Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[C:22]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15].C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[C:22]([S:26](=[O:28])(=[O:29])[NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15]
Reactant: O=C(O)c1ccccc1Cl
Reactant: COCCNC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCNC(=O)c1cc(S(=O)(=O)NC(=O)c2ccccc2Cl)c(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
At room temperature, 1.0 g (6.1 mmol) of 2-chlorobenzoic acid are dissolved in 120 ml of tetrahydrofuran and mixed with 1.0 g (6.1 mmol) of N,N′-carbonyldiimidazole. After 30 minutes at room temperature and a further 30 minutes at reflux temperature, 2.0 g (6.1 mmol) of 2,4-dichloro-N-(2-methoxyethyl)-5-sulfamoylbenzamide are added at reflux temperature. After 10 minutes, 0.9 g (6.1 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene are added and the mixture is kept at reflux temperature for a further 3 hours. The mixture is subsequently evaporated to dryness, the residue is taken up in 60 ml of acetonitrile and the solution is poured into 60 ml of water. The solution is acidified to pH 1 using 2N HCI and the precipitate is separated off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C([N:13](CC)CC)C.[C:18]1([CH2:24]N)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:24]([C:4]1[N:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:13])=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: NC(=O)c1ccc(Cl)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
Combined 6-chloronicotinoyl chloride (1.76 g, 10.00 mmol) and DCM (20 mL) and cooled in an ice-bath then triethylamine (2.09 mL, 15.0 mmol) and phenylmethanamine (1.072 g, 10.00 mmol) were added. The reaction was then stirred at room temperature for 3 hours before being diluted in DCM (30 ml), washed with 1N aqueous HCl (50 ml), saturated aqueous sodium bicarbonate (50 ml), brine (50 ml), dried over Na2SO4, and concentrated to give the title compound (2.19 g, 89%) as a light beige solid which was used without further purification. MS m/z [M+H]+ 247.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:29][C:28]4[C:23]3=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.[OH-:47].[K+]>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:29](=[O:44])(=[O:47])[C:28]4[C:23]3=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2c(-c3ccc(N4c5ccccc5Sc5ccccc54)cc3)nc3ccccc32)cc1
Reactant: [OH-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Product: O=S1(=O)c2ccccc2N(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.14 g of 10-[4-(N-phenyl-2-benzimidazolyl)phenyl]phenothiazine in 180 ml of methylene chloride was admixed at room temperature with 7.17 g (28.9 mmol) of 70% m-chloroperbenzoic acid with cooling and stirred at room temperature for 1 h. The solution was admixed with 60 ml of 10% KOH. After the methylene chloride had been removed, the suspension was diluted with 100 ml of hot water. The precipitate was filtered off with suction, washed with hot water and dried at 80° C. under reduced pressure. The crude product (4.82 g) was recrystallized from 48 ml of acetic acid. 3.02 g (46% of theory) of beige microcrystals having an m.p. of 286-288° C. were obtained.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH:23]=1)[CH2:21][OH:22]>C(OCC)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH:23]=1)[CH:21]=[O:22]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])c(C=O)c1
Yield: 83 %

Procedure:
Pyridinium chlorochromate (25.0 g, 116 mmol) was added to methylene chloride (65 ml) while stirring, and then thereto was added 5-methyl-2-nitrobenzyl alcohol (12.9 g, 77.3 mmol). The mixture was stirred at room temperature for 15 hours, and diethyl ether (155 ml) was added. The ether layer was removed by decantation. Diethyl ether (30 ml) was added to the residue, and the ether layer was removed by decantation (3 times). The ether layers were combined, and passed through 15.5 g of silica gel. The obtained solution was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (8:1), whereby 10.6 g of 5-methyl-2-nitrobenzaldehyde was obtained.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.Br[C:22]1[CH:36]=[CH:35][C:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>CN(C)C(=O)C.[Zn].O>[C:31]([Si:28]([O:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:36][CH:35]=1)([CH3:30])[CH3:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Reactant: IC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.2 %

Procedure:
To a mixture of zinc powder (5.52 g, 84.5 mmol) and Celite (1.1 g) in N,N-dimethylacetamide (14 ml) was added dropwise chlorotrimethylsilane (0.930 ml, 7.33 mmol) in 1,2-dibromoethane (0.665 ml, 7.54 mmol) at 0° C. under nitrogen atmosphere. The mixture was warmed to room temperature, and stirred for 20 minutes. 8-Iodo-1,4-dioxa-spiro[4.5]decane (18.1 g, 67.6 mmol) in N,N-dimethylacetamide (34 ml) was then added dropwise at 0° C. The mixture was stirred for 30 minutes at room temperature, and the supernatant solution was added dropwise to the mixture of (4-bromobenzyloxy) (tert-butyl)dimethylsilane (15.7 g, 52.0 mmol), copper iodide(I) (792 mg, 4.16 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II)dichloromethane complex (1.70 g, 2.08 mmol) in N,N-dimethylacetamide (74 ml) at room temperature under nitrogen atmosphere. The mixture was stirred at 80° C. for 5 hours. The mixture was poured into the cold water, and extracted with ethyl acetate. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=92/8) to afford tert-butyl-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)benzyloxy]dimethylsilane as a pale yellow oil (14.0 g, 38.6 mmol, 74%).
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)C.Cl.[NH2:24][OH:25].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[O:25][N:24]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2ccc(Oc3ccccc3)cc2)on1
Yield: 81.7 %

Procedure:
α,β-Dibromo-4-phenoxycinnamic acid ethyl ester (7.0 g), hydroxylamine hydrochloride (1.4 g) and sodium hydroxide (3.3 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (3.4 g, 83%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH:11][C:12]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-:50].[Na+].[Na+]>>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:43]2[CH:44]=[CH:45][C:40]([C:12]([OH:11])([C:16]3[N:17]=[CH:18][N:19]([C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)[CH:13]([CH3:14])[CH3:15])=[CH:41][CH:42]=2)=[CH:9][C:6]=1[C:7]([NH2:8])=[O:50]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C(O)(c1ccc(-c2ccc(F)c(C(N)=O)c2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 5-bromo-2-fluorobenzonitrile (1.04 g), a crude product (3.40 g) of 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid, 2M aqueous sodium carbonate solution (5.20 ml) and tetrakis (triphenylphosphine)palladium(0) (211 mg), the title compound (1.25 g) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][CH:13]([OH:15])[CH3:14].O>N1C=CC=CC=1>[CH:13]([O:15][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:14])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 4-methyl-benzenesulfonyl chloride (3.8 g) was added to a solution of 2-propanol (6.12 ml) in pyridine (6.6 ml). The reaction mixture was stirred at 0° C. for 2 h and then at 20° C. for 16 h. The reaction mixture was poured into water (150 ml) and extracted with dichloromethane. The combined organic phases were washed with 3M aqueous HCl and sat. NaHCO3. After drying (MgSO4) and concentrating in vacuo, the title product was obtained as a pale yellow oil. Yield: 2.89 g. MS-ESI: [M+H]+=215.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:38](O)(=[O:41])[CH2:39][CH3:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1(/[CH:11]=[C:12]2/[CH:13]([O:22][C:38](=[O:41])[CH2:39][CH3:40])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Reactant: CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of Compound 20b (10.0 mg, 3.50×10−2 mmol), DCC (7.2 mg, 3.50×10−2 mmol), and DMAP (8.5 mg, 6.99×10−2 mmol) in dry CH2Cl2 (4 mL) cooled in an ice-water bath was added propionic acid (3.8 mg, 5.24×10−2 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 8.3 mg (69 percent) of Compound 36: pale yellow oil; Rf=0.43 (20 percent EtOAc in hexane); IR (neat) 2958, 2235, 1726, 1189, 1067 cm−1; 1H NMR (300 MHz, CDCl3) δ8.31 (d, J=7.23 Hz, 1H), 8.01 (d, J=7.56 Hz, 1H), 7.83 (t, J=8.01 Hz, 2H), 7.54-7.46 (m, 3H), 7.45 (s, 1H), 6.24 (s, 1H), 2.52-2.24 (m, 6H), 1.96-1.67 (m, 4H), 1.20 (t, J=7.56 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ174.5, 134.2, 133.0, 132.7, 132.2, 129.7, 129.3, 127.0, 127.0, 126.5, 126.0, 124.2, 123.8, 103.3, 93.6, 81.0, 79.5, 69.4, 28.5, 28.3, 28.2, 22.6, 21.5, 9.8; MS (+CI) m/z (relative intensity) 342 (M+, 5), 269 (100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:26]=1[CH2:27][NH:28][C:29]1[C:30]([NH2:36])=[CH:31][CH:32]=[C:33]([F:35])[CH:34]=1>C(#N)C.[Cl-].[Na+].O>[CH3:23][O:24][C:25]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:26]=1[CH2:27][NH:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: COc1ccc(CNc2cc(F)ccc2N)c(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CNc2cc(F)ccc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Temperature: 65 °C
Yield: 37.7 %

Procedure:
A mixture of (R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine (32 mg), N1-(2,4-dimethoxybenzyl)-5-fluorobenzene-1,2-diamine (28 mg) and KCO3 (41 mg) in ACN was heated at 65° C. for 3 hr, cooled to RT, diluted with brine and extracted with EtOAc (2×). The combined organics were evaporated, and purified by column chromatography (eluted with 30% EtOAc/Hex) to yield the titled product (21 mg). 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.6 (br d, 1H), 7.2-6.8 (m, 6H), 6.5-6.3 (m, 4H), 4.4-4.2 (m, 4H), 3.8 (s, 6H), 2.3-2.2 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.Cl.ClC1C=CN=CC=1.ClCCl>O1CCOCC1>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1c(N)cccc1Cl
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1c(Cl)cccc1-n1cccc1
Yield: 87.8 %

Procedure:
A solution of 2-amino-6-chloro-benzonitrile (30 g), 2,5-dimethoxytetrahydrofuran (30 g) and 4-chloropyridine hydrochloride (17 g) in dioxane was heated to 70° C. for 2.5 h. The solvent was evaproated in vacuo. Dichloromethane was then added to the residue and the spent 4-chloropyridine hydrochloride filtered off. The dichloromethane was evaporated in vacuo to give 1-(3′chloro-2′-cyanophenyl)pyrrole (35 g)
Reaction SMILES: B(Cl)(Cl)Cl.ClCCl.COC1C(CC2C=CC=CC=2)=NC=CN=1.[CH3:23][O:24][C:25]1[C@@H:26]([CH:45]([CH3:47])[CH3:46])[N:27]=[C:28]([O:43][CH3:44])[C@H:29]([CH2:31][C:32]2[CH:37]=[C:36]([CH:38]=[O:39])[C:35]([O:40]C)=[CH:34][C:33]=2[I:42])[N:30]=1>>[CH3:23][O:24][C:25]1[C@@H:26]([CH:45]([CH3:47])[CH3:46])[N:27]=[C:28]([O:43][CH3:44])[C@H:29]([CH2:31][C:32]2[CH:37]=[C:36]([CH:38]=[O:39])[C:35]([OH:40])=[CH:34][C:33]=2[I:42])[N:30]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(C=O)c(OC)cc1I
Agent: COc1nccnc1Cc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(C=O)c(O)cc1I
Temperature: 0 °C
Yield: 31.1 %

Procedure:
A 1M solution of BCl3 in dichloromethane (11.8 mL, 11.8 mmol) was added drop wise to a solution of the methoxybenzyl pyrazine analog 22 (134.80 mg, 0.30 mmol) and stirred at 0° C. under argon. The solution changed in color from the initial orange to light brown and finally to greenish brown. The reaction mixture was stirred for one hour at 0° C. and warmed slowly to room temperature over night. The reaction mixture was poured into ice-water and stirred for 15 min. The mixture was extracted with dichloromethane and the organic phase was dried with Na2SO4. Evaporation of the solvent gave a yellow brown oil which upon flash chromatographic purification provided pure 2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2′-iodo-4′-hydroxy-5′-formylbenzyl)-(2R,5S)-pyrazine (24) (41.40 mg, 32%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[Br:13][C:14]1[CH:21]=[CH:20]C(CO)=[CH:16][CH:15]=1.N1CC=CC1>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:2]([CH2:1][N:3]2[CH2:6][CH:7]=[CH:5][CH2:4]2)=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccc(Br)cc1
Agent: C1=CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1ccc(CN2CC=CC2)cc1
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
Triethylamine (0.135 ml, 0.958 mmol) and 60 μl (0.760 mmol) of methanesulphonyl chloride were added to a solution of 70.5 mg (0.377 mmol) of 4-bromobenzylalcohol in dichloromethane (2 ml) under ice cooling, and the mixture was stirred for 1.5 hr. The reaction solution was diluted with 10 ml of ethyl acetate, and the diluted solution was washed with an 8% aqueous sodium hydrogencarbonate solution. The aqueous layer was extracted twice with 3 ml of ethyl acetate. The organic layers were combined, were washed with 25% brine, and were dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under the reduced pressure. The residue was dissolved in 1.8 ml of N,N-dimethylformamide, 87 μl of 2,5-dihydro-1H-pyrrole (70% purity, 0.793 mmol) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was diluted with 10 ml of ethyl acetate, and the diluted solution was washed thrice with 5 ml of water. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined, were washed with 25% brine, and were dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform:methanol=18:1) to give 63.8 mg (yield 71%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]1[N:16]=[N:17][C:18]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=12.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:8][C@H:9]1[N:10]([C:15]2[N:16]=[N:17][C:18]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=23)[CH2:11][CH2:12][N:13]([C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:42])[CH2:14]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2ccncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2ccncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To triethylamine (0.315 ml, 2.26 mmol) and (R)-4-(2-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 21 (0.352 g, 0.943 mmol), in CH2Cl2 (3.1 ml) was added benzoyl chloride (0.120 ml, 1.04 mmol). The reaction was stirred at 25° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (3×15 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 20 to 90% EtOAc in CH2Cl2) afforded 347 mg of desired product (R)-(3-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)(phenyl)methanone 22 (77% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.57 (s, 1H) 8.96 (d, J=6.1 Hz, 1H) 7.81-7.97 (m, 4H) 7.77 (d, J=5.5 Hz, 1H) 7.47 (s, 5H) 3.30-4.82 (m, 7H) 1.29-1.53 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH3:18])=[C:4]([C:15]#[N:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2Cl)=[CH:6][CH:7]=1.[ClH:19].[CH3:20][C:21](O)=O>O>[Cl:19][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH3:21])[N:17]([CH3:18])[C:3]=2[C:4]=1[C:15]#[N:16]
Reactant: CNc1c(N)ccc(-c2ccccc2Cl)c1C#N
Reactant: Cl
Reactant: CC(=O)O
Solvent: O
Product: Cc1nc2ccc(-c3ccccc3Cl)c(C#N)c2n1C

Procedure:
A solution of 4-Amino-2′-chloro-3-methylamino-biphenyl-2-carbonitrile (intermediate in the preparation of Example 8B) in AcOH (10 mL) and HCl (1 mL) was refluxed for 1 hour. The residue was diluted with water and extracted with AcOEt, and then washed with saturated NaHCO3 aqueous solution. The organics were dried over MgSO4 and the solvent removed in vacuo to give crude product, which used for the next step without further purification. MS (ES) [m+H] calc'd for C16H12ClN3, 281.1; found, 281.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]=[O:23])[CH3:20].CCOC(C)=O>C1COCC1.Cl>[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]([C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1)[OH:23])[CH3:20]
Reactant: COc1ccc(-n2cccn2)cc1
Reactant: CCC(C=O)CC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)C(O)c1ccnn1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a chilled reaction vessel at −78° C. containing 1-(4-methoxyphenyl)-1H-pyrazole (Tetrahedron Lett. 39(19), 2941-2944, (1998)) (1.096 g, 6.3 mmol) in THF (40 mL) was added a solution of n-butyllithium (2.5M in hexanes, 2.5 mL, 6.4 mmol) dropwise and the mixture was stirred for 1 h. 2-Ethylbutyraldehyde (0.93 mL, 7.5 mmol) was then added dropwise and, after 15 min, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with 0.1N HCl and stirred for 15 min, then poured into a separatory funnel containing EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to yield a pure oil in 68% yield.
Reaction SMILES: CCOCC.C1COCC1.[F:11][C:12]([F:20])([F:19])[C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[CH3:16].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>[Cu]I.CCOCC>[F:11][C:12]([F:20])([F:19])[C:13](=[O:18])[CH2:14][C:15]([C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)([CH3:17])[CH3:16]
Reactant: CC(C)=CC(=O)C(F)(F)F
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CC(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 M ether/THF solution of 1,1,1-trifluoro-4-methylpent-3-en-2-one was added 3.8 g of copper (I) iodide and 10 mL of a 2 M ether solution of 4-fluorophenylmagnesium bromide at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl, and extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to yield 460 mg of 1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one.