Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl)([O-:16])=[O:15].[Cl-].[NH4+]>C(O)C>[CH3:2][C:3]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1cccc([N+](=O)[O-])c1)C(=O)OCC

Procedure:
In ethanol (45 ml) was dissolved sodium (0.7 g), and diethyl methylmalonate (5.26 ml) and 3-nitrobenzyl chloride (5 g) were added thereto, followed by heating under reflux for 2 hours. The reaction mixture was ice-cooled, an aqueous saturated ammonium chloride was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (9.724 g) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:20]I>CN(C=O)C>[CH3:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC2CCCCO2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An ice-cold yellow solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (7.60 g, 32.17 mmol) in DMF (150 mL), was treated with NaH (0.93 g, 38.63 mmol) in portions over 30 min. The suspension was stirred for 15 min, then methyl iodide (3.0 mL, 48.09 mmol) was added dropwise. The mixture was warmed to rt, stirred for 1 h, then quenched with water and extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered and concentrated to a yellow liquid. The crude product of 2-methoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 6.50 (s, 1H), 6.49 (s, 1H), 5.54-5.52 (m, 1H), 3.87 (s, 1H), 3.88-3.80 (m, 1H), 3.67-3.61 (m, 1H), 2.57 (s, 3H), 2.10-1.95 (m, 1H), 1.95-1.82 (m, 2H), 1.80-1.58 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:18]([O-])=O)[CH:12]=3)[S:7][C:6]=2[CH:5]=1)([O-])=O.NN>C(O)C>[NH2:18][C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([NH2:1])[CH:5]=3)[S:14][C:13]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1S2
Agent: NN
Solvent: CCO
Product: Nc1ccc2c(c1)Sc1ccc(N)cc1S2
Temperature: 25 °C

Procedure:
To a solution of 2,7-dinitrothianthrene (550 mg, 1.8 mmole) in 100 mL of ethanol was added graphite (1.72 g, 144 mmole) and hydrazine (0.56 mL, 18 mmole) with continued stirring and the mixture was refluxed for over night. The reaction mixture was cooled to room temperature and filter through a short column of celite 545. The solvent was then removed and the resulting white solid was dried in vacuo. It was then recrystallized from CHCl3 or used without further purification. mp 185˜186° C. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 2H, J=8.1 Hz), 6.81 (d, 2H, J=2.7 Hz), 6.52 (dd, 2H, J=8.1, 2.7 Hz), 3.68 (bs, 4H). 13C NMR (75 MHz, d6-acetone) δ: 149.5, 139.1, 130.0, 121.9, 114.8, 114.6. HR-MS (ESI): calcd. for C12H10N2S2+Na 269.0178 [(M+Na)+]. found 269.0176.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:16][C:17]([OH:21])([CH3:20])[C:18]#[CH:19].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Pd].[Cu]I.C(N(CC)CC)C>[OH:21][C:17]([CH3:20])([CH3:16])[C:18]#[C:19][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCOc1ccc(I)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
To 142 g (0.45 mole) of 1-(4'-iodophenoxy)-2-diethylaminoethane, 1.2 liters of triethylamine and 37.8 g (0.45 mole) of 3-methyl-1-butin-3-ol are added, under nitrogen, 3.4 g of the palladium complex PdCl2 [P(C6H5)3 ]2 and 1.9 g of copper(I) iodide. After the exothermic reaction has subsided, the reaction mixture is stirred for 15 hours at room temperature, then filtered, and the solution is evaporated in vacuo to dryness. The oily residue crystallises immediately. The product is dried in vacuo at 40° C., affording 123 g (99%) of 1-(3-hydroxy-3-methyl-1-butyn-1-yl)-4-(2-diethylaminoethoxy)benzene with a melting point of 64° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].Br[CH2:22][CH2:23]Br.Cl.O1CCOCC1.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:23][CH2:22]2)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(-c3ccccc3)c(F)c2)CC1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, methyl (2-fluoro-biphenyl-4-yl)-acetate (5.0 g) was dissolved in tetrahydrofuran (50 ml) and then sodium hydride (8.29 g, 60% oily) was added under ice-cooling, after which the resulting mixture was stirred for 30 minutes. Subsequently, N,N-dimethylformamide (100 ml) was added and then 1,2-dibromoethane (17.6 ml) was added, after which the resulting mixture was stirred for 1.5 hours. To the reaction mixture was added 4 N hydrochloric acid-1,4-dioxane solution (60 ml) and the solution was then neutralized with a saturated aqueous ammonium chloride solution and thereafter subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=20/1), to obtain methyl 1-(2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylate (4.28 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20](=O)[CH:21](Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[S:36])=[CH:33][CH:32]=1.ClCCCl.O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[N:37]=[C:35]([C:34]2[CH:33]=[CH:32][C:31]([C:30]([F:40])([F:29])[F:41])=[CH:39][CH:38]=2)[S:36][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a 500ml round-bottom flask equipped with a magnetic stir-bar was mixed ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-2-chloro-3-oxobutanoate (20.4g, 52.88mmoles, 1eq), 4-trifluoromethylthiobenzamide (12.2g, 59.5mmoles, 1.1eq), 1,2-dichloroethane (150ml, 0.44M) and H2O (3ml). This mixture was refluxed for 12hrs. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2(100ml) and washed with sat. NaHCO3. Once the phases were separated, the organic phase washed with water, brine and dried over Na2SO4. This was then filtered, concentrated in vacuo and purified via silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 20.3g (76%) of the titled compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni]>[C:1]1([N:7]2[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCN(c2ccccc2)CC1
Agent: [Ni]
Solvent: CO
Product: NC1CCN(c2ccccc2)CC1
Yield: 77.6 %

Procedure:
A solution of 1-phenyl-piperidin-4-one oxime (0.18 g, 0.95 mmol) in methanol (10 mL) was hydrogenated over Raney nickel (0.15 g) under balloon pressure at ambient temperature for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The semi-solid residue was treated with n-pentane (2×5 mL) and dried to afford 1-phenyl-piperidin-4-ylamine (0.13 g, 78%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)[CH:11]=2)O)=[CH:4][CH:3]=1.O=S(Cl)[Cl:31]>C1C=CC=CC=1>[Cl:31][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([CH:26]([CH3:28])[CH3:27])[CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[CH:13]=[CH:14][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cc(-c2cccc(C(O)c3ccc(Cl)cc3)c2)c2ncccc2c1
Solvent: c1ccccc1
Product: CC(C)c1cc(-c2cccc(C(Cl)c3ccc(Cl)cc3)c2)c2ncccc2c1
Reaction time: 0.75 h

Procedure:
To a solution of (4-chloro-phenyl)-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol from Step 1 (1.0 g, 2.58 mmol) in benzene (7 mL) at 0° C. was added SOCl2 (0.375 mL, 5.2 mmol) dropwise. After 45 min. at 0-10° C., the resulting reaction mixture was filtered through silica gel and celite and then concentrated.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=1)#[CH:7].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[N:31][OH:32])=[CH:25][CH:24]=1.C(N(CC)CC)C>O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[O:32][N:31]=[C:30]([CH2:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)=[CH:28][CH:27]=3)[CH:7]=2)=[CH:13][N:12]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(Cc3ccc(COc4ccccn4)cc3)no2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 5-ethynyl-2-methyl-pyridine (10 mg, 85 μmol) described in Manufacturing Example 190-1-1 were added 4-(pyridin-2-yloxymethyl)-phenyl-acetohydroximoyl chloride (31 mg, 0.11 mmol) described in Manufacturing Example 2-1-5 and triethylamine (18 μL, 0.13 mmol), which was stirred for 2 hours and 30 minutes at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrated was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (14 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:18](=[O:19])[CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:8]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(NC(=O)C(c2ccccc2)c2ccccc2)c(C#N)c1C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
To a stirred solution of 2-Amino-3-cyano-4,5-dimethylthiophene (152 mg; 1.0 mmol) and diphenylacetyl chloride (300 mg; 1.3 mmol) in dry methylene chloride (10 mL) under nitrogen at room temperature was added triethylamine (0.42 mL; 3.0 mmol) dropwise. After 1.5 h, the mixture was washed with 1N HCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with cold 30% ethylacetate/hexanes and filtered to give 162 mg (47%) of N-(3-Cyano-4,5-dimethyl-thiophen-2-yl)-2,2-diphenyl-acetamide as a white solid. ES-HRMS m/e calcd for C21H18N2OS (M+H+) 347.1213, found 347.1217.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>>[CH:25]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=2)[CH2:27][CH2:26]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Yield: 83.3 %

Procedure:
To 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride obtained by using the intermediate 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.86 g) described in Preparation Example 84 and cyclopropylboronic acid (5 g) and by the reaction and treatment in the same manner as in Preparation Example 82 was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (3.62 g).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1>>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: CS(=O)(=O)Nc1ccc(N/C=C2\C(=O)Nc3ccccc32)cc1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one (0.164 g, 1.02 mmol) and N-(4-aminophenyl)-methanesulfonamide [53250-82-1, 0.186 g, 1.0 mmol] to provide a yellow solid (0.249 g). 1H NMR (DMSO) 10.67 (d, 1H); 10.45 (s, 1H); 9.56 (s, 1H); 8.50 (d, 1H); 7.52 (d, 1H); 7.35 (d, 2H); 7.18 (d, 2H); 6.95 (m, 1H); 6.89 (m, 1H); 6.80 (m, 1H); 2.92 (s, 3H), MP>250. APCI (−ve) 328. Analytical Calculated for C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76; S, 9.73. Found: C, 58.40; H, 4.63; N, 12.75; S, 9.63.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:6][C:5]=2[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][NH:39][CH2:40][C:41]1[O:42][C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[C:45]=1[CH3:46].CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH3:38][N:39]([CH2:40][C:41]1[O:42][C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[C:45]=1[CH3:46])[C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]1[CH:8]=[N:9][C:10]2[NH:11][C:2](=[O:1])[CH2:3][CH2:4][C:5]=2[CH:6]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1oc2ccccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)oc2ccccc12
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7.5 L, 5 v) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (1.49 kg, 4.98 mol, 1.0 eq.). To the yellow suspension, HOBT (0.74 kg, 5.48 mol, 1.1 eq.), EDCI (1.15 kg, 5.98 mol, 1.2 eq) and N-methyl-1-(3-methylbenzofuran-2-yl)methanamine (0.96 kg, 5.48 mol, 1.1 eq) were added. During the addition an exotherm was observed and the temperature increased from 20.3° C. to 36.4° C. To the resulting thick suspension was added DIPEA (1.93 kg, 14.94 mol, 3 eq.) and an exotherm was observed to 41.9° C. During the addition the suspension changed to a clear brown solution. The resulting solution was stirred at 38-42° C. After about 45 min a new solid started to form. After stirring for 1.5 h, ˜1 mL of suspension was taken, the progress of the reaction was monitored by HPLC and the results indicated >95% reaction completion. After another 16 hours of stirring at the same temperature, 1H NMR and HPLC analysis indicated the reaction was complete. Half of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask containing a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. The contents of both flasks were allowed to cool to 20-25° C. and each reaction mixture was diluted with H2O (8 L, 5.3 v) over 15 min. Both reaction mixtures showed an exotherm during the water addition to 30-35° C. The resulting suspensions were allowed to stir at 20-25° C. for 3.5 h. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with water (4×1.4 v), heptane (1×1.4 v) and ethyl acetate (3×1 v). The damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 120 h to a constant weight to give 1.67 kg of the title compound as yellow solid. The material was analyzed indicating 98.48 area % HPLC purity with 146 ppm residual Pd.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20](Br)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C:32]([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>C(OCC)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:43][CH2:42][CH2:41][CH2:40][NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To a solution of 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide (1.4 g, 1 eq.) in of N,N-dimethylformamide (10 ml), was added N-Boc-1,3-diaminopropane (2.8 g, 5 eq.). The reaction was stirred at room temperature for 4 h and then heated to 40° C. The mixture was stirred at 40° C. overnight. Water and ethyl acetate were added to the mixture. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography to give tert-butyl 3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (1 g) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH2:3][C:4]([O:6]C)=[O:5].CO[CH:21](OC)[CH2:22][C:23](=O)[CH3:24].C[O-].[Na+].[OH-].[Na+].Cl>O.C(O)C>[CH3:21][C:22]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:24][CH:23]=1
Reactant: COC(CC(C)=O)OC
Reactant: COC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 73.5 %

Procedure:
Methyl 3-oxo-3-(3-(trifluoromethyl)phenylamino)propanoate (62.0 kg, 1 mol eq, limiting reagent) was charged followed by ethanol (310 L, 5 rel vol, 5.3 rel vol). 4,4-dimethoxybutan-2-one (37.6 kg, 1.2 mol eq) was charged followed by an ethanol line rinse (18.6 L, 0.3 rel vol) and the temperature adjusted to 50° C. Sodium methoxide (30% w/w in methanol) (141.0 kg, 3.3 mol eq) charged maintaining the temperature below 55° C. An ethanol line rinse (31.0 L, 0.5 rel vol) was applied. The reaction was stirred until complete as judged by HPLC. Water (105.4 L, 1.7 rel vol) and 29% aqueous sodium hydroxide solution (17.2 kg, 0.52 mol eq) were charged. The reaction was stirred for 60 minutes. Hydrochloric acid (30% w/w) was charged until pH 2 achieved and was then cooled. The product was isolated by filtration, washed five times with water (5×124 L, 5×2 rel vol) and dried under vacuum to constant weight yielding the title compound (50.9 kg, 171.4 mol, 73.5%).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[N+:6]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:6]([C:9]1[CH:10]=[N:11][N:12]([CH2:2][C:3]([OH:5])=[O:4])[CH:13]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Yield: 77.9 %

Procedure:
Bromo-acetic acid (1.23 g, 8.84 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.0 eq) in tetrahydrofuran (50 mL), followed by potassium carbonate (6.15 g, 44.2 mmol, 10.0 eq). The reaction mixture is heated under reflux for 2 hours, solvent is then evaporated, the residue is extracted with ethyl acetate (3×40 mL) and water (40 mL), and the pH is adjusted to 4 by the addition of a 0.1N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (4-nitro-pyrazol-1-yl)-acetic acid as a light yellow solid (589 mg, 78% yield).
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8](C)=[CH:7][CH:6]=1)(O)(=O)=O.CNCCCCC=C.[C:20]([N:27]1C=CN=[CH:28]1)([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:21].C(N(CC)CC)C>CN(C=O)C>[CH2:6]([N:27]([CH3:28])[C:20]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:21])[CH2:7][CH2:8][CH2:10][CH:11]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C=CCCCCNC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCCCCN(C)C(=O)n1ccnc1
Yield: 94 %

Procedure:
Compound 2a (3 g, 1 eq.), carbonyldiimidazole (2.04 g, 1.2 eq.), and triethylamine (1.74 g, 1.2 eq.) in anhydrous DMF (60 mL) were stirred at room temperature for 2 days. The reaction mixture was then washed with water. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 3a as a pale yellow oil in 94% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.33 (quint, J=8.04 Hz, 2H), 1.61 (quint, J=8.04 Hz, 2H), 2.02 (q, J=7.46 Hz, 2H), 3.00 (s, 3H), 3.05 (t, J=7.46 Hz, 2H), 3.35 (t, J=7.46 Hz, 1H), 4.89-4.96 (m, 2H), 7.02 (m, 1H), 7.15 (m, 1H), 7.81 (s, 1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[OH:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=1[OH:19])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc(N)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-(tert-butyl)6chloro-2-hydroxy-3-nitrobenzenesulfonamide (1 .54 g) was reduced with hydrogen and 10% Pd/C (670 mg). The crude product (1.23 g) was carried on to the next step without purification. 1H NMR (MeOD-d4): 8 6.82 (m, 2H), 1.22 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2cccc(C(F)(F)F)c2)ccn1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2cccc(C(F)(F)F)c2)ccn1
Yield: 48.3 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 797 mg (2.00 mmol) of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-(3-trifluoromethylphenyl)-1H-pyrazole obtained in Example 25-4) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 387 mg of the title compound as a white powder. (Yield: 48%)