Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:22][C:23]1[CH:30]=[CH:29][C:26](CCl)=[CH:25][CH:24]=1.[C:31]1(C)C=CC=CC=1>[OH-].[Na+]>[CH3:31][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:9]([C:26]2[CH:29]=[CH:30][C:23]([CH3:22])=[CH:24][CH:25]=2)([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:10]#[N:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(CC(C#N)Cc2ccccc2)cc1
Reactant: Cc1ccc(CCl)cc1
Reactant: Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(CC(C#N)(Cc2ccc(C)cc2)c2ccc(C)cc2)cc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
Part b. Preparation of 4-Methyl-(α-(4-methylphenyl)-(α-[(4-methylphenyl)methyl]-benzenepropanenitrile: A flask containing 1.0 g (2 mmol) of sodium cyanide (95%) dissolved in 5 mL of 50% NaOH aqueous solution is charged with 0.3 g silica catalyst, followed by 4-methylbenzyl chloride (6.8 mmol) and 1 mL toluene. The flask is placed in an oil bath and heated at 40° C. with stirring for 48 h, after which 10 mL toluene is added. The organic layer is filtered and the filtrate evaporated to yield 4-methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanenitrile.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:48])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:47][O:46][CH2:45][CH2:44][NH:43][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:48])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COCCNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-{3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K51) (212 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (169 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([NH2:34])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24].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>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:19])[NH:34][C:31]3[NH:30][C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:23]([O:22][CH3:21])=[O:24])[C:33]=4[N:32]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC(=O)c1cccc2[nH]c(NC(=O)c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12
Yield: 9 %

Procedure:
6-(4-Methoxycarbonyl-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (114 mg, 90%) was synthesized according to General Procedure A using 798 mg (2.82 mmol) of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester, 540 mg (2.82 mmol) of intermediate A (2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester), 1.28 g (3.38 mmol) of HBTU, 0.992 mL (5.64 mmol) of DIEA and 15 mL of DMF stirring at room temperature overnight. LCMS: 451 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.542 min, m/z=430.23; 1H NMR (CDCl3) 1.02-1.15 (d, 6H), 1.50 (d, 3H), 2.09-2.21 (m, 6H), 2.32 (m, 1H), 2.78 (m, 1H), 5.65 (m, 1H), 6.98 (d, 2H), 7.15-7.30 (m, 6H), 7.55 (m, 1H), 7.70 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:59])[CH2:36][C:37]1[C:38](=[O:58])[N:39]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][NH2:50])[CH:41]=2>>[CH2:51]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][NH2:50])[CH:41]=2)[CH:46]=[C:37]([CH2:36][C:35]([OH:59])=[O:34])[C:38]1=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: COC(=O)Cc1cc2ccc(OCCN)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1ccc2cc(CC(=O)O)c(=O)n(Cc3ccccc3)c2c1

Procedure:
The title compound is prepared according to the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester trifluoroacetate is replaced with [l-benzyl-7-(2-aminoethoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:20]([CH3:22])C)[NH:5][S:6]([NH:9]C(OCC1C=CC=CC=1)=O)(=[O:8])=[O:7].[CH3:24]O>[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:5][S:6]([NH2:9])(=[O:7])=[O:8])[CH2:20][CH2:22][CH3:24]
Reactant: CO
Reactant: COC(=O)C(NS(=O)(=O)NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of N-(carbobenzyloxyaminosulfonyl)-DL-valine methyl ester (28.5 g) in methanol (200 ml) under nitrogen was cooled to 0° C. and 1.8 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated at 55 psi for 2 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (ethyl acetate/hexane, 1:1) to afford 17.2 g (46%) of N-(aminosulfonyl)-DL-valine methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =isopropyl; R3 =H) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Br:12].C([O-])(O)=O.[Na+:17].[NH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C.O>[Na+:17].[Br:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([NH:18][CH2:19][C:20]([O-:22])=[O:21])[CH:4]=1
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 2,5-dichloro-4-nitrobromobenzene (1.000 g, 3.691 mmol, as prepared above) in DMF (10.0 mL) at 65° C., was added, dropwise, a solution of NaHCO3 (0.316 g, 3.76 mmol) and glycine (0.280 g, 3.73 mmol, Aldrich, used as received) in water (3.8 mL). The resulting suspension was stirred at 65° C. for 65 h. The bright orange suspension was then cooled to room temperature, filtered, washed with water (1.0 mL), and dried under vacuum to afford 0.284 g (98%, based on recovered starting material) of the pure (1H NMR) title compound as an orange powder, m.p. 264-265° C. (decomposed); 1H NMR (DMSO-d6): δ 3.451 (d, 2H, J=3.9 Hz), 7.199 (s, 1H), 8.130 (s, 1H), 8.793 (t, 1H, J=3.6 Hz). It was used as such for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]=[N:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH3:24]I>>[CH3:24][N:13]1[C:12](=[O:15])[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][C:6]=3[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8](=[O:16])[CH:9]=[C:10]2[NH:14]1
Reactant: CI
Reactant: O=c1cc2nnc(=O)n-2c2ccc(Cl)cc2n1-c1ccccc1
Product: CN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled, stirred solution of 3.7 g of 8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 100 ml of dried and distilled 1,2-dimethoxyethane is added, in a portionwise manner, 0.57 g of a 57% dispersion of sodium hydride in mineral oil. After the evolution of hydrogen has ceased (15 min), a solution of 1.79 g (0.014 mole) of methyl iodide is added, the ice bath removed and stirring continued at room temperature for 2 hours, followed by heating under reflux for 1 hour. The solvent is then removed by distillation. The residue is dissolved in 100 ml of chloroform, washed twice with 100 ml portions of water, dried and concentrated. Treatment of the residue with a small amount of ether precipitates the title compound which is filtered off, dried and recrystallized from ethyl acetate.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)nc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)C)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of N-isopropyl-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 204 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (466 mg, 315 μL, 4.09 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo then the residue obtained was dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL). After 3 h at room temperature, the mixture was concentrated in vacuo then triturated with water and ether. The solid was collected by filtration to give N-isopropyl-2-(5-methylpyridin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 74.1 μmol, 36%) as an off white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.40 (s, 1H), 9.92 (s, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=3.2, 1 H), 7.86 (s, 1H), 7.85 (d, J=15.1 Hz, 1H), 7.55 (dd, J=8.5, 2.3 Hz, 1H), 4.16 (m, 1H), 2.26 (s, 3H), 1.25 (d, J=6.5, 6 H); MS (EI/CI) m/z: 311.1 [M+H].
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][C:10](O)([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH3:12].S(=O)(=O)(O)O>CO>[CH2:11]([C:10]([C:3]1[CH:4]=[C:5]([OH:6])[C:7]([C:10]([CH3:9])([CH2:11][CH3:12])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][C:1]=1[OH:2])([CH3:9])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: CCC(C)(O)CCCC(C)C
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(C)(CCCC(C)C)c1cc(O)c(C(C)(CC)CCCC(C)C)cc1O
Temperature: 0 °C
Yield: 33.8 %

Procedure:
55 g of hydroquinone and 71.5 g of 3,7-dimethyloctan-3-ol were dissolved in 100 ml of methanol. Then, 50 ml of concentrated sulfuric acid (36 N) was added dropwise thereto under stirring and cooling so as to maintain the temperature at 40° C. or less. Subsequently, the reaction mixture was maintained at 50° to 55° C. for 4 hours. The resulting reaction mixture was added to ice-water, and extracted with 500 ml benzene. The benzene layer was washed with water and, after drying over anhydrous sodium sulfate, benzene and unreacted 3,7-dimethyloctan-3-ol were distilled off under reduced pressure. The residual oil was chromatographed on silica gel using benzene as a developing solvent. Thus, 29.8 g of 2,5-bis(1-ethyl-1,5-dimethylhexyl)hydroquinone (the same compound as obtained in Synthesis Example 1) was first eluted, and then 15.1 g of 2-(1-ethyl-1,5-dimethylhexyl)hydroquinone was eluted.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.ClC1C=CC=CC=1>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A chlorobenzene solution (45.0 ml) of N-acetylglycine ethyl ester (1.50 g, 10.33 mmol) and N-methylimidazole (1.02 g, 12.40 mmol) was cooled to 0° C., and palmitoyl chloride (2.84 g, 10.33 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 25 minutes at the same temperature, titanium tetrachloride (6.86 mg, 36.16 mmol) and triethylamine (4.18 g, 41.31 mmol) were added thereto. The resulting mixture was stirred for 2 hours at 0° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 2.93 g of the title compound (yield: 74%).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:12]([OH:14])=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C([N+]#[C-])(C)(C)C>O1CCOCC1>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:12](=[O:14])[C@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:3][CH:1]=[O:2])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: O=CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [C-]#[N+]C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC=O
Yield: 55.2 %

Procedure:
A solution of 3.9 g (20 mM) N-formyl-L-phenylalanine, 2.5 g (24 mM) glycine ethyl ester, and 1.7 g (20 mM) tert-butyl isonitrile in 30 ml dioxane was heated at 40°-50°C for 28 hours. It was then evaporated to dryness, and the residue was dissolved in 300 ml methylene chloride. The solution was washed as in the preceding examples, dried, and evaporated. The residue was crystallized from carbon tetrachloride and petroleum ether to produce 3.1 g N-formyl-L-phenylalanyl-glycine ethyl ester (48 percent yield based on the glycine ethyl ester).
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:44][CH:43]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([N:48]5[CH2:49][CH2:50][N:51]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:52][CH2:53]5)=[CH:44][CH:43]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:55])=[O:56])[CH:34]=2)[CH:30]=[N:29]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)cc4)cnc32)cc1
Yield: 71.42 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was mesylated with methane sulfonyl chloride (17 mg, 0.148 mol) using triethylamine (35 μL, 0.247 mmol) in DCM (5 mL) to afford 60 mg (71.42% yield) of the titled compound. MS: m/z=685.1 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5]C1C=C(S([O-])(=O)=O)C=CC=1C.[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)[CH3:31].C1(C)C=CC=CC=1.CCCCCCC>ClCCl>[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH2:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:36][CH:35]=1)[CH3:31]
Reactant: CCCCCCCCCCCC[Si](C)(C)CCCc1cc(S(=O)(=O)[O-])ccc1C
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC[Si](C)(C)CCCNc1ccc(C(=O)OCC)cc1

Procedure:
Under nitrogen, 26.8 g of 4,4-dimethyl-4-sila-n-hexadecyl-p-toluenesulphonate, mixed with 35 g (in excess) of ethyl-p-aminobenzoate is heated at 123° to 128° for 4 hrs. The hot mixture is diluted with about 120 ml. of toluene and allowed to cool. The solution is then further diluted with dichloromethane. The resulting mixture is then washed with about 50 ml. of dilute aqueous sodium hydroxide, then washed with brine, and then dried over anh. sodium sulfate, filtered, and the filtrate concentrated by evaporating to obtain an oily residue. Heptane is added to the residue and upon standing two crops of solids (ethyl-p-aminobenzoate) are removed by filtering. The filtrate is concentrated to give an oily product which is placed on a chromatographic column, eluted with ethyl acetate/dichloromethane (5/95) to obtain several high quality fractions, which upon recrystallization from heptane, cooling to -20° gives refined title product, m.p. (39)--40°-41°. Additional crops of product are obtained from other fractions.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CN1CCCC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCCO
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: CN1CCCC1
Solvent: c1ccncc1
Product: Cc1c(NCCO)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 90 °C
Reaction time: 71 h
Yield: 11.1 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (500 mg), monoethanolamine (410 mg) and N-methylpyrrolidine (170 mg) were added to pyridine (1,500 mg), and the mixture was stirred at 90° C. for 71 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (1.5 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. The resultant residue was subjected to column chromatography (silica gel: 15 g, eluent; chloroform:methanol=50:1→10:1). Ethanol (0.5 ml) was added to a concentrate of a fraction containing a main product, and the mixture was stirred at room temperature. Deposits formed were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (62 mg) as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N)(=[S:28])C.Cl.O1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:24](=[S:28])[NH2:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2nc(C(N)=S)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (665 mg) and thioacetamide (451 mg) in DMF (3.2 ml) was added a 4N hydrogen chloride solution of dioxane (3.2 ml) and the mixture was stirred at 100-105° C. for 2 hours. Water (65 ml) was added to the mixture to yield a precipitate. The precipitate was collected by filtration, subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give a solid. The solid triturated with acetone and collected by filtration to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbothioamide as a solid (417 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:4]=1.[Cl:32]CCl>>[ClH:32].[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([CH:15]3[CH2:16][NH:17][CH2:18]3)=[O:14])=[CH:9][CH:10]=2)[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(NC(=O)C3CN(C(=O)OC(C)(C)C)C3)ccc12
Reactant: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)C3CNC3)ccc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 3-((3-(methylthio)-1-phenyl-1H-indazol-6-yl)carbamoyl)azetidine-1-carboxylate (105 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (4 mL). The resulting solution was bubbled with HCl (gas) and stirred for 30 min at 0° C. The resulting solids were collected by filtration to yield N-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)azetidine-3-carboxamide hydrochloride as a yellow solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][CH3:17])=O.[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].C[O-].[Na+].O>CN(C)C=O.C(O)(=O)C>[C:19]([C:21]1[C:22](=[O:23])[NH:24][C:5]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[O:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1)#[N:20]
Reactant: CCCOc1ccc(F)cc1C(=O)C=CN(C)C
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)cc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A stirred mixture of 3-dimethylamino-1-(5-fluoro-2-propoxyphenyl)-2-propene-1-one (2.46 g), cyanoacetamide (0.93 g), sodium methoxide (from 50% sodium hydride, 1.69 g, and methanol, 0.85 ml) in dimethylformamide (20 ml) was heated under reflux for 7 hours. The mixture was poured into water (150 ml) and acetic acid added to pH 4 to give a crude product. Recrystallization twice from acetonitrile gave a solid, 0.68 g, which was washed with petroleum ether and recrystallized again from acetonitrile to give the pure title compound, 0.15 g, m.p. 242-243° C.