Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[NH:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:18]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=[CH:20][C:21]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[NH:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1NCc2cc(N3CCNCC3)ccc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1NCc2cc(N3CCN(Cc4ccc(-c5ccccc5)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of compound 6 (0.15 g, 0.43 mmol) and biphenyl-4-carbaldehyde a (0.1 g, 0.55 mmol) in DMSO (2 mL) at 0° C. was added Et3N (0.13 mL, 0.97 mmol). After being stirred for 0.5 h at room temperature, NaBH(OAc)3 (0.11 g, 0.53 mmol) was added and the mixture was stirred for 6 h. The reaction was added sat. NaHCO3 solution (5 mL) and stirred for 15 min, followed by the addition of ethyl acetate (20 mL). The organic layer was separated and washed with sat. NaHCO3, brine, and dried over Na2SO4 and evaporated. Column chromatography on silica gel, eluting with methanol:dichloromethane (5:95) and then changing (10:90) afforded 0.102 g (60%) of compound 6a as an off-white solid. IR (KBr) νmax. cm−1: 3436 (NH), 3052 (Ar—H), 2953 (Alph-H), 1702 (C═O), 1614, 1515, 1425 (C═C), 1229 (C—N), 1162 (C—O). 1H NMR (500 MHz, DMSO-d6) δ=2.76 (m, 4H, 2CH2), 3.18 (m, 4H, 2CH2), 3.67 (s, 2H, CH2), 4.49 (s, 2H, CH2), 6.60 (d, 1H, J=2.3 Hz, aromatic H), 6.70 (dd, 1H, J=2.2, 8.5 Hz, aromatic H), 7.43-7.48 (m, 6H, aromatic H), 7.58-7.62 (m, 4H, aromatic H). 13C NMR (125.7 MHz, DMSO-d6) δ=43.70 (CH2), 48.23 (CH2), 53.03 (CH2), 62.64 (CH2), 114.56 (aromatic-C), 117.64 (aromatic-C), 119.82 (aromatic-C), 124.58 (aromatic-C), 127.19 (aromatic-C), 127.26 (aromatic-C), 127.55 (aromatic-C), 127.90 (aromatic-C), 128.95 (aromatic-C), 129.26 (aromatic-C), 130.25 (aromatic-C), 130.59 (aromatic-C), 136.66 (aromatic-C), 138.22 (aromatic-C), 138.66 (aromatic-C), 140.95 (aromatic-C), 146.88 (aromatic-C), 156.32 (C═O). Calculated (%) for C25H26N4O (398.21); C, 75.35; H, 6.58; N, 14.06. found (%); C, 75.27; H, 6.65; N, 13.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[N:23]=3)=[CH:15][CH:14]=2)=[CH:5][N:4]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 2-Methoxy-5-pyrimidine boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 365.2 (M+1)
Reaction SMILES: [C:1]1([P:7]([CH2:14][C:15]([CH2:24][P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:18][C:19]2[CH2:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][OH:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CC2(CP(C3C=CC=CC=3)C3C=CC=CC=3)COC2)C=CC=C1.[Li]CCCC.[C-]1C2C3C=CC=CC=3PC=2C=CC=1.[Li+]>>[CH:19]1([CH2:18][C:15]([CH2:14][P:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]2=3)([CH2:24][P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:16][OH:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: OCC(CC1=CC=CC1)(CP(c1ccccc1)c1ccccc1)CP(c1ccccc1)c1ccccc1
Agent: C1=CC(CC2(CP(c3ccccc3)c3ccccc3)COC2)C=C1
Agent: [Li+]
Agent: [Li]CCCC
Product: OCC(CC1C=CC=C1)(CP(c1ccccc1)c1ccccc1)Cp1c2ccccc2c2ccccc21

Procedure:
The preparation was carried out using a method similar to that for 3a. 1.6 g (4.8 mmol) of 2a were deprotonated with 2 ml (4.8 mmol) of n-BuLi solution and reacted with 1.2 equivalents of lithium dibenzophospholide solution to give the crude product 3c. The colorless oil which remained was dissolved in methylene chloride and absorbed on kieselguhr. This was followed by flash chromatography on silica gel (23*4 cm; eluant: PE/diethyl ether in a ratio of 8.5:1.5, RF =0.27). This gave 1.36 g (55%) of 3c in the form of a colorless, viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:29]=[CH:28][C:27](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:49])[C:21]([C:24]1[CH:25]=[CH:26][C:27]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:28][CH:29]=1)([CH3:23])[CH3:22]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.057 g, 0.25 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.112 g, 0.37 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a brown oil (0.035 g, 35%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([O:14][CH3:15])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1C(=O)OC

Procedure:
A mixture of allyl bromide (152.4 g, 1.27 mol), methyl salicylate (162.44 g, 1.06 mol), and potassium carbonate (219.75 g, 1.59 mol) in THF (600 ml) and DMF (600 ml) was heated to reflux for 6 hr. The mixure was poured into water (3 L) and extracted with ethyl acetate three times. The ethyl acetate extracts were combined and washed with water and dried with brine. The ethyl acetate extracts were concentrated in vacuo to a yellow oil that was vacuum distilled to a clear oil (163.45 g, 80%).
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH:30]=O.C([BH3-])#N.[Na+]>C(OC(=O)C)C.C(O)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:4]([NH:3][CH2:28][C:29]([CH3:33])([CH3:32])[CH3:30])=[C:5]([CH:23]=1)[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(O)c2cc(Cl)ccc2N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a methanol (8 ml) solution of 2-amino-5-chloro-α-(4-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.83 g) were added trimethyl acetaldehyde (220 mg) and acetic acid (170 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (160 mg). The mixture was stirred overnight at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 5-chloro-α-(4-tert-butoxycarbonylaminomethylphenyl)-2-neopentylaminobenzyl alcohol (0.99 g) as a colorless oily product.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8](=[O:12])[N:9]([CH3:11])[NH2:10])([CH3:7])[OH:6])C.[NH3:14]>>[NH2:10][N:9]([C:8]([C:5]([CH3:7])([OH:6])[C:4]([NH2:14])=[O:3])=[O:12])[CH3:11]
Reactant: N
Reactant: CCOC(=O)C(C)(O)C(=O)N(C)N
Product: CN(N)C(=O)C(C)(O)C(N)=O

Procedure:
2-Azaalanyl-dl-lactic acid ethyl ester (0.02 mole) is treated with liquid ammonia (50 ml) at room temperature for 16 hours. The mixture is evaporated to dryness. Chromatography on silica gel (80 gm) and elution with 15% methanol in chloroform gives 2-azaalanyl-dl-lactamide.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22](C(OC(C)(C)C)=O)[N:23]=1)=O)(C)(C)C.[NH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C([BH3-])#N.C(OC(N1C2C(=CC(CNCC3CCCCC3)=CC=2)C=C1C1C2SC=CC=2N(C(OC(C)(C)C)=O)N=1)=O)(C)(C)C.C(OC(N1C2C(=CC(CNCC3CCCCC3)=CC=2)C=C1C1C2SC=CC=2NN=1)=O)(C)(C)C.C(OC(N1C2C=CSC=2C(C2NC3C(C=2)=CC(CNCC2CCCCC2)=CC=3)=N1)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.ClCCl.C(O)(=O)C>[CH:36]1([CH2:35][NH:34][CH2:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:19]2[C:20]4[S:33][CH:32]=[CH:31][C:21]=4[NH:22][N:23]=2)=[CH:10]3)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: CC(C)(C)OC(=O)n1c(-c2n[nH]c3ccsc23)cc2cc(CNCC3CCCCC3)ccc21
Agent: CC(C)(C)OC(=O)n1nc(-c2cc3cc(CNCC4CCCCC4)ccc3[nH]2)c2sccc21
Agent: CC(C)(C)OC(=O)n1nc(-c2cc3cc(CNCC4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc2[nH]nc(-c3cc4cc(CNCC5CCCCC5)ccc4[nH]3)c2s1
Reaction time: 8 h

Procedure:
A mixture of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester [200 mg, 1 eq, Intermediate (11) prepared as described in Step 1 of Example 24], aminomethylcyclohexane (1.1 eq), MP-cyanoborohydride (macroporous triethylammonium methylpolystyrene cyanoborohydride, 1.5 eq), and acetic acid (0.5 ml) in dimethyl formamide (10 ml) at room temperature was shaken overnight. The resin was filtered and the filtrate was poured into water. The mixture was extracted twice with ethyl acetate; the extract was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column (eluted by 20% methanol in ethyl acetate) to yield a mixture of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-[(cyclohexylmethyl-amino)-methyl]-indole-1-carboxylic acid tert-butyl ester [major product, LC/MS: 565 (M+H), RT=3.5 minutes], 5-[(cyclohexylmethyl-amino)-methyl]-2-(1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester and 3-{5-[(cyclohexylmethyl-amino)-methyl]-1H-indol-2-yl}-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester. This mixture was treated with trifluoroacetic acid in dichloromethane (10 ml, 1:1) at room temperature for 2 hours and the reaction mixture was passed through SCX column eluting with 7N ammonia in methanol affording cyclohexylmethyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-ylmethyl]-amine [Example 52]. LC/MS: 365 (M+H), RT=2.5 minutes; 1H NMR [(CD3)2SO)]: δ 11.4 (1H, s), 7.8 (d, 2H), 7.5 (1H, s), 7.4 (1H, d), 7.2 (1H, d), 7.0 (1H, d), 6.6 (1H, s), 3.8 (2H, s)2.2 (2H, d), 1.8-2.0 (4H, m), 1.0-1.2(4H, m), 0.8-1.0(3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:15]([CH2:22][CH:23]1[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]1)[C:16](=O)[C:17]([F:20])([F:19])[F:18].C(=O)([O-])O.[Na+]>C(O)CCC>[Cl:13][C:11]1[N:12]2[C:15]([CH2:22][CH:23]3[CH2:24][CH2:25][C:26]([F:29])([F:30])[CH2:27][CH2:28]3)=[C:16]([C:17]([F:18])([F:20])[F:19])[N:1]=[C:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1
Reactant: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Reactant: CCOC(=O)c1cc(N)nc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
Ethyl 2-amino-6-chloroisonicotinate (510 mg, 2.54 mmol) obtained in step 1 was suspended in n-butanol (5.08 mL), and the suspension was stirred overnight at 130° C. after adding 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (821 mg, 2.54 mmol) obtained in step 2 of Example 36, and molecular sieve 4A (510 mg). The reaction mixture was allowed to cool to room temperature, and, after adding a sodium hydrogen carbonate aqueous solution, the mixture was filtered through Celite (registered trademark), and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→2/1), amino silica gel column chromatography (hexane/ethyl acetate=20/1→9/1), and preparative thin-layer chromatography (hexane/ethyl acetate=9/1) to give ethyl 5-chloro-3-{(4,4-difluorocyclohexyl)methyl}-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate (62.0 mg, yield 5.7%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:31])[N:9]([CH3:30])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][CH:19]([CH3:20])[CH3:21])=[CH:28][CH:27]=1
Reactant: CC(C)Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cnc2c(c1Cc1ccc(F)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
To a solution of 3-(5-(4-fluorobenzyl)-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (89 mg, 0.21 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (17.4 mg, 0.42 mmol). The reaction was stirred at RT for 15 min then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 36% yield) as a white solid. 1H NMR (CDCl3) δ: 8.33 (s, 1H), 7.22 (dd, J=8.6, 5.5 Hz, 2H), 6.95-6.84 (m, 2H), 4.73 (s, 2H), 4.64 (dt, J=12.1, 6.0 Hz, 1H), 4.27-4.15 (m, 2H), 3.69 (s, 3H), 3.52 (dd, J=11.6, 6.1 Hz, 2H), 3.19 (t, J=6.9 Hz, 1H), 1.96-1.84 (m, 2H), 1.35 (d, J=6.0 Hz, 6H). LCMS: MH+ 402 and TR=2.728 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[C:22]2[C:21](=[O:23])[NH:20][CH:19]=[N:18][C:17]=2[CH:16]=[C:15]([Cl:24])[N:14]=1>C1COCC1>[Cl:24][C:15]1[N:14]=[C:13]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[C:22]2[C:21](=[O:23])[NH:20][CH:19]=[N:18][C:17]=2[CH:16]=1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=c1[nH]cnc2cc(Cl)nc(Nc3cccc(C(F)(F)F)c3)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(trifluoromethyl)aniline (225.6 mg, 1.4 mmol) in THF (6 mL) cooled to 0° C. under dry N2 was added a solution of sodium bis(trimethylsill)amide in THF (1.0 M, 2 mL, 2 mmol) with a syringe resulting a mixture which was stirred at 0° C. for 20 min A solution of 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (216 mg, 1.0 mmol) in THF (4 mL) was added and the reaction mixture was stirred at 0° C. for 30 minutes and at the room temperature for 5 hours and concentrated to a residue. Chromatography of the residue with gradient mixed solvents from DCM/MeOH/28% aqueous NH4OH (320:10:1) to (160:10:1) afforded the title compound. 1H NMR (DMSO-d6) δ 6.99 (s, 1H), 7.42 (d, J=9 Hz, 1H), 7.59 (m, 1H), 7.86 (d, J=9 Hz, 1H), 7.72 (s, 1H), 8.30 (s, 1H), 8.38 (s, 1H); ESI-MS m/z 341.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[F:8].[N+:10]([O-])([OH:12])=[O:11]>>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[F:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1F
Product: Cc1cc([N+](=O)[O-])cc(C)c1F
Reaction time: 1 h

Procedure:
In 120 ml of nitric acid was dissolved 120 g of 3,5-dimethyl-4-fluorobenzene (mfd. by Columbia Organic Chemical Co., Inc.) at -10° C. over a period of 1 hour, after which the temperature was adjusted to -15° C. and the reaction was carried out with stirring for another 1 hour. After completion of the reaction, the reaction solution was poured onto ice and the yellow crystals thus precipitated were collected by filtration and subjected to distillation at atmospheric pressure to obtain 40 9 of 3,5-dimethyl-4-fluoro-1-nitrobenzene as distillate having a boiling point of 111°-112° C.
Reaction SMILES: [OH-].[Na+].C(O[C:6]([C:8]1[N:16]([CH3:17])[C:15]2[CH:14]=[CH:13][N:12]=[N:11][C:10]=2[C:9]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:7])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH:57]([O:59][CH2:60][CH2:61][O:62][NH2:63])=[CH2:58]>C1COCC1>[CH:57]([O:59][CH2:60][CH2:61][O:62][NH:63][C:6]([C:8]1[N:16]([CH3:17])[C:15]2[CH:14]=[CH:13][N:12]=[N:11][C:10]=2[C:9]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:7])=[CH2:58]
Reactant: C=COCCON
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2nnccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2nnccc2n1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
Sodium hydroxide (0.9 mL, 1M) was added to a suspension of 7-(2-fluoro-4-iodo-phenylamino)-5-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid ethyl ester (242 mg, 0.55 mmol) in IMS (10 ml) and the reaction heated at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue azeotroped with toluene (×3) to give a solid. The resultant crude solid was suspended in THF and HOBT (103 mg, 0.77 mmol), EDCI (136 mg, 0.69 mmol), DIPEA (0.144 ml, 0.83 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (85 mg, 0.825 mmol) were then added and the reaction stirred at room temperature for 72 hours. The mixture was then concentrated in vacuo and the resultant residue dissolved in ethyl acetate (20 ml) and washed with water. The organic layer was separated, dried (Na2SO4), and filtered before concentrating in vacuo. The crude residue was purified by flash chromatography (Si-PPC, gradient 0-90% ethyl acetate in cyclohexane then 20% methanol in ethyl acetate) to yield the title compound as an orange solid (148 mg, 54%). LCMS (method B): RT=2.64 min, M+H+=498.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[F:5][C:6]([F:16])([F:15])[C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.C([Li])CCC.CCCCCC>>[F:14][C:7]([F:13])([C:6]([F:5])([F:15])[F:16])[C:8]([CH:2]([CH3:3])[C:1]#[N:4])=[O:10]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CCC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C#N)C(=O)C(F)(F)C(F)(F)F

Procedure:
Propionitrile (13.2 g, 0.24 mole), ethyl pentafluoropropionate (23.05 g, 0.12 mole) and a solution of n-butyllithium in n-hexane (168 ml, 0.264 mole) were reacted as the procedure illustrated in the preceding Preparation 1 to give 22.72 g (crude yield 94.1%) of the crude title compound. The yield calculated as the pure product was 84.1%. The resulting compound was dissolved in CDCl3 to measure NMR, the ratio of the keto form/the enol form was found to be 71/29, b.p. 63°-65° C./28 mmHg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:2]=1.Br[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].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.C1(C)C(C)=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C:17]3[CH:16]=[CH:15][C:20]([CH3:21])=[C:19]([NH:13][C:9]4[N:8]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:12]=[CH:11][N:10]=4)[CH:18]=3)=[O:38])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: Nc1nccc(-c2cccnc2)n1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-(3-pyridyl)-2-pyrimidine-amine (172.2 mg, 1.0 mmol), N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (402.4 mg, 1.0 mmol) and sodium tert.-butylate (144.2 mg, 1.5 mmol) is added a mixture of rac-BINAP (31.2 mg, 0.050 mmol) and Pd2(dba)3*CHCl3 (13 mg, 0.013 mmol) under argon. After addition of 3 ml of xylene the suspension is sonicated for 10 minutes then stirred for 5 hours under reflux. After cooling to room temperature, water (10 ml) is added to the dark brown oil and the product extracted 4 times with methylene chloride (10 ml each). The combined organic extracts are dried over MgSO4 and concentrated in vacuo. The brown oil is purified by flash-chromatography (SiO2, methanol). The product, a pale yellow solid is dissolved in methylene chloride, filtered and concentrated in vacuo. Yield: 484.3 mg of the title compound, 72% of theory, (99.9% area by HPLC). The product contains typically roughly 10% of isomers which can be eliminated by preparative reversed phase chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:33][NH2:34])(C(C)(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:34][OH:33])=[O:22])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NO)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Yield: 50.6 %

Procedure:
To a suspension of Example 63 (190 mg) was added O-(tert-butyldimethylsilyl)-hydroxylamine (81 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg). After stirring overnight at room temperature ethyl acetate (100 mL) was added and the organic layer was washed with water (2×25 ml), saturated NaHCO3 (2×25 ml) and water (25 ml), dried over MgSO4, filtered and evaporated. The colourless oil was dissolved in dichloromethane (20 ml) and treated with 1.0 M HCl solution in ether (1.5 ml). Filtration afforded the title compound as a white solid (100 mg, 50%).