Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[Na+].C1(C)C=CC=CC=1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:30]>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C:24]1[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=1[N:15]([CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNc1ccccc1
Reactant: Cc1ccc(C)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C)c(N(C)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 94.7 %

Procedure:
An oven-dried test tube was purged with argon and charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1.0 mol % Pd), 2 [Example 1] (6.0 mg, 0.015 mmol, 1.5 mol %), and NaOt-Bu (135 mg, 1.40 mmol). The test tube was fitted with a septum, then toluene (2.0 mL), N-methylaniline (135 μL, 1.25 mmol), and 2-chloro-p-xylene (135 μL, 1.01 mmol) were added. The mixture was stirred at 80° C. for 13 h, then cooled to room temperature, diluted with ether (20 mL), filtered and concentrated. The crude material was purified by flash chromatography on silica gel to afford 202 mg (95%) of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH3:2]
Reactant: CCOCCN
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Product: CCOCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and 2-ethoxyethylamine (0.37 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/3) was performed to give N-(2-ethoxyethyl)sulfuric diamide (Compound GH) (296 mg, yield: 42%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Na+].CN(C)[CH:27]=[O:28]>C(Cl)Cl.C1CCCCC1>[C:6]1([C:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14][C:13]=2[CH:27]=[O:28])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: C1=C(c2ccccc2)c2ccccc2OC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=CC1=C(c2ccccc2)c2ccccc2OC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
71 ml (0.773 mol) of phosphorus oxychloride are added dropwise to 300 ml of dimethylformamide maintained at 0° C. The reaction mixture is left stirring for 20 minutes at a temperature of between 0 and 5° C. A solution of 16.1 g (77.3 mmol) of 4-phenyl-2H-1-benzopyran in 22.5 ml of dimethylformamide is then added to the reaction mixture. The reaction mixture is allowed to return to room temperature and is then brought to 60° C. for 7 hours. The reaction mixture is then poured into a mixture of ice and water which is neutralized with NaOH. The organic phase is extracted with ethyl acetate and then the organic phase is washed 3 times with water. After drying over anhydrous sodium sulphate, the organic phase is concentrated under reduced pressure. A pasty solid is thus obtained, which solid, after silica column chromatography using a 1/1 methylene chloride/cyclohexane mixture as eluant, results in 15.3 g of the title compound in the form of a yellow solid, the melting point of which is 82-83° C. (yield=83%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[CH3:7][N:6]1[C:2]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cn1ncc([N+](=O)[O-])c1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 57 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 4-aminopiperidine-1-carboxylate gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)piperidine-1-carboxylate as a pale yellow solid (0.23 g, 57%). 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 6.40 (d, J=9.8 Hz, 1H), 4.06-3.95 (m, 2H), 3.81 (s, 3H), 3.70-3.59 (m, 1H), 3.05-2.93 (m, 2H), 2.00-1.92 (m, 2H), 1.60-1.50 (m, 2H), 1.49 (s, 9H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][O:10][N:11]1[C:15](=[O:16])[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:21])[CH3:9]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(=O)CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of ethyl 4-bromo-n-butyrate (1.2 g, 6.13 mmol) in dimethylformamide (9 ml), N-hydroxyphthalimide (1.5 g, 9.19 mmol) and Hunig base (N,N-diisopropylethylamine, 2.13 mL) were added at room temperature, and the mixture was stirred at 80° C. overnight. The reaction solution was poured into saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate=2:1) to give 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester (1.47 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:20])[CH:18]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[CH:16][CH:17]([CH3:20])[CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1
Reactant: CC(C)C=O
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)C(=CC(C)C)C(=O)c1ccc(F)cc1

Procedure:
A solution of 210 g (1 mol) of ethyl 4-fluorobenzoylacetate and 144 g (2 mol) of 2-methylpropanal are stirred overnight at 50° C. with 7 ml of piperidine and 5 ml of acetic acid in 100 ml of isopropanol. After reaction is complete, the batch is concentrated at about 15 Torr and the crude product (270 g, about 85%) is reacted without further purification.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nnc(C)s2)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nnc(Sc2cnc(N)s2)s1
Yield: 30.5 %

Procedure:
A mixture of 2-acetylamino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (3.3 g) in a mixture of ethanol (70 ml), tetrahydrofuran (50 ml) and aqueous 6N-hydrochloric acid (200 ml) was refluxed for 6.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The organic solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(2-methyl-1,3,4-thiadiazol-5-ylthio)thiazole (0.85 g, Yield: 58.2%). mp: 203°-205° C. (dec.)
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:30])[CH:21]=1.CC([O-])=O.[K+].Br[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]2[S:45][C:46]3[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:47]=3[N:48]=2)=[C:39]([F:54])[CH:38]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:54][C:39]1[CH:38]=[C:37]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:30])[CH:21]=2)[CH:42]=[CH:41][C:40]=1[NH:43][C:44]1[S:45][C:46]2[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:47]=2[N:48]=1
Reactant: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1C
Temperature: 80 °C

Procedure:
As shown in Reaction Scheme 6, a mixture of bis(pinacolato)diboron (0.55 g, 2.2 mmol), methyl 4-bromo-2-methylbenzoate (0.50 g, 2.2 mmol), palladium(II) acetate (0.01 g, 0.07 mmol), and KOAc (0.64 g, 6.6 mmol) in DMF (7.5 mL) was degassed with argon for 30 min at rt. The mixture was then heated at 80° C. for 4 h. After cooling the mixture to rt, N-(4-bromo-2-fluorophenyl)-6-fluoro-1,3-benzothiazol-2-amine (0.74 g, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.07 mmol), and saturated aqueous NaHCO3 (5 mL) were added. The mixture was heated at 85° C. overnight. The mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (20% EtOAc in hexanes). This yielded 0.345 g (39%) of the title compound. LC/MS m/z 411.3 (MH+; retention time 4.15 min. 1H NMR (400 MHz, CD2Cl2) 2.62 (s, 3H), 3.90 (s, 3H), 7.10 (t, 1H), 7.39-7.53 (m, 5H), 7.62-7.70 (m, 1H), 7.99 (d, 1H), 8.58 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
Stir a mixture of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzo-nitrile (0.50 mmol) in 70% H2SO4 (10 ml) at 110° C. for 1 hour. Cool to room temperature, neutralize with NaOH, extract with EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (3:2 hexanes/EtOAc) to give 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)O)=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: COc1ccc(C(c2ccc(Cl)cc2)c2c[nH]c3c(CSC)cccc23)cc1

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.05 g (4.23 mmol) of the compound from Example 175A in analogy to the synthesis of the compound from Example 278. 262 mg (15% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(=O)nc(-c3cccc(C(=O)O)n3)sc12
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2c(=O)nc(-c3cccc(C(=O)NCCCCCCNC(=O)OC(C)(C)C)n3)sc12
Temperature: 80 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
6-(8-Methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (1.5 g, 5.0 mmol) was dissolved in DMF (15 ml), and N-(tert-butoxycarbonyl)-1,6-diaminohexane (2.1 g, 10.0 mmol), WSC (3.0 g, 15.5 mmol) and HOBt (2.0 g, 14.9 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 10 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (4:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.1 g, 45%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:11][OH:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[CH3:20][S:21]([O:12][CH2:11][C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([F:8])([F:9])[F:10])(=[O:23])=[O:22]
Reactant: OCc1sc(Cl)nc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OCc1sc(Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 34.7 g (0.161 mol) of the compound of Example 4 in 150 ml of toluene there was added over a 30 minute period, 18.2 g (0.18 mol) of triethylamine. To this mixture was added 20.5 g (0.18 mol) of methanesulfonyl chloride. The reaction mixture was stirred at room temperature for 2 hours and was allowed to stand in the refrigerator for 4 days. The insoluble salt was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether and the ether solution was washed with water, dried over MgSO4 and concentrated under reduced pressure to give 43.8 g (92%) of crude [2-chloro-4-(trifluoromethyl)thiazol-5-yl]methyl methanesulfonate. A 5.5 g portion of the crude material was dissolved in 50 ml of acetone. To this solution was added 2 g (0.0169 mol) of potassium xanthogenate. The reaction mixture was stirred for 2 hours at room temperature and filtered. The acetone filtrate was concentrated to give 6.9 g of oil which was chromatographed on silica gel using ether petroleum ether (1:9 v/v) as eluant. The earlier fraction was 4.1 g (69.9%) of S-[2-chloro-4-(trifluoromethyl)-5-thiazolyl]methyl O-ethyl carbonodithioate; nD25 1.5497-1.5517.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(C)c1C(=O)O
Reaction time: 20 h

Procedure:
A mixture of ethyl 6-methyl-2-methoxybenzoate (642.0 g, 3.3 mol), water (2.5 l), ethanol (4.0 l) and sodium hydroxide (270 g, 6.6 mol) is heated under reflux with stirring for 20 hours. Subsequently, ethanol is distilled off and the reaction mixture is diluted with water, acidified with concentrated hydrochloric acid. The solid material is collected by vacuum filtration, washed with water and dried yielding off-white crystals, 460.0 g (83.9%).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([Cl:11])=[CH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([N:5]1[C:10]([Cl:11])=[CH:9][C:8](=[O:12])[N:7]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(Cl)cc(=O)[nH]c1=O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(Cl)cc(=O)n(Cc2ccccc2F)c1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
The crude product from step 1 (3.0 g, 14.8 mmol) was dissolved in N,N-dimethylformamide (30 mL) and treated with potassium carbonate (4.08 g, 29.6 mmol) and 2-fluorobenzyl bromide (Aldrich) (1.8 ml, 14.8 mmol). The reaction was stirred at 23° C. for 2 hours and then at 48° C. for 3 hours. The reaction was mixed with diluted brine and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were then washed with diluted aqueous sodium chloride solution and brine, dried (sodium sulfate) and concentrated to dryness to afford 1-butyl-6-chloro-3-(2-fluorobenzyl)-1H-pyrimidine-2,4-dione as a yellow oil (4.07 g, 89%). 1H NMR (CDCl3, 200 MHz) δH 0.96 (t, 3H), 1.25–1.48 (m, 2H), 1.58–1.76 (m, 2H), 4.03 (t, 2H), 5.20 (s, 2H), 5.97 (s, 1H), 6.97–7.10 (m, 2H), 7.17–7.30 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.[C:30]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)(=[O:32])[CH3:31]>C1COCC1>[OH:32][C:30]([C:17]1[S:13][C:14]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=2)=[N:15][CH:16]=1)([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH3:31]
Reactant: CC(=O)c1ccncc1
Reactant: N#Cc1ccc(-c2nccs2)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(C#N)c(C(F)(F)F)c2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of diisopropylamine (0.08 mL, 0.59 mmol) in THF (7 mL) was cooled to −78° C., and 1.6M n-BuLi in hexanes (0.49 mL, 0.78 mmol) added. The reaction mixture was allowed to stir at 0° C. for 30 min, again cooled to −78° C. and a solution of 4-(thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (0.1 g, 0.39 mmol) in THF (2 mL) added dropwise at −78° C. for 30 min. 4-Acetyl pyridine (0.048 mL, 0.43 mmol) in THF (2 mL) at −78° C. was then slowly added, the reaction was stirred for 1 hour and quenched with saturated ammonium chloride (2 mL), and water (10 mL). The reaction mixture was extracted with ethyl acetate (20 mL), the organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain crude product. The crude product was product purified by Prep TLC (5% methanol in dichloromethane) to give 4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (30 mg, 21%) as pale yellow solid in 99.1% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, 2H), 8.36-8.32 (m, 2H), 8.24 (d, 1H), 8.03 (s, 1H), 7.52-7.51 (m, 2H), 6.81 (s, 1H), 1.97 (s, 3H). LC-MS m/z calculated for [M+H]+ 376.07, found 375.7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH2:22][NH2:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1N1CCCCC1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3N3CCCCC3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-piperidin-1-yl-benzylamine (122 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (251 mg, 2.61 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-piperidin-1-yl-benzylamino)-2H-phthalazin-1-one: 62 mg (29.0%): m/z (M+H)=369. 1H-NMR (DMSO-d6) δ: 12.35 (s, 1H), 7.90 (d, 1H), 7.77 (m, 1H), 7.32 (dd, 1H), 7.15 (m, 3H), 6.96 (m, 1H) 6.62 (s, 1H), 4.41 (d, 2H), 1.71 (m, 4H), 1.55 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:19][NH:20][CH3:21])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:20]([CH3:21])[O:19][CH2:17][CH3:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCONC
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)OCC)n1
Yield: 93 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-ethyl-N-methyl-hydroxylamine hydrochloride as described in Example 13, to yield XCVI in 93% yield. ESI-MS (m/z) 269 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[I:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:20])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(I)cc32)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (3 g, 7.87 mmol)) in DCM (40 mL), was added thionyl chloride (6.85 ml, 94.46 mmol) followed by DMF (catalytic, 3 drops). The mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The crude acid chloride (assumed 7.87 mmol) was suspended in more DCM (30 mL) and morpholine (1.37 ml, 15.74 mmol) was added at 0 dropwise. The reaction was stirred at RT overnight. The reaction mixture was diluted with more DCM (25 ml) and 2M Na2CO3 added (35 ml). A pale brown precipitate was collected by filtration and washed with more DCM. The precipitate was slurried in water:acetonitrile (3:1, 10 ml) and the off-white solid collected by filtration and washed with more water:acetonitrile (3:1, 2×1 ml). The solid was then dried under vacuum to give the title compound (2.72 g, LC-MS purity=86%): 1H NMR (500 MHz, DMSO) delta 3.41-3.76 (6H, m), 3.85-3.97 (2H, m), 7.05 (1H, d, J=5.5 Hz), 7.18 (2H, s), 7.74 (1H, dd, J=8.4, 1.1 Hz), 7.80 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=5.5 Hz), 9.33 (1H, s); LC-MS: m/z=+450.90 (M+H)+.