Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:19](=[O:21])[CH3:20])=[CH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CC(=O)c1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetyl-phenylboronic acid to give 1-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 343(MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([F:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:39][N:40]([CH3:44])[C:41]([NH2:43])=[O:42].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>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].CN(C=O)C.CCOC(C)=O>[F:32][C:16]1[CH:17]=[C:18]([F:31])[C:19]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])=[CH:20][C:15]=1[C:7]1[C:8](=[O:14])[N:9]([CH2:12][CH3:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:43][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])[CH:11]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(Cl)cc21
Reactant: CN(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)N(C)C)cc21
Temperature: 100 °C
Yield: 20 %

Procedure:
A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (211 mg, 0.464 mmol), Cs2CO3 (453 mg, 1.392 mmol), N,N-dimethylurea (204 mg, 2.319 mmol) and Xantphos (81 mg, 0.139 mmol) in dioxane (5 mL) was sparged with Ar, treated with Pd2(dba)3 (64 mg, 0.070 mmol) and heated at 100° C. for 4 h. The mixture was cooled to RT, treated with EtOAc, DMF and 50% satd. NaHCO3 and the solids removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and stirred. The resulting solid was collected via filtration and dried to afford 3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (47 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 9.03 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.17 (dd, J=9.1, 7.8 Hz, 1H), 8.01 (d, J=2.1 Hz, 2H), 7.45-7.38 (m, 3H), 7.26 (t, J=7.8 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.97 (s, 6H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 507.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:24][CH2:25]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCN(CCc2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4.65 g of 4-chlorobenzoyl chloride in 50 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 5 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine in 75 ml of methylene chloride. The reaction mixture is heated under reflux for 5 minutes, allowed to stand at room temperature for 1 hour and then concentrated by evaporation. The residue is made into a slurry with hot acetone and, after the addition of hexane, the whole is filtered. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-chlorobenzoyl)-piperazine is obtained and can be purified and characterised via the hydrochloride which has a melting point of 254°-254.5° (decomposition).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[K+].C(OCC)(=O)C>C(O)C.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[CH:32][C:33]=1[CH2:38][C:49]#[N:50]
Reactant: Clc1ccc(C2O[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran (195 mmol) from Step 7 in ethanol (260 mL) and water (130 mL) was added potassium cyanide (31.8 g, 488 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® apparatus (silica gel, 5 to 40% ethyl acetate in hexanes gradient) gave the title compound (105 g, 156 mmol, 80%, mixture of α,β-anomer in about 1:2 ratio) as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[OH:11])[CH2:9][CH2:8]1.CCOCC>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[N:14]1[CH:13]=[C:12]([C:10]([CH:7]2[CH2:8][CH2:9]2)=[O:11])[CH:17]=[N:16][CH:15]=1
Reactant: OC(c1cncnc1)C1CC1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1cncnc1)C1CC1
Reaction time: 2 h

Procedure:
To a suspension of chromium (VI) oxide (42.4 g, 0.41 mol) in dry dichloromethane (1000 ml) was added dry pyridine (66 ml, 0.825 mol) and the mixture was stirred for half an hour. A solution of the product of Stage 1 (10 g, 66 mmol) in dry dichloromethane (125 ml) was then added dropwise with stirring. After 2 hours, the reaction mixture was poured into ether and filtered. The filtrate was washed with copper sulphate solution, and brine and then dried over magnesiums sulphate before removing the solvent. Flash chromatography gave the product as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:34]([O:41][CH3:42])=[CH:33][C:16]=2[CH2:17][N:18]2[C@H:22]([C:23](C)(C)[O:24][SiH2]C(C)(C)C)[CH2:21][CH2:20][C:19]2=[O:32])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:36]=[C:35]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:34]([O:41][CH3:42])=[CH:33][C:16]=2[CH2:17][N:18]2[C@H:22]([CH2:23][OH:24])[CH2:21][CH2:20][C:19]2=[O:32])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)CC[C@H]2CO)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 95.8 %

Procedure:
step 3—To a solution of 106 (128 mg, 0.22 mmol) and THF (10 mL) under an argon atmosphere was added dropwise (n-Bu)4N+F− (0.24 mL, 1M in THF). After 1 h the mixture was poured into 1N HCl, extracted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated to afford 100 mg (97%) of (S)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-hydroxymethyl-pyrrolidin-2-one (108).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([C:15]3[NH:19][N:18]=[CH:17][CH:16]=3)=[CH2:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20]>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[NH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20]
Reactant: C=C(c1ccc2c(c1)sc(=O)n2COC)c1ccn[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCn1c(=O)sc2cc(C(C)c3ccn[nH]3)ccc21
Reaction time: 8 h
Yield: 92 %

Procedure:
Add 5% palladium/carbon (15 g; 7.0 mmoles) to a N2 purged flask and add EtOAc (250 mL). Add 3-(methoxymethyl)-6-[1-(1H-pyrazol-5-yl)ethenyl]-3H-1,3-benzothiazol-2-one (29 g, 101 mmoles) as a solution in EtOAc (250 mL). Degas under vacuum and charge with hydrogen via balloon. Stir overnight, evacuate excess hydrogen under pressure and flush with N2. Filter through diatomaceous earth and concentrate to give 3-(methoxymethyl)-6-[1-(1H-pyrazol-5-yl)ethyl]-3H-1,3-benzothiazol-2-one as a thick yellow oil (27 g, 93 mmoles; 92% yield). Material may be carried into the next step without further purification. LCMS (Low) rt=1.73 min., M+1=290.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([CH:32]=[O:33])=[C:13]([CH2:34][O:35][CH3:36])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]1([Li])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.CCOCC.CCCCCC.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([CH:32]([OH:33])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:13]([CH2:34][O:35][CH3:36])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: COCc1c(C=O)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COCc1c(C(O)c2ccccc2)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g of 6-benzyloxy-3-formyl-4-methoxymethyl -9-(4-methylphenylsulfonyl)-beta-carboline in 60 ml of absolute tetrahydrofuran was mixed at -60° C. under argon with 2.4 ml of a 1.08 molar phenyllithium solution in ether/hexane, stirred for 1 hour at -60° C. and then heated slowly to room temperature. After taking up in ethyl acetate/water, the organic phase was separated, washed with saturated sodium chloride solution, dried and concentrated by evaporation. After column chromatography on silica gel with the eluants dichloromethane/ethanol 15:1 and cyclohexane/ethyl acetate 1:1, 717 mg of the title compound was obtained with melting point 169°-171° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3]1)[N:11]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:10]=[CH:9]3.[Li]CCCC.[CH:30]1([C:33](OC)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([CH:33]([C:10]2[N:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:12]3[C:8]([CH:9]=2)=[C:7]2[CH2:24][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]2=[CH:14][CH:13]=3)[OH:34])[CH2:32][CH2:31]1
Reactant: COC(=O)C1CC1
Reactant: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCOc2ccc3c(cc(C(O)C4CC4)n3S(=O)(=O)c3ccccc3)c2C1
Reaction time: 8 h
Yield: 4.1 %

Procedure:
2-Methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 5, 0.030 g, 0.088 mmol) was dissolved in dry THF (1 mL) at −78° C. under an atmosphere of nitrogen gas. BuLi (2.5 M in hexanes, 0.053 mL, 0.13 mmol) was added. The solution was stirred for 15 minutes before methyl cyclopropane carboxylate (0.013 mL, 0.13 mmol) was added. The temperature of the reaction mixture was allowed to rise to room temperature overnight. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1.5 mg). MS m/z 413 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH3:16].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27]>>[CH3:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH2:14][CH2:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[NH:1][C:26]1=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(CCNc1ccc(C(F)(F)F)cc1N)NC(=O)OC(C)(C)C
Product: CC(C)(CCn1c(=O)[nH]c2cc(C(F)(F)F)ccc21)NC(=O)OC(C)(C)C

Procedure:
5.00 g (13.8 mmol) tert-butyl [3-(2-amino-4-trifluoromethyl-phenylamino)-1,1-dimethyl-propyl]-carbamate and 6.73 g (41.5 mmol) 1,1′-carbonyldiimidazole are reacted and worked up analogously to method 2c). White solid. Yield: 4.18 g (78%); mass spectroscopy: [M−H]+=386.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-3-methylbutan-1-one (44 mg, 0.14 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (92 mg, 0.43 mmol) to afford the desired product (13 mg, 21%) as an off-white solid: ESI MS m/z 433 [C22H30BrN3O+H]+.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:4][CH:3]1[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][C:6]1([OH:19])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(CC2CC2(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 11C (1 eq.) in DCM, was added TFA (10 eq.), the reaction mixture was stirred at room temperature for about 2 hours, when TLC detected no s.m. The reaction mixture was concentrated to afford the desired product 11D. The crude product was used for the next step directly without further purification. LC-MS: m/z 192.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.I[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2cccc(-c3cccc(Cl)c3)n2n1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2nc3cccc(-c4cccc(Cl)c4)n3n2)cc1

Procedure:
A solution of 5-(3-chlorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.46 g, 5.97 mmol, 1 equiv), methyl 4-iodobenzoate (1.57 g, 5.99 mmol, 1.00 equiv), palladium diacetate (134 mg, 0.597 mmol, 0.100 eq), cesium carbonate (1.96 g, 6.02 mmol, 1.01 equiv), and XantPhos (173 mg, 0.299 mmol, 0.050 eq) in 1,4-dioxane was heated at 80° C. overnight. The mixture was concentrated, and the residue was diluted with methanol and water. The resulting solid was filtered and rinsed with water, isopropanol, and hexanes. The crude product was used for the next step without further purification (1.85 g, 80%). LCMS (ESI) m/z: 379.0.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>C(#N)C>[CH2:12]([NH:19][CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: BrCC1Cc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: c1ccc(CNCC2Cc3ccccc3O2)cc1
Yield: 73 %

Procedure:
1.07 g (5.0 mmol) of compound 001C, which had been prepared in Step C of Reference Example 1, was dissolved in 11 ml of acetonitrile. To the resultant solution were added 1.64 ml (15.0 mmol) of benzylamine and 2.07 g (15.0 mmol) of potassium carbonate. The resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 100 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 002A, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 50 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with chloroform, to thereby obtain 873 mg of compound 002A as a yellow oily substance (yield: 73%).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.C(O)(=O)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]([CH2:25][CH:26]=[CH2:27])[CH:23]=O)[CH:19]=[CH:20][CH:21]=1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH3:4][NH:6][CH2:23][CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=1)[CH2:25][CH:26]=[CH2:27]
Reactant: C=CCC(C=O)c1cccc(Cl)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCC(CNC)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
Methylamine hydrochloride (595 mg, 8.81 mmol), triethylamine (1.23 mL, 893 mg, 8.82 mmol) and acetic acid (0.290 mL, 304 mg, 4.98 mmol) were added to a stirred solution of of 2-(3-chlorophenyl)pent-4-enal (350 mg, 1.80 mmol) in 8 mL of methanol at room temperature. After 10 min, sodium cyanoborohydride (97 mg, 1.6 mmol) was added and stirring was continued overnight. The mixture was then diluted with 100 mL of ethyl acetate and washed with a mixture of 30 mL of saturated sodium bicarbonate and 10 mL of brine, followed by 40 mL of brine. The organic layer was dried over sodium sulfate, decanted, and evaporated. The residue was partitioned between 25 mL of ethyl ether and 20 mL of 2.0 N aqueous HCl. The aqueous layer was washed with 25 mL of ethyl ether, made basic with 15 mL of 2.5 N aqueous sodium hydroxide, and extracted with 3×25 mL of ethyl acetate. The ethyl acetate layers were dried over sodium sulfate and evaporated to give 180 mg of the title compound as a colorless syrup. 1NMR (400 MHz, CDCl3): δ 7.26-7.17 (m, 3H), 7.08 (dt, 1H, J=8, 1 Hz), 5.67 (ddt, 1H, J=17, 10, 7 Hz), 4.99 (dq, 1H, J=17, 1 Hz), 4.96 (dm, 1H, J=10 Hz), 2.90-2.80 (m, 2H), 2.78-2.70 (m, 1H), 2.45-2.28 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]>C1COCC1.CN(C1C=CN=CC=1)C>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 75.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3 mmol), described in Example 318A. The crude was purified by silica gel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether to afford 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (127 mg, 75%) as a solid. 1HNMR (300 MHz, DMSO-d6) δ 1.99 (t, J=18 Hz, 3H), 3.99 (s, 6H), 6.67 (s, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.34 (d, J=5 Hz, 2H), 7.38-7.59 (m, 7H), 7.77 (s, 1H), 8.66 (s, 1H), 8.68 (s, 1H), 9.27 (s, 1H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15](=O)[NH:14][CH:13]=[N:12]2.P(Cl)(Cl)(Cl)=O.C([N:27]([CH2:31][CH3:32])[CH:28](C)C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC1.C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[N:27]1([C:15]2[C:16]3=[C:8]([C:3]4[CH:4]=[N:5][N:6]([CH3:7])[C:2]=4[Br:1])[N:9]=[C:10]([CH3:18])[N:11]3[N:12]=[CH:13][N:14]=2)[CH2:28][CH2:32][CH2:31]1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(=O)[nH]cnn12
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cnn(C)c2Br)c2c(N3CCC3)ncnn12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (5.02 g, 16.2 mmol) and toluene (100 mL) was treated with phosphorus oxychloride (7.50 mL, 80.5 mmol) and heated to 45° C. N,N-Diisopropylethylamine (17.0 mL, 97.6 mmol) was added in four equal portions, waiting for the exotherm to subside before adding another portion. The reaction mixture was heated to 95° C. for 42 hours, cooled to 35° C. and added to an aqueous solution of potassium phosphate (2.5 M, 45.0 mL), also at 35° C., in four portions; during this addition the temperature rose to 63° C. The resulting mixture was filtered through Celite, which was then rinsed with additional toluene. The organic layer of the filtrate was washed with aqueous citric acid solution (0.57 M, 30 mL), then washed with saturated aqueous sodium chloride solution (25 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to a volume of approximately 100 mL. This was added to a solution of azetidine (2.34 g, 41.0 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was stirred for 1 hour at room temperature, at which time it was poured in four portions into an aqueous sodium bicarbonate solution (0.65 M, 125 mL) with vigorous stirring. The aqueous layer was extracted with toluene (3×50 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a volume of approximately 75 mL. Heptane (100 mL) was added with vigorous stirring, and the mixture was granulated at room temperature for 2 hours, then cooled in an ice bath for 15 minutes. The resulting solid was collected by vacuum filtration to provide C7. Yield: 4.45 g, 12.8 mmol, 79%. 1H NMR (400 MHz, CDCl3) δ 2.24-2.33 (m, 2H), 2.68 (s, 3H), 3.5-4.5 (v br m, 4H), 3.96 (s, 3H), 7.65 (s, 1H), 7.88 (s, 1H).