Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]1[CH2:20][CH2:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[CH2:13]1)(=[O:10])=[O:9].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:24]([CH2:23][CH2:22][C:21]([C:17]1[S:16][C:15]2[CH2:19][CH2:20][CH:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])(=[O:9])=[O:10])[CH2:13][C:14]=2[CH:18]=1)=[O:27])([OH:26])=[O:25]
Reactant: Cc1ccccc1S(=O)(=O)NC1CCc2sccc2C1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccccc1S(=O)(=O)NC1CCc2sc(C(=O)CCC(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.3 %

Procedure:
To 2.25 g of 5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene and 1.61 g of succinic anhydride suspended in 25 ml of dichloroethane was added 4.39 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. After the resulting organic layer was washed and dried, the solvent was removed to obtain 3.47 g of 2-(3-carboxypropionyl)-5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[N:12]=[C:11]([CH3:25])[N:10]=2)=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C.C(Cl)(Cl)Cl>ClCCCl>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:13]2[N:12]=[C:11]([CH3:25])[N:10]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)[CH:14]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc(Nc3ccc(N)cc3)nc(C)n2)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(-c2cc(Nc3ccc(NS(C)(=O)=O)cc3)nc(C)n2)cc1OC

Procedure:
To a solution of 4-(4-aminophenylamino)-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (1.0 g) in 1,2-dichloroethane (20 ml) were added methanesulfonyl chloride (0.28 ml) and triethylamine (0.83 ml) and the mixture was refluxed for 3 hours. After cooled, chloroform (50 ml) was added thereto, and washed with water. The solution was dried over magnesium sulfate, evaporated, and chromatographed on silica gel eluting with chloroform to give 6-(3,4-dimethoxyphenyl)-4-(4-mesylaminophenylamino)-2-methylpyrimidine (0.45 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=C1CCCN1c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCCC3=O)cc2F)cn1

Procedure:
Title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)pyrrolidin-2-one. MS (ESI): mass calcd. for C20H17FN4O, 348.14; m/z found, 349.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.54-7.14 (m, 6H), 6.72 (s, 2H), 3.44 (t, J=6.7, 2H), 2.26 (t, J=7.9, 2H), 1.97-1.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (109)(100 mg, 0.27 mmol) was coupled to 3-fluoro-phenylboronic acid (41 mg, 0.29 mmol) using Method E. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:19]>C(Cl)Cl>[CH2:18]([O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH3:19]
Reactant: Cc1ccc(N)cc1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-Amino-4-methylbenzene (1.821 g, 17.0 mmol) was dissolved in DCM (25 mL). N,N-Diisopropylethylamine (3.1 mL, 18.1 mmol) and 4-ethoxy-benzenesulfonyl chloride (2.50 g, 11.3 mmol) were added successively. The reaction mixture was stirred at room temperature overnight and then washed with 10% HCl (2×20 mL) and brine (1×20 mL). Organic phase was dried with sodium sulfate before filtering and removal of solvent. The desired product, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (3.087 g, 94%), was obtained as a colorless solid, in 99.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[F:11][C:12]([F:18])([CH:15]([F:17])[F:16])[CH2:13][OH:14].[Br:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[C:22]([F:27])[CH:21]=1>O>[Br:19][C:20]1[CH:25]=[C:24]([O:14][CH2:13][C:12]([F:18])([F:11])[CH:15]([F:17])[F:16])[CH:23]=[C:22]([F:27])[CH:21]=1
Reactant: OCC(F)(F)C(F)F
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Br)cc(OCC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a 50 mL flask flushed with nitrogen, equipped with a stir bar was added potassium tertbutoxide (1.1 g, 10 mmol, 95%). DMSO was added (10 mL) followed by addition of a solution of 2,2,3,3-tetrafluoropropan-1-ol (0.95 mL, 11 mmol) via syringe. After 5 min, 1-bromo-3,5-difluorobenzene (1.1 mL, 9.5 mmol) was added and the reaction mixture stirred at room temperature for 18 h. Water was added (100 mL), and the aqueous phase extracted with ether (2×100 mL). The organic portion was then washed successively with water (2×100 mL) and saturated NaCl solution (2×100 mL), dried over Na2SO4, decanted and concentrated under reduced pressure yielding a crude yellow liquid which was purified by distillation under reduced pressure at 140° C. yielding the 1-Bromo-3-fluoro-5-(2,2,3,3-tetrafluoropropoxy)benzene as a colorless oil (1.6 g, 54% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11](Cl)=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:11]([C:7]2[CH:8]=[N:9][O:10][C:6]=2[CH3:5])=[O:12])=[CH:17][CH:16]=1
Reactant: Clc1ccccc1
Reactant: Cc1oncc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1oncc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of aluminium chloride (16 g) and 5-methylisoxazole-4-carbonyl chloride (5.0 g) in dry chlorobenzene (50 ml) was stirred in an atmosphere of nitrogen for 16 hours. The mixture was heated to 80° C. for 1.5 hours. The cooled mixture was quenched with excess ice and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous magnesia sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with a mixture of ethyl acetate and cyclohexane (1:20) to give 4-(4-chlorobenzoyl)-5-methylisoxazole (compound 9, 5.2 g) as a yellow solid mp 65°-66° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[N+:17]([C:20]1[CH:21]=[C:22]([NH:26][NH2:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].Cl.C(O)C>O>[N+:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[N:27]2)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (432.3 mg, 2 mmol), 3-nitrophenylhydrazine hydrochloride (379.2 mg, 2 mmol), concentrated hydrochloric acid (0.2 mL) and ethanol (8 mL) was reflued for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→3:1) to give the title compound (631.5 mg, 94.7%) as a light yellowish white powder.
Reaction SMILES: [CH3:1][Mg+].[Br-].CC[O:6][CH2:7][CH3:8].C(OC([C:14]1[N:15]([CH3:25])[C:16]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][N:18]=1)=O)C.O>C1COCC1>[CH3:25][N:15]1[C:16]([C:19]#[C:20][Si:21]([CH3:22])([CH3:24])[CH3:23])=[CH:17][N:18]=[C:14]1[C:7]([OH:6])([CH3:8])[CH3:1]
Reactant: CCOCC
Reactant: C[Mg+]
Reactant: CCOC(=O)c1ncc(C#C[Si](C)(C)C)n1C
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C#C[Si](C)(C)C)cnc1C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.67 mL of 3M MeMgBr in ether (2.0 mmol) was added to a stirring 0° C. solution of 200 mg of 1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethyl ester (0.80 mmol) in 5 mL of THF over 15 min. The mixture was allowed to warm to rt and stirred overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine and dried with MgSO4, filtered, concentrated and chromatographed (10-100 EtOAc in hexanes) to give 2-(1-methyl-5-trimethylsilanylethynyl-1H-imidazol-2-yl)-propan-2-ol as a yellow oil (110 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH2:37][N:38]6[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzaldehyde [Intermediate AJ] (0.11 g, 0.214 mmol) in CH2Cl2 (3 mL) was added 1-methylpiperazine (40 μL, 0.40 mmol) and sodium triacetoxyborohydride (68 mg, 0.32 mmol). The reaction mixture was stirred for 1 hr at room temperature, after which it was partitioned between CH2Cl2 and 1 M NaOH. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in 3:2 MeOH:acetone (5 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to provide a residue that was subjected to preparatory HPLC to yield the title compound. HPLC retention time: 1.63 minutes; MS ESI (m/z) 422.4 (M+1)+, calc. 421.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.C(O)CCC.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>O>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1)[CH3:27]
Reactant: CCOC(=O)CN
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Agent: Cl
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and butanol (3 ml) was added glycine ethyl ester hydrochloride (152 mg, 1.10 mmol) at room temperature. After the mixture was stirred for 4 hours at 90° C., the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by silica gel chromatography (3% MeOH/CHCl3) to give the object compound (98.3 mg, 72.1%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[C:7]([CH3:14])=[CH:6][CH:5]=1.CO>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(Cl)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A solution of aqueous 1N NaOH (10 ml) is added to a stirred solution of methyl 6-chloro-3-methyl-pyridine-2-carboxylate (1.0 g, 5.39 mmoles) in THF:MeOH (10 ml:2 ml). The mixture is stirred at room temperature for 3 hours. The organic solvent is removed under reduced pressure and the semi-solid is dissolved in water and acidified to pH 1-2 with aqueous 1N HCl. The resulting precipitate is filtered, washed with water, and dried at 40° C. in a vacuum oven for 12 hours to give the title compound as a white solid (780 mg, 84%). Mass spectrum (m/z): 172.0 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:23]([O:25][C:26](=[O:45])[C:27](=[CH2:44])[CH2:28][CH:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:24].CCCCCC>C1COCC1>[CH2:23]([O:25][C:26](=[O:45])[CH:27]([CH2:44][S:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:28][CH:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH3:24]
Reactant: C=C(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Triphenylmethanethiol (20.58 g, 74.5 mmol) in dry THF (40 mL) was first added drop wise at 0° C. to a suspension of sodium hydride (3.00 g, 74.5 mmol) in dry THF (60 mL). After the addition was complete, the mixture was stirred for 15 min at 0° C. followed by 45 minutes at room temperature. To the resulting suspension, the compound of example 32 (20.58 g, 62.4 mmol) dissolved in dry THF (40 ml) was added drop wise at 0° C. The mixture was then stirred at room temperature until complete consumption of the starting material (2 hours as confirmed by TLC: 97% hexane-3% ethyl acetate). The crude product was isolated as in example 32 and was then purified by flash chromatography (SiO2, 5% hexane-95% ethyl acetate) to afford 28.28 g (75.5% yield) of the desired compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 15H), 4.17 (q, 2H), 3.03 (m, 1H), 2.49 (m, 1H), 2.42 (m, 1H), 2.31 (m, 2H), 2.21 (m, 1H), 1.44 (s, 18H), 1.29 (t, 3H); 13C NMR (CDCl3, 400 MHz) 176.3, 167.9, 144.4, 129.4, 127.7, 126.5, 81.5, 66.6, 60.6, 51.4, 42.6, 33.6, 30.4, 27.7, 14.1.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccnc1C=O
Temperature: 90 °C
Yield: 63.2 %

Procedure:
A stirred solution of 3-bromo-pyridine-2-carbaldehyde (128 mg, 0.69 mmol) and 2-methoxybenzeneboronic acid (111 mg, 0.73 mmol) in a mixture of THF (0.75 mL), DME (2.0 mL) and 2M Na2CO3 (0.75 mL) was degassed with Ar for 15 minutes, after which Pd(PPh3)4 (41 mg, 0.034 mmol) was added and the heterogeneous mixture heated to 90° C. overnight. The reaction was quenched with brine (15 mL) and diluted with EtOAc (40 mL). The organic layer was separated, washed with brine (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (EtOAc/Hexanes, 80:20, then 70:30) gave 3-(2-methoxy-phenyl)-pyridine-2-carbaldehyde (93 mg, 63%) as a yellow solid. 1H NMR (CDCl3) δ 3.74 (s, 3H), 6.99 (d, 1H, J=8.3 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.25 (dd, 1H, J=7.4, 1.7 Hz), 7.40-7.49 (m, 1H), 7.55 (dd, 1H, J=7.9, 4.8 Hz), 7.74 (dd, 1H, J=7.9, 1.8 Hz), 8.80 (dd, 1H, J=4.6, 1.5 Hz), 9.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O[CH2:27][CH2:28][C:29](=[O:31])[CH3:30].N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:27][CH2:28][C:29](=[O:31])[CH3:30])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCO
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2O)cc1
Agent: N
Product: CC(=O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 460 starting with 2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-hydroxy-2-butanone in place of acetol. (yield: 85.0 mg, 20%). mp 133–136° C.; 1H NMR (300 MHz, CDCl3) δ 2.04 (s, 3H), 2.80 (t, J=9 Hz, 2H), 3.13 (s, 3H), 4.76 (t, J=9 Hz, 2H), 7.20 (t, J=9 Hz, 2H), 7.55 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.91 (s, 1H), 8.05 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 431 (M+H)+, 448 (M+NH4)+. Anal. calc. for C21H19FN2O5S: C, 58.60; H, 4.42; N, 6.52. Found: C, 58.87; H, 4.55; N, 6.51.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O[C:14]([C:17](O)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([B:10]2[O:12][C:17]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:15])[O:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(O)C(C)(C)O
Solvent: C1CCCCC1
Product: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Temperature: 40 °C
Yield: 85.6 %

Procedure:
A suspension of the crude 3-fluoro-4-cyanophenyl boronic acid (9.2 Kg, 55.8 mol) in cyclohexane (150 L) was treated with pinacol (13.2 Kg, 111.6 mol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 40° C. for 4 h. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was cooled down to room temperature before being washed with water (2×75 L). The organic layer was then dried over magnesium sulfate (MgSO4) and concentrated under the reduced pressure to afford 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 11.8 Kg, 13.8 Kg theoretical, 85.6% yield) as a light yellow solid. For 19: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (t, 1H, J=7.00 Hz), 7.62 (m, 2H), 1.29 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:13][C:14]1[N:15]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:17]2[C:22]=1[CH:21]=[N:20][C:19](SC)=[N:18]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2>O1CCCC1>[CH3:13][C:14]1[N:15]=[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:17]2[C:22]=1[CH:21]=[N:20][C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:18]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: Nc1ccccc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
A solution of aniline (18 mg, 0.19 mmol) in tetrahydrofuran (5 mL) at −78° C. was treated with n-butyllithium (0.13 mL of a 1.6M solution in hexanes, 0.21 mmol) and the resulting mixture stirred at this temperature for 0.5 h. The mixture was then treated with a solution of of 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol) in tetrahydrofuran (5 mL) and the mixture allowed to warm slowly to room temperature overnight. The mixture was then reduced under vacuum and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the layers separated. The organic layer was then dried with magnesium sulfate, filtered and reduced. The crude product was purified by chromatography on silica gel eluting with 50% ethyl acetate in petrol to afford 5-methyl-N,7-diphenylimidazo[5,1-f][1,2,4]triazin-2-amine (10 mg) as a yellow solid. MS m/z 302 (M+1).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([CH2:14][NH:15][CH:16]2[CH2:18][CH2:17]2)[CH2:9]1)C1C=CC=CC=1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(O)C.[C].[Pd]>[CH:16]1([NH:15][CH2:14][C@@H:10]2[C@@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]2)[CH2:17][CH2:18]1.[F:19][C:20]([F:25])([F:24])[C:21]([O-:23])=[O:22]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1CNC1CC1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CNC[C@@H]1CNC1CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 9 h

Procedure:
(3S,4R)-1-Benzyl-3-cyclopropylaminomethyl-4-methylpyrrolidine (25.0 g) was dissolved in ethanol (200 mL). To this solution, trifluoroacetic acid (15.7 mL) and 10% palladium carbon (12.5 g) were added and the mixture was stirred at room temperature under hydrogen pressure of 3.9×105 Pa for 9 hours. The catalyst in the reaction mixture was filtered and the collected catalyst was washed with a 25% aqueous ethanol (300 mL). The filtrate and the washings were combined and concentrated under reduced pressure. The remaining pale brown crystals were suspended in tetrahydrofuran (100 mL) and were filtered. The collected crystals were washed with tetrahydrofuran and dried under reduced pressure to give (3R,4R)-3-cyclopropylaminomethyl-4-methylpyrrolidine-trifluoroacetate as white crystals (34.1 g).