Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:34]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH2:42][NH2:43])[CH2:36][CH2:35]1>O>[CH:34]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH2:42][NH:43][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:36][CH2:35]1
Reactant: COc1cc(N)c(S(=O)(=O)N(C)C)cc1C(=O)O
Reactant: NCC1CCCN1C1CC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(S(=O)(=O)N(C)C)cc1C(=O)NCC1CCCN1C1CC1
Temperature: 0 °C

Procedure:
68.5 g of 2-methoxy-4-amino-5-dimethylsulphamoyl benzoic acid (0.25 mole), 740 ml of water and 25.4 g of triethylamine (0.25 mole) are placed in a 2 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The solution is cooled to about 0° C, and 34.1 g of isobutyl chloroformate (0.25 mole) is poured in drop by drop. The mixture is reacted for 40 minutes at room temperature then cooled, and 42 g of 1-cyclopropyl-2-aminomethylpyrrolidine is added drop by drop, while the temperature is kept between 0° and +5° C. The medium is reacted for 3 hours at room temperature, then the solution is evaporated dry under vacuum. The residue is dissolved in 250 ml of water and 50 ml of hydrochloric acid. The solution is extracted twice with 125 ml of methylene chloride, which is eliminated. The aqueous phase is made alkaline with 70 ml of soda lye.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[CH:38]=[N:37]1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:43][C:39]3[CH:38]=[N:37][N:36]([CH3:35])[C:40]=3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc2sc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc21
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass vessel, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (102 mg, 0.205 mmol), 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (175 mg, 0.410 mmol) and tetrakis(triphenylphosphine) palladium(0) (118 mg, 0.102 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The reaction mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparative HPLC, eluting with a gradient of 15-65% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (75 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.55 (m, 2H), 1.60 (d, J=14.15 Hz, 1H), 1.67-1.93 (m, 3H), 1.98 (dd, J=13.64, 4.29 Hz, 2H), 3.85 (br s, 1H), 3.99 (s, 2H), 4.24 (d, J=3.54 Hz, 1H), 4.38-4.54 (m, 2H), 7.14 (d, J=5.81 Hz, 1H), 7.62-7.88 (m, 3H), 8.62 (s, 1H), 9.27 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6OS, 401. found, 401.
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])Cl)[C:3]([CH3:11])([CH3:10])[CH:4]([C:8]#[N:9])C(O)=O.N>CN(C)C=O.O>[Cl:16][C:13]([Cl:15])=[CH:12][CH:2]1[C:3]([CH3:10])([CH3:11])[CH:4]1[C:8]#[N:9]
Reactant: CC(C)(C(Cl)CC(Cl)(Cl)Cl)C(C#N)C(=O)O
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 140 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-Chloro-2-cyano-3,3-dimethyl-6,6,6-trichlorohexanoic acid (40 g) was dissolved in dimethyl formamide (66 ml) and the solution, at room temperature, was saturated with gaseous ammonia with no external cooling. The solution was stirred at 140° C. for 5 hours, then diluted with water and extracted with ether (3×100 ml). The ether solution was washed with saturated NaCl, dried over MgSO4 and evaporated to afford Compound A as a yellow oil (purity 85%) which partly crystallized on standing. Yield 79%.
Reaction SMILES: [F:1][C:2]([F:15])([CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Cl:16][C:17]([F:25])([CH2:22][CH2:23]Br)[C:18]([Br:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:21][C:18]([F:20])([F:19])[C:17]([Cl:16])([F:25])[CH2:22][CH2:23][C:4]([CH2:3][C:2]([F:15])([F:1])[CH:9]([F:14])[C:10]([F:12])([F:13])[F:11])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)C(F)(F)F
Reactant: FC(F)(Br)C(F)(Cl)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(Cl)C(F)(F)Br)CC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.3 %

Procedure:
1.2 g of 2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile and 1.5 g of 2-chloro-1,4-dibromo-1,1,2-trifluorobutane were dissolved in 10 ml of dimethyl sulfoxide, 0.7 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.14 g of 2-(4-bromo-3-chloro-3,4,4-trifluorobutyl)-2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile (hereinafter, referred to as the present compound (46)).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>>[C:16]1([C:3]2[C:2]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccsc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccsc3)nc2c1
Yield: 41.5 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and thiophen-3-ylboronic acid (55.7 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 40 mg (39%) of 2-phenyl-3-(thiophen-3-yl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [OH-].[Li+].[O:3]=[S:4]1(=[O:41])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]([O:20]CC)=[O:19])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7][C:6]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:35][CH3:36])[CH2:5]1>C1COCC1.O>[O:41]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]([OH:20])=[O:19])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7][C:6]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:35][CH3:36])[CH2:5]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C(=O)OCC)c3ccccc3)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C(=O)O)c3ccccc3)cc2S(=O)(=O)C1
Yield: 92.3 %

Procedure:
Lithium hydroxide (0.019 g) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-phenyl-1′-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 3; 0.244 g, 0.397 mmol) in THF/H2O (2/1, 3 ml). After 2 days the solvent was removed under reduced pressure and the crude mixture was purified by HPLC to give the title compound 0.215 g (92%) as a white solid. NMR (CD3OD) 0.60–0.80 (m, 6H), 0.90–1.25 (m, 4H), 1.30–1.60 (m, 4H), 3.05–3.30 (m, 2H), 3.40–3.90 (m, 2H), 5.55 (s, 1H), 6.85–7.70 (m, 12H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)C(C)Oc1ncncc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 1 hour at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([OH:22])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[CH:30][CH:29]=1)=[O:27])[CH3:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([N:37]2[CH2:38][CH2:39][CH2:40][CH:36]2[C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:29][CH:30]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3)c(OC)c2)cc1
Yield: 60.9 %

Procedure:
A mixture of 3-methoxy-4-(N′-phenylureido)phenylacetic acid (180 mg, 0.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine (146 mg, 0.6 mmol), EDC (173 mg, 0.9 mmol), DMAP (73 mg, 0.6 mmol), and cat. HOBt in DMF (10 mL) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected with suction. The residue was dissolved in CHCl3 and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica-gel with CHCl3-MeOH (10:1, v/v) as eluent to give 192 mg (61%) ethyl 4-[2-[1-[3-methoxy-4-(N′-phenylureido)phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate as a light yellow amorphous solid. 1H-NMR (CDCl3) δ 1.38 (3 H, t, J=6.8 Hz), 1.98–2.24 (4 H, m), 3.48–3.89 (2 H, m), 3.53 (2 H, s), 3.62 (3 H, s), 4.33–4.40 (2 H, m), 4.78–5.04 (1 H, m), 6.77–8.00 (14 H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([O:9][Si](C)(C)C)[C:7]#N.C(Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: C[Si](C)(C)OC(C#N)c1nccs1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1nccs1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
To a solution of the product from Step 1 (0.4 g, 1.9 mmol) in degassed THF (4 mL) at −78° C. was added LHMDs. After stirring at −78° C. for 15 min, benzyl bromide (0.27 mL, 2.3 mmol) was added, and stirring was continued at −78° C. for 15 min, followed by 1 h at r.t. The reaction was then quenched by the addition of saturated NH4Cl solution, and the product was extracted with EtOAc. The organic layer was washed with H2O and brine, and was then dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (1:10 EtOAc:hexane) to give 0.16 g of the product.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[Cl:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:4])[C:14]=1[CH2:23][CH:18]=[CH2:19]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(Cl)ccc1C(=O)OC
Product: C=CCc1c(Cl)ccc(C(=O)OC)c1O
Yield: 71.1 %

Procedure:
A solution of methyl 2-allyloxy-4-chlorobenzoate (3f) (50.6 g, 0.22 mol) in 100 ml of N,N-dimethylaniline was heated under argon in an oil bath at 190°-205° C. for 20 hours. The solvent was removed by distillation and the residue purified by column chromatography (silica gel, CH2Cl2 /hexane) to give 4f (36.0 g, 71.1% yield) as a very light oil. IR (nujol) 1665 (C=0) cm-1. NMR (CDCl3) δ 11.23 (s, 1H, OH), 7.47 (d, 1H, J=9 Hz, aromatic proton meta to Cl), 6.77 (d, 1H, aromatic proton alpha to Cl), 6.17-4.77 (m, 3H, olefinic protons), 3.87 (s, 3H, CH3) and 3.50 (m, 2H, CH2).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([F:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[CH3:21].[OH-].[Na+]>O1CCOCC1.CO>[CH3:21][C:5]1[CH:6]=[C:7]([C:11]([F:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:19])([F:18])[F:17])[CH:8]=[C:9]([CH3:10])[C:4]=1[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
2,6-Dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoic acid methyl ester (7 g, 0.021 mol) (Example I2) was dissolved in dioxane (70 ml) and methanol (15 ml), then aqueous sodium hydroxide (4N) (52.2 ml, 0.21 mol) was added. The mixture was stirred at 60° C. for 15 hours. The methanol was evaporated and the mixture was cooled to 0° C. before acidifying to pH=1 by addition of concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to give the 2,6-dimethyl-4-(1,2,2,2-tetra-fluoro-1-trifluoromethyl-ethyl)-benzoic acid (6.52 g, 98% yield). 1H-NMR (CDCl3, 400 MHz): 7.31 (s, 2H), 2.49 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCCC2
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 mL) is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is heated at 90° C. for 20 h. The reaction mixture is partitioned between ethyl acetate and aqueous saturated NaHCO3. The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCCO)s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCCO)s1
Reaction time: 4 h
Yield: 95 %

Procedure:
To a Parr flask were added 2 (1.17 g, 5.6 mmol), 10% palladium on activated carbon (600 mg), and MeOH (100 mL). Hydrogenation was carried out at 55 psi of H2 for 4 h. The reaction mixture was filtered through Celite, washed with MeOH (100 mL) and concentrated under reduced pressure to give 1.14 g of 3 as yellow oil. 1H NMR (DMSO-d6): δ 1.41-1.48 (m, 2H), 1.61-1.68 (m, 2H), 2.81-2.85 (t, J=7.2 Hz, 2H), 3.37-3.42 (m, 2H), 3.77 (s, 3H), 4.40-4.43 (t, J=5.2 Hz, 1H), 6.94-6.95 (d, J=3.6 Hz, 1H), 7.63-7.64 (d, J=3.6 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C([O-])([O-])=O.[Na+].[Na+].[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[NH:6][CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCN
Reactant: COC(=O)CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCCCNS(=O)(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1.03 g (12.0 mmol) pent-4-enylamine, 8 ml DCM and 5 ml 10% aqueous Na2CO3 at 0° C. are added dropwise 2.25 g (12.0 mmol) 3-chlorosulfonyl-propionic acid methyl ester. After stirring for 2 h at 25° C. the phases are separated and the organic phase is dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc, hexane 1:2) gives the 3-pent-4-enylsulfamoyl-propionic acid methyl ester. This ester is dissolved in 2 ml DMF and heated to 65° C. in the presence of 1.58 g (11.5 mmol) K2CO3 and 0.716 ml methyl iodide for 5 h. The mixture is diluted with EtOAc and washed with water, dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc, hexane 1:4) gives the 3-(methyl-pent-4-enyl-sulfamoyl)-propionic acid methyl ester. Hydrolysis of this ester with LiOH in water/MeOH gives the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 4 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 551.1 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][OH:17]>CN(C=O)C.O>[OH:17][CH2:16][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCO)ccc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-2-methoxybenzaldehyde (1.217 g, 8.00 mmol) in dry DMF (8.88 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.267 mL, 8.00 mmol) in dry DMF (2.22 mL) via cannula at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature. 2-bromoethanol (0.851 mL, 12.00 mmol) was added dropwise and the reaction mixture was stirred at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with 1N aq. NaOH (50 mL), dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 60% EtOAc in hexanes over 4536 mL) to afford 4-(2-hydroxyethoxy)-2-methoxybenzaidehyde, as a colorless solid. Rf=0.29 (50% EtOAc/hexanes). LCMS calc.=197.1; found=197.0 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 10.16 (s, 1 H); 7.68 (d, J=8.7 Hz, 1 H); 6.46 (dd, J=8.7, 2.2 Hz, 1 H); 6.40 (d, J=2.2 Hz, 1 H); 4.09 (t, J=4,6 Hz, 2 H); 3.94 (t, J=4.4 Hz, 2 H); 3.79 (s, 3 H); 3.20 (s, 1 H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:17][CH2:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO.O>[C:1]([S:4][CH2:5][CH:6]([CH2:17][CH2:18][CH:19]([OH:23])[CH:20]([CH3:21])[CH3:22])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CCC(=O)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)SCC(CCC(O)C(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[2-(acetylthiomethyl)-5-oxo-6-methylheptanoyl]-L-proline (1.5 g.) is dissolved in cold methanol (10 ml.) and sodium borohydride (0.12 g.) is added. After two hours the reaction mixture is diluted with water (100 ml.) acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to give 1-[2-(acetylthiomethyl)-5-hydroxy-6-methylheptanoyl]-L-proline.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=CC=[CH:3][CH:2]=1.[CH:8]([OH:11])([CH3:10])[CH3:9]>[Pt]>[CH:2]([CH:1]1[CH2:7][CH2:10][CH:8]2[O:11][CH:9]2[CH2:6]1)=[CH2:3]
Reactant: Cc1ccccc1
Reactant: CC(C)O
Agent: [Pt]
Product: C=CC1CCC2OC2C1
Temperature: 60 °C

Procedure:
Thereafter, 0.44 part of a 0.5% toluene solution of the platinum catalyst (supra) was added to the reaction mixture which was heated up to a temperature of 60° C. where the reaction mixture was admixed dropwise with a mixture of 14.7 parts of the Intermediate 1 obtained in Synthesis Example 3, 19.5 parts of 4-vinylcyclohexene oxide and 1.02 parts of isopropyl alcohol over a period of 1.5 hours during which the temperature of the reaction mixture was gradually increased to 65° C. After completion of the dropwise addition of the mixture, the reaction mixture in the flask was continuously agitated for further 6 hours at 65° C. and then admixed with 0.03 part of triphenyl phosphine to terminate the reaction followed by stripping of toluene and other volatile matters at 80° C. under a pressure of 5 Torr to obtain a light brown, cloudy liquid as the product, referred to as the Product 3 hereinafter, having a viscosity of 276 MPa·s and an epoxy equivalent of 1630.