Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:3]=[C:2]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[CH:7]=2)[CH:9]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Oc1ccc(CCNc2cc(-c3cccnc3)nc(-c3ccccn3)n2)cc1

Procedure:
4-Chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine (Intermediate A) (1 eq, 0.74 mmol, 200 mg) and 4-(2-amino-ethyl)-phenol (1.2 eq, 0.89 mmol, 123 mg) are dissolved in iPrOH (3 ml). Then DIPEA (2 eq, 1.49 mmol, 196 mg) is added and the resulting mixture is heated using microwave radiation at 130° C. for 20 min. The solvent is removed in vacuo and the crude residue is purified by flash chromatography eluting with 0-5% MeOH in DCM yielding the title compound [M+H]+=370.
Reaction SMILES: CC1(C)CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)C2C(=CC(OC)=CC2)N1.[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=2)[CH:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH2:32]2)[NH:27]1>>[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:18]([F:21])([F:20])[F:19])=[CH:38][CH:37]=2)[CH:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH2:32]2)[NH:27]1
Reactant: COC1=CCC2C(=C1)NC(C)(C)CC2c1cccc(C(F)(F)F)c1
Reactant: COC1=CCC2C(=C1)NC(C)(C)CC2c1ccc(Cl)cc1
Product: COC1=CCC2C(=C1)NC(C)(C)CC2c1ccc(C(F)(F)F)cc1

Procedure:
2,2-dimethyl-7-methoxy-4-(3-trifluoromethylphenyl)tetrahydroquinoline; and 2,2-dimethyl-7-methoxy-4-(4-chlorophenyl)tetrahydroquinoline (using Pt as catalyst).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: CC(C)CC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-5-methyl-hexanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=376.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(OCc4ccccc4)cc3)c2CC1
Yield: 67.3 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (706 mg, 1.84 mmol) in methanol (20 mL). Add potassium hydroxide (3.5 g, 55 mmol) and heat the mixture at reflux for 3 h. Cool to ambient temperature. Pour reaction in saturated aqueous NH4Cl solution. Extract three times with EtOAc. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (602 mg, 100%). Dissolve 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (282 mg, 0.9 mmol) in acetone (30 mL). Add 4-benzyloxybenzyl chloride (251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg, 2.7 mmol) and potassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. Cool the reaction to ambient temperature, dilute with acetone, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give 6-(4-benzyloxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (309 mg, 67%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:13](Cl)(Cl)=[S:14].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:13]=[S:14])=[CH:7][N:6]=1)[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CCN(CC)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)c1ccc(N=C=S)cn1
Yield: 19.1 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of i5.9 g (0.096 mole of 5-amino-2-diethylaminopyridine with 22.2 g (0.193 mole) of thiophosgene and 5.0 g (0.036 mole) of potassium carbonate in 50 ml of water and 150 ml of chloroform yielded 3.8 g of (2-diethylaminopyridin-5-yl) isothiocyanate as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]1[C:17](=[O:18])[O:16][CH2:15][C:13]1=O.Cl>C(O)C>[O:18]=[C:17]1[O:16][CH:15]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([O:10][CH3:11])=[O:9])[CH:13]=[CH:12]1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C1COC(=O)C1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccccc1NC1C=CC(=O)O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
15.1 gm of methyl anthranilate and 9.0 gm of β-tetronic acid were dissolved into 100 ml of ethanol, and 2 ml of concentrated hydrochloric acid was added, followed by stirring for 15 hours at room temperature. Deposited crystals were collected by filtration, washed with cold ethanol, and dried to obtain 19.2 gm of methyl N-(2,5-dihydro-5-oxo-2-furanyl)anthranilate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrCCCBr
Reactant: Oc1cc(F)ccc1F
Product: Fc1ccc(F)c(OCCCBr)c1

Procedure:
Analogously to Example 91b, 1.40 g of 2,5-difluorophenol and 21.5 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.59 (1:3 EtOAc-heptane); Rt=4.84.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)=[O:19].O>[Al].[Ni]>[N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:19])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(C#N)cc1)n1ccnc1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Solvent: O
Product: CCCC(c1ccc(C=O)cc1)n1ccnc1

Procedure:
10 g of nitrile of example 4 is refluxed with 10 g of aluminum nickel alloy in 150 ml of formic acid/water (75:25) for 1 hour. It is filtered on kieselguhr, the filtrate is alkalized with solid potassium carbonate, 100 ml of aqueous ammonia is added and extracted with ether. After drying and concentration by evaporation of the ether, it is distilled on a bulb tube; 9.1 g of 4-[1-(1-imidazolyl)butyl]-benzaldehyde is obtained, melting 200° C./0.03 mbar.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]2.Cl[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][C:18]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[Cl:23][C:21]1[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]([NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]3)[CH:22]=1
Reactant: CN1CCc2cccc(N)c2C1=O
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCc2cccc(Nc3cc(Cl)ncc3C#N)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.2 %

Procedure:
Sodium hydride (2.78 g, 69.46 mmol) was added portionwise to 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (3.06 g, 17.37 mmol), in THF (8 mL) under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (3.00 g, 17.37 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (100 mL). The mixture was washed sequentially with water (100 mL), a saturated solution of NaHCO3 (100 mL), and finally with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was loaded onto an SCX column and the product was eluted using a mixture of MeOH in CH2Cl2. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 50-70% EtOAc in isohexane. Fractions containing the required product were combined and evaporated to afford 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.149 g, 21% yield). The mixed fractions were combined and repurified by silica chromatography, eluting with a gradient of 0-20% EtOAc in CH2Cl2. Fractions containing the required product were combined and evaporated to leave 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.287 g, 24% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.98 (2H, t), 3.06 (3H, s), 3.58 (2H, t), 7.07 (1H, dd), 7.36 (1H, s), 7.48-7.52 (2H, m), 8.63 (1H, s), 12.00 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=313.34 and 315.33.
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.S(Cl)([Cl:20])(=O)=O.C(OCC)(=O)C>C(OCC)C>[Cl:20][C:12]1[C:13]([CH3:16])=[C:14]([OH:15])[C:2]([CH3:1])=[C:3]2[C:11]=1[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2
Reactant: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1c(O)c(C)c2c(c1Cl)OC1(CCC1)CC2
Reaction time: 2 h

Procedure:
To a solution of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (350 mg) in ethyl ether (6 mL) was added sulfonyl chloride (0.154 mL, 260 mg) dropwise at room temperature under nitrogen. After 2 hours, ethyl acetate was added, washed with an aqueous sodium bicarbonate solution, water and brine, and dried. Evaporation and chromatography (silica gel hexane-ethyl acetate 0% to 4%, hexane-dichloromethane 5% to 20%) yielded the desired compound. Crystallization with hexane gave colorless crystals of 8-chloro-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (60 mg). 1H-NMR (300 MHz, CDCl3) δ=4.29 (s, 1H), 2.67 (t, J=6.6 Hz, 2H), 2.35-1.80 (m, 13H), 1.75-1.60 (m, 1H) ppm. 13C-NMR (75 MHz, CDCl3) δ=145.2, 143.6, 120.9, 120.1, 119.9, 119.7, 77.3, 33.8, 29.2, 20.8, 13.2, 12.5, 11.5 ppm. MS: (m/z)=253 (100, M+H+), 275 (23, M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].BrC1C=NC([Cl:25])=C(C=1)C(O)=O.CN(C)C=O>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([Cl:25])=[O:8]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: CON(C)C(=O)c1cc(Br)cnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)cnc1Cl
Temperature: 80 °C

Procedure:
5-Bromo-2-chloro-N-methoxy-N-methylnicotinamide. To a mixture of 5-bromo-2-chloronicotinic acid (6 g, 25.5 mmol) in thionyl chloride (30 mL) was added a drop of N,N-dimethylformamide, and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature, and concentrated to give crude 5-bromo-2-chloronicotinoyl chloride. A solution of O,N-dimethyl-hydroxylamine hydrochloride salt (3.45 g, 35.6 mmol) and triethylamine (7.48 g, 74.1 mmol) in dichloromethane (80 mL), and a solution of the above 5-bromo-2-chloronicotinoyl chloride in dichloromethane (20 mL) were added, and the reaction mixture was stirred overnight. The mixture was poured into water, and extracted with dichloromethane (50 mL×3). The combined organic layer was concentrated under reduced pressure, and purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide as a solid (6.2 g, 71.4% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.39 (s, 1H), 3.49 (s, 3H), 3.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[CH2:18]([CH2:22][C:23](=O)[CH3:24])[C:19]([CH3:21])=O.CCOC(C)=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:24][C:23]1[N:1]([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=3[F:14])[N:5]=[C:4]([CH3:15])[C:3]=2[C:16]#[N:17])[C:19]([CH3:21])=[CH:18][CH:22]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccc(O)cc2F)c(-n2c(C)ccc2C)c1C#N
Yield: 98.9 %

Procedure:
A solution of 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (100 mg, 0.43 mmol) and acetonylacetone (507 μL, 4.31 mmol) in glacial acetic (3 mL) acid was heated at 140° C. in the micro for 30 min. The mixture was transferred to a round bottom flask using EtOAc and evaporated, toluene was added and again evaporated, CH2Cl2 and silica was finally added and the mixture was evaporated to dryness. Purification using silica chromatography (short plug) gave 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (132 mg, 99%) as a 1:1 mixture with the starting material acetonylacetone. The product was used as such in the next step.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCCC1.C(Cl)Cl>[CH3:3][NH:5][S:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 125 ml of methylamine (0.25 molar) in tetrahydrofuran and 13.9 ml (0.10 mol) of triethylamine was chilled in an ice bath. To this chilled solution was added dropwise 19.4 g (0.10 mol) of 4-fluorobenzenesulfonyl chloride in 150 ml of CH2Cl2 was added and the mixture refluxed for 2 hours and then stirred overnight at room temperature. The mixture was with CH2Cl2, washed with H2O, 2N citric acid, brine and dried (Na2SO4). The solution was filtered through a pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum to give 18.0 g of white solid, mp 67-70° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][CH:21]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:21]1[CH:20]=[N:19][N:12]2[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)=[N:10][C:11]=12
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.0 g, 15.1 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.40 g, 17.1 mmol) and drop wise a solution of iodine monochloride (2.77 g, 17.1 mmol) in acetic acid (10 mLl). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 94%) as a yellow solid. MS (EI) 457.0 [(M)+]; mp 142° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[CH:11]=[C:10]1[CH3:30])[CH:7]=[CH2:8].CN(C)[CH:33]=[O:34]>ClCCl>[CH2:6]([N:9]1[C:13]2=[C:14]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:15]=[C:16]([C:18]#[N:19])[CH:17]=[C:12]2[C:11]([CH:33]=[O:34])=[C:10]1[CH3:30])[CH:7]=[CH2:8]
Reactant: CN(C)C=O
Reactant: C=CCn1c(C)cc2cc(C#N)nc(N3CCc4ccccc4C3)c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCn1c(C)c(C=O)c2cc(C#N)nc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Phosphorus oxychloride (425 μl, 4.56 mmol) was added at room temperature to a solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (1 g, 3.04 mmol) prepared in Step 3 in a mixture of anhydrous dichloromethane (20 ml) and N,N-dimethylformamide (353 μl, 4.56 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, and then filtered. The resulting solid washed with water and 1M sodium acetate (30 ml) was added thereto. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The resulting solid washed with water and then dried to give 350 mg of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH2:20])[CH3:2].[S:21](=[N:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])=[O:22]>[2H]C(Cl)(Cl)Cl>[S:21](=[N:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:20][C:4]1[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:28])=[O:22]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Agent: [2H]C(Cl)(Cl)Cl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (0.100 g, 0.33 mmol) (prepared according to EP 1,006,102) in deuterochloroform (1.0 ml) was added under stirring at 25° C., a solution of 3-sulfinylamino-benzoyl chloride (0.033 g, 0.165 mmol) (Example 1.1) in dry deuterochloroform (1.0 ml). After stirring for 8 hours at 40° C., a sample of the reaction mixture was submitted to 1H-NMR spectroscopy. The desired compound was detected in the reaction mixture, based on its characteristic signals (see 1H-NMR spectral data as described in Example 2.2), together with unreacted starting materials. Integration of the signals showed a conversion of 85%. An aliquot of the reaction mixture was diluted in dry acetonitrile and was submitted to mass spectrometry via direct injection (same conditions as described in Example 2.1). Calculated exact mass: 468; [M-H]− observed: 467.06.
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O.C1(OC)C=CC=CC=1.C1(O)C=CC=CC=1>>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: COc1ccccc1
Solvent: Oc1ccccc1
Product: O=C(O)CCCCC(=O)O
Yield: 59.2 %

Procedure:
A solution is formed by mixing 60.0 grams of trimellitic acid anhydride and 135.0 grams of p,p'diphenyl methane diisocyanate and 110.0 grams of Anisole and 4.8 grams of phenol by heating the mixture. At approximately 170°C. a clear, homogeneous solution is obtained. Once clarity is obtained 27.0 grams of adipic acid are added slowly. The temperature of the mixture is raised to approximately 170°C. and slow reflux is maintained. After approximately 120 minutes, a yellow viscous resin is obtained and 55.5 grams of cumene and 346.5 grams of phenol are added to quench and stop the reaction. The solution is maintained at 130°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 1200 cps, utilizing a Brookfield viscometer, and a resin solution of approximately 30% weight resin.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[CH:3]1[O:8][CH:7]([C:9](Cl)([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](OCC)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.O.[NH2:25][NH2:26]>C(O)C>[Cl:10][C:9]([Cl:11])=[C:7]1[C:6]2[CH:13]=[C:14]([C:17]([NH:25][NH2:26])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4][CH:3]([C:2]([Cl:23])([Cl:22])[Cl:1])[O:8]1
Reactant: NN
Reactant: CCOC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2c(c1)C(=C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of ethyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate (6.4 g.), 100% hydrazine hydrate (3 ml.) and ethanol (30 ml.) was warmed on the steam bath for 30 hours. The reaction mixture was cooled, and then evaporated to dryness under reduced pressure. The oily residue was triturated with petroleum ether (b.p. 60°-80° C.) and the solid product thus obtained was crystallised from ethanol, to give 4-dichloromethylene-2-trichloromethylbenzo[1,3]dioxin-6-carbohydrazide, m.p. 182°-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(Br)c3)nc2n(CC)c1=O
Yield: 47.2 %

Procedure:
Substantially the same procedure as in Reference Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.08 g (16.7 mmol) of 3-bromo-4-fluorocinnamic acid. The resulting crude crystals were recrystallized from dioxane to give 2.90 g (yield 47%) of Compound k as a pale yellow powder.
Reaction SMILES: C([O:8][C:9](=[O:36])[C@H:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:11][C:12]([N:14]([CH2:16][CH2:17][N:18]([C:20]([N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:19])[CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:22]1([C:20]([N:18]([CH2:17][CH2:16][N:14]([CH3:15])[C:12]([NH:11][C@H:10]([C:9]([OH:36])=[O:8])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:13])[CH3:19])=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 107.2 %

Procedure:
A solution of N-[N-{2-[N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino]ethyl}-N-methylaminocarbonyl]-L-phenylalanine benzyl ester (1.46 g) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (146 mg) at 3 atmospheric pressure of hydrogen gas for 1 hour at ambient temperature. The solution was filtered and concentrated in vacuo to give N-[N-{2-[N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino]ethyl}-N-methylaminocarbonyl]-L-phenylalanine (1.28 g) as an oil. Rf: 0.35 (chloroform:methanol:acetic acid, 16:1:1, V/V)