Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[Si](C(C)C)(C(C)C)C(C)C.[CH:13]1([Si:16]([C:23]([OH:26])(C)[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH2:15][CH2:14]1.Cl[Si](Cl)(C(C)C)C(C)C.C(OC=C[Li])C.C1([Li])CC1.C1([Si](C(OCC)=C)(C(C)C)C(C)C)CC1>CC(C)=O>[C:23]([Si:16]([CH:13]1[CH2:15][CH2:14]1)([CH:20]([CH3:21])[CH3:22])[CH:17]([CH3:18])[CH3:19])(=[O:26])[CH3:24]
Reactant: CC(C)[Si](C(C)C)(C1CC1)C(C)(C)O
Agent: C=C(OCC)[Si](C(C)C)(C(C)C)C1CC1
Agent: CC(C)[Si](CO)(C(C)C)C(C)C
Agent: CC(C)[Si](Cl)(Cl)C(C)C
Solvent: CC(C)=O
Product: CC(=O)[Si](C(C)C)(C(C)C)C1CC1
Yield: 39 %

Procedure:
According to the synthesis of 1-hydroxy-1-methylethyl(diisopropyl)methylsilane (Example 7), cyclopropyl(1-hydroxy-1-methylethyl)(diisopropyl)silane was prepared from dichloro(diisopropyl)silane (5.00 g, 27.0 mmol), ethoxyvinyl lithium (prepared from ethyl vinyl ether (2.17 g, 30.1 mmol) and tert-butyl lithium (1.9 M in pentane, 14.2 ml, 27.0 mmol) in THF (40 ml)) and cyclopropyl lithium (prepared according to Example 1 from bromocyclopropane (3.59 g, 29.7 mmol) and lithium (412 mg, 59.4 mmol) in Et2O). The crude cyclopropyl(1-ethoxyvinyl)(diisopropyl)silane was hydrolysed with acetone/1 N HCl (2:1, 72 ml), and purified by silica-gel flash chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1) to afford 2.11 g (39%) acetyl(cyclopropyl)(diisopropyl)silane. Reaction of acetyl(cyclopropyl)(diisopropyl)silane (1.00 g, 5.04 mmol) with methyl lithium (1.6 M in Et2O, 25.2 ml, 40.3 mmol) afforded after purification by silica-gel chromatography (silica gel 15-40 μm, hexane/EtOAc, 9:1) 590 mg (55%) of the odoriferous title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:6])[CH3:5].Cl[CH2:8][C:9]1[CH:26]=[CH:25][C:12]2[N:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=2[CH:10]=1.O>CN(C)C=O>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([CH2:8][S:6][CH:4]([CH3:5])[CH3:3])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: CC(C)S
Reactant: CC(C)(C)Cc1nc2cc(CCl)ccc2n1CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)SCc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of sodium hydride (washed with hexane, 30 mg, 1.3 mmol) in N,N-dimethylformamide (2 mL) was added 2-propanethiol (117 μL, 1.3 mmol) at 0° C. After stirring for 30 min, a N,N-dimethylformamide solution of 5-(chloromethyl)-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (Step E) was added and the mixture was stirred at 100° C. for 17.5 h. Water (5 mL) was added and the mixture was extracted with ethyl acetate (15 mL×2) and washed with brine (5 mL). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by pTLC (hexane:ethyl acetate=3:1) to give the title compound (74 mg, 67% over 2 steps) as pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:31](=[O:33])[CH3:32])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Yield: 87 %

Procedure:
A solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 1 mL of acetic anhydride and 1 mL of pyridine was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 19 mg (87%) of 1-[(3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidin-1-yl]ethan-1-one. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.53-1.92 (m, 3 H) 2.07 (br. s., 4 H) 2.84-3.37 (m, 2H) 3.86-4.59 (m, 3 H) 5.88 (br. s., 1 H) 7.04-7.60 (m, 8 H) 8.37 (br. s., 1 H), [M+H]+ 481.3.
Reaction SMILES: CC([O-])(C)C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.O[CH:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22]1>O1CCCC1.C(O)C>[OH:32][CH:29]1[CH2:30][CH2:31][C:24]2([CH2:25][CH2:26][CH:21]([C:17]#[N:18])[CH2:22][CH2:23]2)[CH2:27][CH2:28]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC2(CC1)CCC(O)CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC1CCC2(CCC(O)CC2)CC1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Potassium tert-butylate (1.44 g) was added in small portions, at 0° C. under nitrogen atmosphere, to a solution of 1.40 g of tosylmethylisocyanide and 1.00 g of 3-hydroxy-9-oxo-spiro[5.5]undecane (II-a, Prep. 1) dissolved in 7 ml of anhydrous tetrahydrofuran and 0.53 ml of absolute ethanol. After 0.5 hrs at room temperature, the mixture was filtered on an alumina cake. The cake was washed with dichloromethane and the filtrates, dried over anhydrous sodium sulfate, were evaporated under reduced pressure to give 0.52 g of crude 9-hydroxy-3-cyano-spiro[5.5]undecane as a light oil. [TLC: Rf=0.52 (SiO2 plates, diethylether). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.63 (1H, hept), 2.57 (1H, m), 1.90-1.05 (16H, m)].
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5](=[O:27])[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:12]=[C:11]([O:23][CH3:24])[C:10]=1[O:25][CH3:26])=[O:8])C.[OH-].[Na+]>CO.CC(O)=O.C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:13]2[CH:12]=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[C:9]([C:7](=[O:8])[CH2:6][C:5](=[O:27])[C:4]([OH:28])=[O:3])[CH:14]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(Cc2ccc(F)cc2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Cc2ccc(F)cc2)cc(C(=O)CC(=O)C(=O)O)c1OC

Procedure:
In a manner similar to example AIV-2-1, 4-[5-(4-fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L3 as a yellow solid. Rf=0.67 (6:6:94 MeOH/AcOH/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ7.38 (s, 1H), 7.25 (m, 1H), 7.14 (m, 2H), 7.00 (m, 2H), 6.88 (m, 1H), 3.94 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H). mass spec (FAB, M+1) 361 m/e.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[C:11]([C:7]1[C:8]([CH3:10])=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[C:5]([O:24][CH3:25])[C:6]=1[CH:13]1[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16]1)#[N:12]
Reactant: COc1c(C(C)=O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1c(C(C)O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
The tert-butyl 3-(3-acetyl-6-cyano-2-methoxy-5-methylphenyl)azetidine-1-carboxylate (2.2 g, 6.4 mmol) was dissolved in methanol (20 mL) and cooled in ice bath. The sodium tetrahydroborate (0.26 g, 7.0 mmol) was added portionwise and the reaction was monitored by LC/MS. After stirring for 1 h the reaction was complete. This was diluted with ethyl acetate and water. The combined organic layer was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude tert-butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate as a yellow foam (2.1 g, 99%). LCMS calculated for C15H19N2O4(M+H)+: m/z=291.1; found: 291.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([OH:16])=O)[CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:17]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[CH3:18]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:22][C@H:21]([C:20]([O:19][CH2:17][CH3:18])=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)Cn1ccc2cc([N+](=O)[O-])ccc21
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21

Procedure:
Ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate was prepared from (5-nitro-1H-indol-1-yl)acetic acid and L-phenylalanine ethyl ester following the procedure of Example 10 Step 3: MS (ESI) m/z 396; MS (ESI) m/z 394.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]#[N:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.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].O1CCOCC1>[C:18]([C:17]1[CH:16]=[CH:15][C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[CH:3][C:2]=1[NH:32][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)#[N:19]
Reactant: N#Cc1ccc(C(=O)OCc2ccccc2)cc1Br
Reactant: NC1CCCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Temperature: 95 °C
Yield: 74.5 %

Procedure:
To a pressure vessel were added benzyl 3-bromo-4-cyanobenzoate (150 mg, 0.47 mmol) prepared as described in example 11 (steps 1, 2), cesium carbonate (310 mg, 0.95 mmol), cyclohexylamine (108 uL, 0.95 mmol), XANTPHOS (27 mg, 0.047 mmol), tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.023 mmol), and dioxane (3 mL). The vessel was sealed and heated to 95° C. for 4 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and was washed with water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (10% ethyl acetate in hexanes) to provide benzyl 4-cyano-3-(cyclohexylamino)benzoate (118 mg, 0.35 mmol, 75% yield) as a yellow syrup. 1H NMR (400 MHz, CDCl3): 7.45-7.30 (m, 7H), 7.27 (dd, 1H), 5.36 (s, 2H), 4.56 (d, 1H), 3.48-3.38 (m, 1H), 2.08-2.01 (m, 2H), 1.83-1.75 (m, 2H), 1.71-1.64 (m, 1H), 1.46-1.35 (m, 2H), 1.31-1.20 (m, 3H); MS (EI) for C21H22N2O2: 333 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([C@@H:55]([NH2:59])[CH2:56][O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1.BrBr.ClCl>CN(C)C=O.ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:59][C@H:55]([C:53]1[NH:52][C:51]2[CH:60]=[CH:61][C:48]([Cl:47])=[CH:49][C:50]=2[N:54]=1)[CH2:56][O:57][CH3:58])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 83 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, N-methylmorpholine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in N,N-dimethylformamide. Yield: 83%; Rf value: 0.41 (silica gel; dichloromethane/methanol=95:5); C22H20BrClN4O3 (503.79); mass spectrum: (M+H)+=503/505/507 (bromine/chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[C:4](=[O:23])[C:3]=1[C:24]1[NH:29][C:28]2[S:30][CH:31]=[C:32]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:27]=2[S:26](=[O:39])(=[O:38])[N:25]=1.CNN.C(N(CC)CC)C>O1CCOCC1>[NH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:24]2[NH:29][C:28]3[S:30][CH:31]=[C:32]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:27]=3[S:26](=[O:39])(=[O:38])[N:25]=2)[C:4]1=[O:23]
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N3C(=O)c4ccccc4C3=O)c1=O)N2
Agent: CNN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(N)c1=O)N2
Yield: 66.1 %

Procedure:
A solution of the product of Example 350D (185 mg, 0.326 mmol), methylhydrazine (43.47 μL, 2.5 equivalents), and triethylamine (0.126 mL, 3 equivalents) in 1,4-dioxane (10 mL) was heated at 102° C. for 3 hours. The reaction was concentrated under reduced pressure, and treated with a solution of methanol (75 mL) and 1N hydrochloric acid (100 mL). The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound as a white solid (94 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 4.65 (s, 2 H), 4.71 (s, 2 H), 5.84 (br.s, 1 H), 7.44 (m, 2 H), 7.88 (m, 1 H), 8.04 (d, 1 H), 8.15 (d, 1 H), 14.73 (br.s, 2 H). MS (ESI−) m/z 435 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: O=C(O)Cc1ccncc1
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2=C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccncc1)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1

Procedure:
The title compound was prepared according to the method of Example 4 from 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine, 4-pyridine-acetic acid hydrochloride, HOBT, EDCl and NMM in DMF. 4-(8-Chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-(4-pyridine-acetyl)piperidine was obtained as a white foam; MS (CI, M+H)=432; anal.: found: C, 68.71; H, 5.44; N, 9.44; C25H22ClN3O2 requires: C, 69.52; H, 5.13; N, 9.73.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[F:14].C[O:16][B:17]([O:20]C)[O:18]C.Cl>CCCCCC.O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:16][B:17]([OH:20])[OH:18])=[C:8]([F:14])[CH:9]=1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)Oc1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, n-butyllithium (1.6 mol/L-n-hexane, 18.8 mL) was added dropwise at −78° C. to a solution of n-hexane (11 mL) and tetrahydrofuran (30 mL). Then, a solution of 1-bromo-4-chloro-2-fluorobenzene (5.24 g) in n-hexane (15 mL) and tetrahydrofuran (15 mL) was added dropwise. The mixture was stirred at −78° C. for one hour, boric acid trimethyl ester (4.0 mL) in tetrahydrofuran (15 mL) was added dropwise. The mixture was raised to room temperature. After 2 hr, aqueous hydrochloric acid solution (3 mol/L, 120 mL) was added, and the mixture was extracted with diethyl ether (100 mL). The aqueous layer was extracted again with diethyl ether (100 mL), and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure, n-hexane was added to the residue, and the precipitated solid was collected by filtration to give the title compound (2.0 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[C:15]([C:20]([NH:22][CH3:23])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[C:15]([C:20]([NH:22][CH3:23])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ncccc1N
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ncccc1Nc1cc(Cl)ncc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
The mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (0.615 g, 2.0 mmol, 1.0 eq), 3-amino-N-methylpicolinamide (0.303 g, 1.2 eq), Pd2(dba)3 (0.183 g, 0.1 eq), Xantphos (0.347 g, 0.3 eq), Cs2CO3 (1.3 g, 2.0 eq) in dioxane (15 mL) was stirred at 90° C. in an oil bath overnight. The mixture was cooled to room temperature and filtered through a celite pad. The celite pad was washed with methanol. The solvent was removed to obtain the crude which was purified by silica gel chromatography (20%˜80% EtOAc/Hex) to obtain the desired product (0.146 g, isolated yield 22%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.I[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: Ic1cnccn1
Product: Cc1cc(-c2cnccn2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 2-iodopyrazine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=312.1 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:8]2[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[NH2:28]>>[C:1]1([C@@H:7]2[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[C@H:8]2[C:14]([NH:28][C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:18]=2[Cl:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C(O)[C@H]1[C@H](c2ccccc2)C12CCCC2
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)[C@H]1[C@H](c2ccccc2)C12CCCC2
Yield: 57 %

Procedure:
trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg, 1.39 mmol) and 2-chloro-4-trifluoromethyl-phenylamine (272 mg, 1.39 mmol) were reacted as described under General Procedure D to furnish the title compound (312 mg, 57%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.91 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.67 (d, J=8.5, 1.6 Hz, 1H), 7.31 (t, J=7.3 Hz, 2H), 7.22-7.16 (m, 3H), 2.80 (d, J=5.7 Hz, 1H), 2.70 (d, J=5.7 Hz, 1H), 1.82-1.73 (m, 2H), 1.66-1.42 (m, 5H), 1.29-1.10 (m, 1H). mp 131-133° C. ESIMS m/z [M+H]+ 394.3.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pt](=O)=O>[C:2]1([NH:1][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Nc2ccc3ncccc3c2)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: c1ccc(Nc2ccc3c(c2)CCCN3)cc1
Yield: 98.2 %

Procedure:
A solution of 20.4 grams of 6-anilinoquinoline (prepared as described in Buu-Hoi, Royer and Hubert-Habart, J. Chem. Soc., 1956, 2048-2051) in 400 mL of acetic acid containing 1.3 grams of platinum(IV) oxide was hydrogenated at 30 psi for 4.2 hours on a Parr low-pressure hydrogenator. The solution was filtered; and the filtrate was neutralized with 6N aqueous sodium hydroxide. The aqueous phase was extracted three times with dichloromethane. The combined dichloromethane layers were washed with 6N aqueous sodium hydroxide followed by brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 20.4 grams of a dark residue. The dark residue was recrystallized from 95% ethanol to yield 15.2 grams of the desired product as a grey solid. 1H NMR (CDCl3) δ 7.2 (m, 2H), 6.8 (m, 4H), 6.45 (d, 1H), 5.35 (bs, 1H), 3.4 (bs, 1H), 3.25 (t, 2H), 2.75 (t, 2H), 1.95 (p, 2H).
Reaction SMILES: Cl.[F:2][C:3]([F:9])([F:8])[O:4][CH2:5][CH2:6][NH2:7].[H-].[Na+].[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].CCOC(C)=O>C1COCC1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:7][CH2:6][CH2:5][O:4][C:3]([F:9])([F:8])[F:2])=[O:17]
Reactant: O=C=NCCCl
Reactant: NCCOC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCl)NCCOC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 139.7 %

Procedure:
A 0° C. suspension of 2-(trifluoromethoxy)ethylamine hydrochloride (0.308 g, 1.861 mmol) in THF (10 mL) was treated with NaH (60% in mineral oil, 0.082 g, 2.047 mmol), stirred at 0° C. for 0.5 h, treated drop-wise with 2-chloroethyl isocyanate (0.175 mL, 2.047 mmol), allowed to warm to RT and stirred overnight. The mixture was treated with EtOAc, the solids removed via filtration and the filtrate concentrated to dryness to afford 1-(2-chloroethyl)-3-(2-(trifluoromethoxy)ethyl)urea (610 mg, 140%) containing EtOAc. 1H NMR (400 MHz, DMSO-d6): δ 6.29 (br s, 2 H), 4.04-3.97 (m, 2 H), 3.55 (t, J=6.2 Hz, 2 H), 3.33-3.24 (m, 4 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]>C(#N)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:25][CH2:2][C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1
Reactant: Cn1ccc(CCl)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(chloromethyl)-1-methyl-1H-pyrazole (15.6 g, 0.12 mol) in acetonitrile (200 mL) was added K2CO3 (67 g, 0.48 mol) followed by 3-fluoro-4-nitrophenol (19 g, 0.12 mol). The mixture was stirred at 90° Celsius overnight. When the reaction was complete, it was cooled to RT and the solvent was concentrated to dryness. The resulting residue was dissolved in DCM (500 mL) and then washed with water (500 mL). The organic phase was separated, concentrated to dryness and purified by recrystallization from ethyl acetate (100 mL) to give the title compound. MS (ESI): mass calcd. for C11H10FN3O3, 251.07; m/z found, 252.2 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 8.05-7.99 (t, 1H), 7.33 (d, J=3, 1H), 6.86-6.84 (m, 1H), 6.81-6.78 (m, 1H), 6.29 (d, J=3, 1H), 5.11 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[NH:33]N>>[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1cccc(NN)c1C
Product: Cc1cccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)c1C

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,3-dimethyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=421.3 (M+H)+