Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]([OH:33])[C:28]([F:35])([F:34])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, light yellow solid (91 mg, 81%), MS (ISP) m/z=453.3 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxy-propionic acid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Br:13][C:14]1[NH:15][CH:16]=[C:17]([CH3:19])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[N:15]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:16]=[C:17]([CH3:19])[N:18]=1
Reactant: Cc1c[nH]c(Br)n1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(F)cc(F)c2[N+](=O)[O-])c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 1,3,5-trifluoro-2-nitrobenzene (2.2 mL, 18.6 mmol), 2-bromo-4-methylimidazole (3 g, 18.6 mmol) and K2CO3 (5.66 g, 41 mmol) in 80 mL DMF was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water. Standard work up procedure followed by column purification using 10% ethyl acetate in dichloromethane as eluent provided 3.18 g (54% yield) of the product as a yellow powder. EIMS 317.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:17][C:18]#[N:19])([CH:11]1[C:15](=[O:16])[O:14][CH2:13][CH2:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>C(O)(=O)C.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:17][CH2:18][NH:19][C:15](=[O:16])[CH:11]1[CH2:12][CH2:13][OH:14])=[O:20])[CH3:2]
Reactant: CCOC(=O)C(CC#N)(C(=O)OCC)C1CCOC1=O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)CCNC(=O)C1CCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
To a solution of 4.35 g (0.015 mol) of the cyanodiester from Example 5 in 100 mL of glacial acetic acid was added 150 mg of platinum (IV) oxide, and the mixture was agitated under hydrogen (60 psi) until hydrogen uptake had ceased. The mixture was filtered and the acetic acid was removed under reduced pressure (Ca. 0.5 mm) at 30°-35° C. To the oily residue (containing a trace amount of acetic acid) was added 300 mL of chloroform and the mixture was stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue was triturated in pet ether and filtered. The resultant solid was subjected to flash chromatography (silica, 9:1 EtOAc/MeOH). The major isolated compound was recrystallized in CHCl3 /hexane to give 3.54 g (80%) of white solid: mp 120°-121° C.
Reaction SMILES: Br[C:2]1[NH:21][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=[O:18])[S:17][C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[NH:21][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:20]=[CH:19][C:14]5[NH:15][C:16](=[O:18])[S:17][C:13]=5[CH:12]=4)[C:4]=3[CH:3]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(Br)cc34)cc2s1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)c2cc3c(Nc4ccc5[nH]c(=O)sc5c4)ncnc3[nH]2)cc1

Procedure:
50 mg (138 μmol) 6-[(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1,3-benzothiazol-2(3H)-one (prepared according to example 8) were transformed in analogy to intermediate example 23 using sodium 4-methylbenzenesulfinate to give after working up and purification 6.7 mg (11%) of the title compound.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(F)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 125 mg 1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyazetidine hydrochloride, and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.8 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 90 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=O)=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[NH2:25][NH2:26]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19]([NH:25][NH2:26])=[O:21])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Solvent: CCO
Solvent: O
Product: COc1cc(-c2nc(C)c(C(=O)NN)s2)cc(OC)c1OC
Yield: 59 %

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylate prepared in Example 4 (6.2 g corresponding to its 0.02 mol), 6.1 g (0.1 mol) of hydrazine hydrate of purity of 82% and 150 ml of ethanol were heated for 6 hours at a temperature of 90° C. The crystals, which separated out after cooling the reaction mixture, were recrystallized from 95% aqueous ethanolic solution to obtain the object consisting of faintly yellow scale-like crystals, amounting to 3.8 g and melting at 179.5° to 181° C. at a yield of 59%.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][O:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:40]=[N:41][O:42][CH:43]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3cnoc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 22.5 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (55.8 mg, 0.286 mmol), potassium carbonate (79 mg, 0.573 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol). Water (0.5 mL) was then added and the mixture heated at 100° C. in a microwave for 15 min. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (2×20 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (22 mg). LCMS (A) m/z: 512 [M+1]+, Rt 1.36 min (acidic).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)=O)=[C:9]([C:24]#[N:25])[C:8]([CH2:26][CH3:27])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:28].[K+].O.OO>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=[CH:16][CH:15]=4)=[N:25][C:24](=[O:28])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CCc1nn(C2CCCC2)c(NC(=O)c2ccnc3ccccc23)c1C#N
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccnc4ccccc34)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.5 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-(4-quinolinecarboxamido)-1H-pyrazole (4.6 g, 12.7 mmol), potassium hydroxide (1.7 g, 25.4 mmol) and water (250 ml) at room temperature was added 30% hydrogen peroxide (7.8 ml, 76.0 mmol). The reaction mixture was heated to reflux and stirred for 24 hours. One equivalent of potassium hydroxide and 2 equivalents of 30% hydrogen peroxide were added and the mixture was refluxed for another 24 hours. One equivalent of potassium hydroxide and 2 equivalents of 30% hydrogen peroxide were again added and the mixture was heated at reflux for 3 days. The reaction mixture was cooled to room temperature, treated with acetic acid until a pH of 6.5 was obtained and the resulting precipitate was collected by filtration. The product was purified by column chromatography on silica eluting with ethyl acetate to afford 1.3 g (35%) of 1-cyclopentyl-3-ethyl-6-(4-quinolinyl)-pyrazolo[3,4-d]pyrimidin-4-one as a white solid, m.p. 205°-206° C., when recrystallized from ethyl acetate and dried at 110° C. for 16 hours in high vacuum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][C:47]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:48]=1[NH2:49]>CN(C=O)C>[CH3:46][C:47]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:48]=1[NH:49][C:10]([C:8]1[S:7][C:3]2=[N:4][CH:5]=[CH:6][N:1]=[C:2]2[CH:9]=1)=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1cc2nccnc2s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (250 mg, 1.387 mmol), HATU (633 mg, 1.665 mmol) and DIPEA (0.459 mL, 2.77 mmol) in DMF (5 mL) was stirred for 15 min. 2-methyl-5-nitroaniline (211 mg, 1.387 mmol) was added and stirred at 60° C. for 4 h. Quenched in citric acid solution and the resulting precipitate was collected to give N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 92%). (m/z)=315 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[CH:15]2[CH2:18][O:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:14]([CH:15]1[CH2:16][O:17][CH2:18]1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C1CCNCC1)C1COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.55 mmol) and TFA (4 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methyl(oxetan-3-yl)piperidin-4-ylamine as a white solid (94 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.67 (t, J=6.7 Hz, 2H); 4.61 (t, J=6.7 Hz, 2H); 3.97 (p, J=6.7 Hz, 1H); 3.14 (d, J=12.3 Hz, 2H); 2.56 (td, J=12.2, 4.0 Hz, 2H); 2.48-2.26 (m, 2H); 2.22 (s, 3H); 1.63 (d, J=12.3 Hz, 2H); 1.40 (qd, J=12.2, 4.0 Hz, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 6-quinolinecarboxylic acid (500 mg, 2.89 mmol) and 4-benzyloxyphenylamine (681 mg, 2.89 mmol) in dichloromethane (25 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.53 g, 3.47 mmol) and triethylamine (0.96 mL, 6.94 mmol), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (194 mg, 19%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@H:16]3[O:21]C(C)(C)[O:19][C@@H:18]([CH2:24][C:25]([O:27]C(C)(C)CC4C=CC=CC=4)=[O:26])[CH2:17]3)=[C:12]([CH:38]([CH3:40])[CH3:39])[N:11]=[C:10]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+:49]>O1CCCC1>[Na+:49].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[CH2:17][C@@H:18]([OH:19])[CH2:24][C:25]([O-:27])=[O:26])=[C:12]([CH:38]([CH3:40])[CH3:39])[N:11]=[C:10]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@H](CC(=O)OC(C)(C)Cc2ccccc2)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 40 °C
Reaction time: 24 h

Procedure:
2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (15.38 g) prepared in Example 19 was dissolved in tetrahydrofuran (80 ml) and a 0.1M hydrochloric acid aqueous solution (19.21 ml) was added thereto, followed by stirring for 24 hours while heating to 40° C. The reaction liquid was cooled to room temperature and a 0.5M sodium hydroxide aqueous solution (81 ml) was added thereto over 5 minutes, followed by stirring for 4 hours. Ethyl acetate (250 ml) and purified water (250 ml) were added to the reaction liquid, and the organic layer was separated, washed with saturated sodium chloride (150 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid sodium salt.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CO>O>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 93 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To 720 g of polyphosphoric acid (112%) heated at 89° C. were added 160 g of 2,5-di(4-methylanilino)terephthalic acid over a period of approximately 40 minutes, the temperature being maintained below 100° C. by adjustment of the addition rate. The reaction mixture was held at 123° C. for two hours, cooled to 93° C., and poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant presscake was reslurried in water. After adjustment of the pH to 7.1, 74.2 g of 50% sodium hydroxide were added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled to 65° C., filtered, and washed with water until alkaline free, then reslurried in water. After adjustment of the pH to 9, the slurry was heated at 143° C. for two hours and allowed cooled to 45° C. After the slurry was acidified to pH 3.5, an emulsion of 4.7 g of an anionic surfactant, 69.6 g of a petroleum distillate, and 160 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 135 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:32][C@@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20](=[O:31])[C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25][CH:26]=3)[C:16]([NH:32][C@@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:18])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirring solution of (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid INT-27 (1.50 g, 3.10 mmol) in DMF (15 mL) were added tert-butyl D-alaninate (680.0 mg, 3.73 mmol) and Et3N (802.3 mg, 6.2 mmol). The reaction was stirred for 1 hour at 0° C. and then HATU (877.5 mg, 3.37 mmol) in 2 mL DMF was added. The reaction was stirred for 1 hour at 0° C. and then warmed to room temperature with stirring for 18 hours. The reaction solution was extracted with aqueous NaHCO3 (3×20 mL). The combined organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (50%) EA in hexanes) to afford 1.44 g (76%) of tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninate INT-32 as a solid powder. LCMS-ESI (m/z) calculated for C31H37BrN4O4: 609.6. found 610.2 [M+H]+, tR=4.05 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 2H), 8.49 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 7.73 (t, J=7.4 Hz, 2H), 7.54-7.37 (m, 4H), 4.85 (td, J=10.1, 4.6 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H), 3.24-2.97 (m, 2H), 1.50-1.29 (m, 9H), 1.32-1.17 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[B:15](OC)([O:18]C)[O:16]C.Cl>C(OCC)C.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([B:15]([OH:18])[OH:16])[CH:5]=[C:4]([Br:9])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To 9.44 g of 1,3,5-tribromobenzene in 200 mL of diethyl ether was added 19.4 mL of 1.55M n-butyllithium in hexane at -78° under nitrogen. The suspension was stirred for 30 min, then added to 30 mL of trimethyl borate in 300 mL of diethyl ether at the same temperature. The now clear solution was stirred at -78° for 30 min then warmed to room temperature overnight. Fifty mL of 1 N hydrochloric acid were added and allowed to react for 2 h. The aqueous layer was discarded and the ether layer was extracted with 2 N sodium hydroxide solution (5 times with 100 mL). The extract was washed once with 50 mL of ether, then acidified with 6N HCl to pH 2 at 0°. A white precipitate was collected by filtration after the solution had been kept at 0° for 2 h. After air drying, 8.49 g (95%) of the title product was obtained. Melting point was >300° and the purity was confirmed by chromatography.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]4[CH:18]=[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:20]5[C:25]=4[C:24]([NH2:26])=[N:23][CH:22]=[N:21]5)[CH:13]=[CH:14]3)=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC[C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:28][CH2:29][N:30]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:31][CH2:32]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 31 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclohexylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 21 mg (31%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1 H) 7.79-7.83 (m, 2 H) 7.65 (s, 1 H) 7.21 (d, 1 H) 6.60 (s, 1 H) 4.28 (d, 2 H) 3.83 (d, 2 H) 3.36-3.41 (m, 1 H) 2.97 (td, 2 H) 2.87 (s, 6 H) 1.99-2.16 (m, 3 H) 1.58-1.85 (m, 7 H) 1.04-1.27 (m, 5 H). LC-MS [M+H]+=501.6, RT=3.04 min.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:13][CH:14]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:22]1([S:28]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:13][CH:14]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CCCc1ccc(N)cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cn1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
Triethylamine (1 ml) in chloroform (10 ml) was added over 10 minutes to a solution of methyl 4-(5-aminopyrid-2-yl)-butanoate (1.5 g, 8.3 mmole) and benzene sulphonyl chloride (2.2 g, 12 mmole) in chloroform (20 ml). The solution was stirred for 4 hours. Chromatography on silica gel eluted with 5% v/v methanol in chloroform gave the title compound (1.46 g) as a straw coloured oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[S:9])=[CH:6][CH:5]=1)[CH3:2].Cl[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[S:9][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]([OH:16])[N:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: CCOc1ccc(C(N)=S)cc1
Product: CCOc1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-ethoxythiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.