Cl)(=O)C>C(Cl)Cl>[C:28]([O:25][C:5]1[C:4](=[O:26])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[C:7](=[O:12])[C:6]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:27])[CH3:29]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCC1=C(O)C(=O)c2c(Cl)cccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCC1=C(OC(C)=O)C(=O)c2c(Cl)cccc2C1=O
Temperature: 25 °C

Procedure:
A solution of 0.95 parts of 5-chloro-2-dodecyl-3-hydroxy-1,4-naphthoquinone in 20 parts of anhydrous tetrahydrofuran was added under nitrogen to a mixture of 0.0635 parts of dispersed sodium hydride in 40 parts of tetrahydrofuran with stirring at room temperature. After 45 minutes of stirring, a solution of 0.275 parts of acetyl chloride in 30 parts of tetrahydrofuran was added and the mixture stirred for 5 hours. The tetrahydrofuran was stripped under reduced pressure and the residue taken up in methylene chloride and then washed with water, 10% hydrochloric acid, four more times with water, dried over sodium sulfate and stripped. The resulting yellow solid was purified by column chromatography on silica gel using 1-chlorobutane as eluent. Solvent removal gave 0.9 parts of 3-acetoxy-5-chloro-2-dodecyl-1,4-naphthoquinone, m.p. 57°-59° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11x, and 4-chlorobenzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.62 (m, 1H), 8.51 (d, 1H), 7.89 (d, 2H), 7.79 (d, 2H), 7.49 (d, 2H), 7.22 (m, 2H), 7.14 (m, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.81 (s, 1H), 4.37 (s, 2H), 4.32 (s, 2H), 3.64 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 536 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[OH-].[Na+].O.Cl>CCO>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(F)(F)F)c(C(F)(F)F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (300 mg, 0.990 mmol) in EtOH (10 ml), 2M NaOH (0.495 ml, 0.990 mmol) was added dropwise over 1 minute. After stirring at RT for 30 minutes the reaction mixture was poured into water (30 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the combined organic extracts were washed with brine (30 ml), dried over MgSO4 (5 g), filtered and concentrated in vacuo to afford the title compound as an off white crystalline solid;
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1)[NH2:27]>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)[N:27]=[CH:3][CH:4]=1
Reactant: CC(=O)Nc1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: CC(=O)Nc1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and N-(3-hydrazino-phenyl)-acetamide according to the method described for example 91. MS: M=456.2 (M+H)+
Reaction SMILES: [ClH:1].C(OC([CH2:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[CH3:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46]1)=[O:37])=[O:14]
Reactant: CC(C)(C)OC(=O)CNCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
242 μl of 4N HCl in dioxane are added to 300 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 3-(tert-butoxycarbonylmethylamino)propionate in 5 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, the precipitate is filtered off with suction and washed with 2 ml of dichloromethane.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Br:11].[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CO>[Br:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3](=[O:12])[C:14]([F:16])([F:15])[F:13]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to −70° C., and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylamonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4 h, after which it was stirred for 10 h at room temperature. The reaction mixture was concentrated to give the crude [1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-1-methoxy-ethoxy]-rimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCl (100 ml) was added. The mixture was kept at 45-50° C. for 12 h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHCO3 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.50 (d,1H), 7.65(d,1H), 7.80(s,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:17]1[CH2:16][CH2:15][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Reactant: ClCc1ccccc1Cl
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4ccccc4Cl)CC3)CC2)cc1

Procedure:
The title compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine and 2-chlorobenzyl chloride by the method described in example 15 to give the product (44%, mp: 83°-85° C.). Calc'd for C23H28ClFN2.0.4H2O: C, 70.09%; H, 7.37%; N, 7.11%. Found: C, 69.99%; H, 7.38%; N, 7.07%.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[CH3:13][S-:14].[Na+]>CO>[Cl:1][C:2]1[N:9]=[C:8]([S:14][CH3:13])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: Cc1c(Cl)c(Cl)nc(Cl)c1C#N
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSc1nc(Cl)c(C#N)c(C)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a slurry of 2,5,6-trichloro-4-methyl-nicotinonitrile (10.0 g, 45.2 mmol, Tetrahedron, 1977, 33, 113-117) in MeOH (150 ml) at 0° C. is added solid sodium thiomethoxide (3.33 g, 45.2 mmol). The mixture is stirred at 0° C. for 1 hour, then room temperature for 1 hour. The reaction is quenched by the addition of water (250 ml). The mixture is partitioned between water and EtOAc (500 ml each), and the layers are shaken and separated. The organic layer is dried (anhydrous magnesium sulfate), filtered, and concentrated to give the title compound as a yellow solid (10.5 g, 99%). Mass (m/z): 233.0 (M++1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([N:15]([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)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:25]1[CH:24]=[CH:23][C:22]([N:15]([C:9]2[CH:10]=[CH:11][C:12]([Br:1])=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Into a 200 ml three-necked flask, 8.0 g (45 mmol) of N-bromosuccinimide and 10.0 g (41 mmol) of triphenylamine were placed, followed by 150 ml of N,N-dimethylformamide. The mixture was stirred overnight at room temperature. Next, N,N-dimethylformamide was removed from the reaction, and the resulting solid matter was extracted with carbon tetrachloride. Then, carbon tetrachloride was removed, and the reaction product was recrystallized twice from ethanol to give a white solid, 4-bromotriphenylamine in an amount of 8.2 g (yield: 61.7%).