Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH:18]=[CH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:29][CH:30]=1)(=[O:33])=[O:13]
Reactant: O=C(O)c1ccc(C=Cc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(C=Cc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)styryl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].[C:31](OC(=O)C)(=[O:33])[CH3:32].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1

Procedure:
A mixture of 1-[4-(2-chloro-4-aminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g), acetic anhydride (15 ml), acetic acid (5 ml) and a drop of sulfuric acid is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from methanol/diethyl ether to give 1-[4-(2-chloro-4-acetylaminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as white powder, m.p. 214-243° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]([O:24]C)=O)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:46][NH2:47]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]([NH:46][NH2:47])=[O:24])=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cnc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cn12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cnc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cn12

Procedure:
A mixture of 740 mg methyl 6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine-3-carboxylate (compound in Production Example 273), 0.32 mL hydrazine monohydrate and 20 mL ethanol was heated for 6 hours under reflux. The reaction solution was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 283 mg of the title compound as a color amorphous.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cc(F)ccc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of [(S)-1-(5-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (661 mg, 1.9 mmol) in DCM (9 mL) was added TFA (4.5 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM (20 mL) and a saturated aqueous solution of NaHCO3 (40 mL). The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a yellow oil (379 mg, 78%). LCMS (Method J): RT 1.77 min [M+H]+ 256.2.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)#[N:2].C(O)C.CC1CCCO1.[O-]CC.[Na+].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>>[C:13]([O:12][C:11]([NH:10][C:7]1[N:8]=[CH:9][C:4]([CH:3]([C:1]#[N:2])[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[N:5][CH:6]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CCO
Product: CCOC(=O)CCC(C#N)c1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
To tert-butyl 5-(cyanomethyl)pyrazin-2-ylcarbamate (0.32 g, 1.37 mmol) in a mixture solvent of ethanol/2-methyltetrahydrofuran (5 mL/5 mL) was added freshly prepared sodium ethoxide (1 M, 1.366 mL), and the mixture was stirred at 0° C. for 10 min, followed by addition of ethyl acrylate (145 ul, 1.366 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction was quenched at this point by adding sat. NaHCO3 (5 mL), and the reaction mixture was stirred for another 10 min, diluted with EtOAc (20 mL), filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), washed with pH 7.0 sodium phosphate buffer, and EtOAc layer was concentrated, and the light brown residual oil was purified by flash column eluted with gradient EtOAc/heptane (0-50%) to afford ethyl 4-(5-(tert-butoxycarbonylamino)pyrazin-2-yl)-4-cyanobutanoate (100 mg, 22% yield). LCMS (m/z): 279.2 (MH+-tBu), 0.86 min.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)ncn1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccccc2)ncn1Cc1ccccc1
Temperature: 0 °C

Procedure:
3-benzyl-6-(benzyloxy)-pyrimidin-4(3H)-one (from Step 1) (5.00 g, 17.1 mmol) and N-bromosuccinimide (3.15 g, 17.7 mmol) are stirred in 100 ml anhydrous dimethylformamide for 20 hours. The solution is poured onto 1 L of ice with stirring and allowed to come to room temperature, when the product is collected by filtration. (5.97 g). The product is recrystallized from 60 mL hot acetonitrile (4.75 g, 75%) 1H-NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.28-7.44 (overlapping m, 9H), 7.24 (s, 1H), 5.43 (s, 2H), 5.12 (s, 2H). LC/MS tr=5.89 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 371 (M+H). HRMS m/z 371 (M+H) 371.0399, calc. 371.0395.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]=1[CH2:9][CH2:10][CH3:11].[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]=1[CH2:9][CH2:10][CH3:11])[C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: CCCc1c(CNC)oc2ccccc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1oc2ccccc2c1CCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
A solution of methyl-(3-propyl-benzofuran-2-ylmethyl)amine (1.10 g, 5.41 mmol) in CH2Cl2 (40 mL) was treated with acryloyl chloride (0.45 mL, 5.68 mmol) and triethylamine (1.5 mL, 10.8 mmol). The mixture was stirred at room temperature for 2 h. The solution was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (1.46 g, 99%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.59 (d, J=5.4 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.28-7.15 (m, 2H), 6.89-6.70 (m, 1H), 6.20 (t, J=2.4 Hz, 1H), 5.75 (t, J=4.5 Hz, 1H), 4.83-4.71 (m, 2H), 3.33-3.07 (m, 2H), 2.87-2.67 (m, 3H), 1.65-1.58 (m, 2H), 0.95-0.88 (m, 3H); ESI MS m/z 258 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Br-].[CH3:14][CH:15]([CH3:18])[CH2:16][Zn+].CN1C=CN=C1.ClCCl>CN1CCCC1=O>[CH2:14]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1)[CH:15]([CH3:18])[CH3:16]
Reactant: CC(C)C[Zn+]
Reactant: N#Cc1ccc2sc(Br)nc2c1
Agent: Cn1ccnc1
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)Cc1nc2cc(C#N)ccc2s1
Yield: 41.5 %

Procedure:
Heat 2-bromo-benzothiazole-5-carbonitrile (0.3 g, 1.26 mmol) in 1-methyl-pyrrolidinone (4.2 mL) with 2-methylpropylzinc bromide (5 mL, 2.5 mmol, 0.5M solution in THF), N-methylimidazole (0.15 g, 1.88 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.5 mg, 0.025 mmol) at 80° C. for 3 h. Cool the mixture and partition between diethyl ether and brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1 gradient) to give the desired intermediate (113 mg, 42%). MS (EI) m/z: 216 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C1COCC1.C([Li])CCC.Cl[P:34]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:34]([CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(C1CCCCC1)C1CCCCC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
Into a reactor were introduced 1.44 g (4.00 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene obtained in Example 4 (2) and 14 mL of THF under a nitrogen atmosphere. The contents were cooled to −60° C. Thereto was gradually added dropwise 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred at that temperature for 1 hour. Thereafter, 0.97 mL (4.4 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred for 30 minutes, subsequently heated to room temperature, and then further stirred for 17 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and hexane to obtain 0.44 g (23%) of the target compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.C(N(CC)CC)C.[N:38]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)(=[O:46])=[O:45])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(=O)(=O)N4CCOCC4)c3)n2)n1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
To a stirred solution of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-phenylamine (example 327) (0.200 g, 0.5 mmol) and triethyl amine (0.21 mL, 1.5 mmol) in dichloromethane (5 mL) was added commercially available morpholine-4-sulfonyl chloride (0.101 mg, 0.55 mmol) and the mixture was stirred at 23° C. for 30 min. Diluted with DCM, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with heptane/diethyl ether to give the title compound as an off-white solid (0.035 g, 13%). MS (ISP) 555.2 [(M+H)+]; mp 191° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2sccc2c(=O)[nH]1
Product: CSc1nc(Cl)c2ccsc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methylsulfanyl-3H-thieno[2,3-d]pyrimidin-4-one (12 g, 60.5 mmol) was combined with POCl3 (56 mL), and the resulting mixture was heated to reflux for about 1 hour. The reaction mixture was concentrated under reduced pressure at 50° C. The residue was diluted with ethyl acetate (700 mL) at 0° C. Saturated sodium bicarbonate solution (600 mL) was added slowly. The resulting mixture was stirred vigorously at 0° C. for one hour and the layers were separated. Saturated sodium bicarbonate solution (600 mL) was added to the organic layer at 0° C., and the mixture was stirred vigorously for 20 minutes. The layers were separated. Brine (600 mL) was added to the organic layer and stirred vigorously for 5 minutes, and the layers were again separated. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (10.7 g) as a dark tan powder (M+=216, M.P.=105.0-107.4° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:11][CH:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH:31]=[CH:32][CH:33]=1>>[C:12]1([CH:10]2[CH2:11][CH:9]2[NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:27][C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC(=O)Nc1cccc(N)c1
Reactant: Clc1ncnc(NC2CC2c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(NC3CC3c3ccccc3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(2-phenyl-cyclopropyl)amine (Step 1)(45.6 mg, 0.185 mmol) in IpOH (2.5 ml) was added DIEA (0.048 mL, 0.277 mmol) and N-(3-aminophenyl)acrylamide (53. mg, 0.203 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{3-[4-(2-phenyl-cyclopropylamino)-[1,3,5]triazin-2-ylamino]phenyl}-acrylamide: MS m/z=373 [M+H]. Calc'd for C21H20N6O: 372.17.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:32])=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg of (R)-4-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid were treated with 1 eq HATU/DIPEA in DMF and added to 1 eq of Rink-Resin. The reaction was shaken overnight at room temperature. The resin was washed with DMF, MeOH, DCM (3 times each) and then treated with TFA/DCM (1:1) for 2 h. The resulting yellow oil was purified via preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O-].[Na+].CO.C(O)(=[S:18])C>CO>[SH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CC(O)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Sc1ccc2nccn2n1
Temperature: 150 °C
Yield: 27.8 %

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (13.5 g), 28 W/W % sodium methoxide-methanol solution (17.5 g) and thioacetic acid (7.0 g) were dissolved in 70 ml of methanol and this solution was heated at 150° C. in a sealed tube for 6 hours. The reaction mixture was cooled to room temperature and distilled to remove the organic solvent. The residue was washed three times with chloroform, and the insoluble material was extracted six times with 50 ml of chloroform-methanol (1:1) solution. The combined extracts were distilled to remove the organic solvent. The precipitated crystals were collected by filtration, thereby obtaining 3.7 g of 6-mercaptoimidazo[1,2-b]pyridazine.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([NH:22][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NN1CCOCC1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NN2CCOCC2)s1
Yield: 37 %

Procedure:
As described for example 102, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (90 mg, 0.29 mmol) was converted, using 4-aminomorpholine instead of 1,1-dimethylhydrazine, to the title compound (43 mg, 37%) which was obtained as an off white solid. MS: m/e=391.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14]O)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1.[F:16][C:17]([F:25])=[CH:18][CH:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14][N:22]3[CH2:23][CH:19]([CH:18]=[C:17]([F:25])[F:16])[CH2:20][C:21]3=[O:24])=[C:9]([CH:11]3[CH2:12][CH2:13]3)[N:10]=2)[N:7]=1
Reactant: O=C1CC(C=C(F)F)CN1
Reactant: OCc1c(C2CC2)nc2ccc(Cl)nn12
Solvent: Cc1ccccc1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nc2ccc(Cl)nn12
Yield: 28 %

Procedure:
A solution of (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 (889 mg, 3.97 mmol), 4-(2,2-difluorovinyl)pyrrolidin-2-one (643 mg, 4.37 mmol, 1.1 eq) and paratoluenesulfonic acid (76 mg, 0.40 mmol, 0.1 eq) in toluene (20 ml) is heated under reflux for 16 h. After cooling, the solvent is removed under reduced pressure, the crude product is dissolved in dichloromethane (100 ml). The organic layer is washed by water (150 ml). The aqueous layer is extracted by dichloromethane (100 ml). The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by preparative chromatography over silicagel (benzine/AcOEt: 60/40) to afford 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 62 after recristallization in diisopropylether.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C@@:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.[N+:17]([O-])([OH:19])=[O:18].O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:17]([C:8]1[CH:9]=[C:4]2[CH2:3][C@:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1)([O-:19])=[O:18]
Reactant: c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reaction time: 1 h
Yield: 98.6 %

Procedure:
(R)-(−)-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (3.03 g, 14 mmol) was dissolved in concentrated sulfuric acid (7 ml) at 0–5° C., fuming nitric acid (3.3 ml, 70.2 mmol) was added over 10 minutes, the mixture was stirred for 1 hour, and heated at 65–70° C. for 24 hours, cooled, poured onto ice (200 g), added 300 ml of water, basified to pH 10 with solid potassium carbonate, stirred for 1 hour, filtered off and dried, provided the solid title compound (3.6 g, 13.8 mmol, 98%): electrospray MS 262 ([MH]+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])=[O:4].C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:30])=[O:9])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(=O)N(C)C)cc(C(=O)O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)C)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoic acid (333 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) was added, and then the mixture was stirred at 60° C. for 6 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).
Reaction SMILES: [OH:1][C:2]([C:8]([F:11])([F:10])[F:9])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]([CH3:7])([C:8]([F:9])([F:10])[F:11])[C:3]([O:5][CH3:6])=[O:4])=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)(O)C(F)(F)F
Reactant: ClCc1ccc(Cl)cc1
Product: COC(=O)C(C)(OCc1ccc(Cl)cc1)C(F)(F)F

Procedure:
In a similar manner, but starting from (±)-methyl 2-hydroxy-2-trifluoromethylpropionate (8.6 g.) and 4-chlorobenzyl chloride (8.05g.), there is obtained (±)-methyl 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-methylpropionate as an oil (8.0g.), b.p. 92°-98° C. (0.1 mm.Hg.).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([O:18][CH2:19][CH2:20][OH:21])([CH3:17])[CH3:16].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:21][CH2:20][CH2:19][O:18][CH:15]([CH3:17])[CH3:16])[N:10]=1
Reactant: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Reactant: CC(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a mixture of 2,6-dichloro-5-cyclopropylnicotinamide (450 mg, 1.95 mmol) and 2-isopropoxyethanol (223 mg, 2.14 mmol) in DMF (30 mL) was added and NaH (86 mg, 2.14 mmol) in portions at 0° C. The mixture was stirred at r.t overnight, quenched by water, extracted by EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to give 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinamide (180 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.08 (s, 1H), 7.93 (s, 1H), 5.85 (s, 1H), 4.60 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 2.05 (m, 1H), 1.18 (d, J=6.0, 6H), 1.02 (m, 2H), 0.71 (m, 2H).