Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[C:7]([NH2:16])=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][O-].[K+].S(=O)(=O)(O)O>C(O)C>[N:1]1([C:6]2[C:7]3[N:8]([C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:16]=3)[CH:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1ncc(C(F)(F)F)cc1-n1cncn1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Yield: 65.2 %

Procedure:
A mixture of 3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)pyridin-2-amine (2.4 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (4.54 g), sulfuric acid (0.670 mL) and ethanol (100 mL) was heated with reflux for 3 days. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with water. The aqueous layer was neutralize with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (2.22 g).
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[CH:32](OCC)=[O:33]>O1CCCC1>[C:2]1([CH:1]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:32]=[O:33])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=CC(c1ccccc1)c1nc(-c2ccncc2)cs1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a solution of 2-benzyl-4-(4-pyridyl)thiazole (4.00 g, 0.016 mol) and tetramethylethylenediamine (2.5 mL) in dry tetrahydrofuran (35 mL) at -78° C. under nitrogen atmosphere was added dropwise n-butyl lithium (1.6M in hexane, 11.4 mL). The resulting dark mixture was allowed to stir at -78° C. for 15 minutes, warmed to 0° C. for 2 hours, then cooled to -78° C. Ethyl formate (1.47 mL) was added dropwise and the mixture allowed to stir at -78° C. for 30 minutes then at 0° C. for one hour. The reaction mixture was quenched with methanol, concentrated, and chromatographed over silica gel. Recrystallization from hexane/ethyl acetate afforded 2-phenyl-2-[4-(4-pyridyl)-2-thiazolyl]acetaldehyde (1.76 g, 39%). mp. 163°-164° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[C:21]([C:37]([O:39]C)=O)[C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:36])[NH:34][CH3:35])=[CH:29][CH:28]=3)=[CH:23][C:24]=2[O:25][CH3:26])[N:12]=1)(=[O:3])[NH2:2].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:34][CH3:35])=[O:36])=[CH:29][CH:28]=3)=[C:21]([C:37]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:39])[CH:20]=2)[N:12]=1)(=[O:3])[NH2:2]
Reactant: C1CCNC1
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(N)=O)n3)cc2C(=O)OC)cc1
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(N)=O)n3)cc2C(=O)N2CCCC2)cc1
Temperature: 100 °C

Procedure:
The mixture of methyl 4-(4-(2-carbamoylphenylamino)-5-chloropyrimidin-2-ylamino)-5-methoxy-4′-(methylcarbamoyl)biphenyl-2-carboxylate (Step 1, 220 mg, 0.75 mmol) and 1 mL of pyrrolidine is heated at 100° C. overnight. The crude is concentrated in vacuo and applied to preparative RP-HPLC to afford 4′-(4-(2-Carbamoylphenylamino)-5-chloropyrimidin-2-ylamino)-5′-methoxy-N-methyl-2′-(pyrrolidine-1-carbonyl)biphenyl-4-carboxamide; ESMS m/z 600.2 (M+H+).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[C:11]([F:13])[CH:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:30][C:29](=[O:31])[CH2:28]2)=[CH:22][CH:21]=1>CCCCCC.C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:28][C:29]([CH:14]([C:9]3[CH:8]=[C:7]([F:6])[CH:12]=[C:11]([F:13])[CH:10]=3)[C:15]([O:17][CH3:18])=[O:16])([OH:31])[CH2:30]2)=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1cc(F)cc(F)c1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(c1cc(F)cc(F)c1)C1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 2 mL of 1.6M butyllithium in hexane and 2 mL of dry THF was cooled to −78° C. under nitrogen. To this was added a solution of 0.626 g (3.2 mmol) of methyl (3,5-difluorophenyl)acetate in 4 mL of THF and the solution was stirred at −78° C. After 20 min, a solution of 0.600 g (1.95 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 4 mL THF was added and the solution was stirred at −78° C. After 1 h, the reaction was quenched by addition of 10 mL of saturated NH4Cl solution and 20 mL of ether. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was filtered through a plug of silica gel using 25% ether-hexane to afford the title compound; 1NMR(CDCl3) δ 2.91 (d, 1H J=8.3 Hz), 3.14 (d, 1H J=8.0 Hz), 3.17 (d, 2H, J=8.2 Hz), 3.32 (d, 1H J=7.8 Hz), 3.74 (s, 3H), 4.03 (s, br, 1H), 4.42 (s, 1H), 4.42 (s, 1H), 6.76 (m, 1H), 6.6.89 (m, 2H), 7.33 (m, 4H), 7.38 (m, 4H); Mass Spectrum: m/e=492 (M+1 35Cl, 35Cl ) and 494 (M+1 35Cl, 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)([OH:22])[CH2:19]1)=[O:17].Cl.[O:37]1CCO[CH2:39][CH2:38]1>CO>[C:38]([O:22][C:20]1([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:19][N:18]([C:16]([C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:17])[CH2:21]1)(=[O:37])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CC(=O)OC1([C@@H]2CCCCN2)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Yield: 62.5 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (24 mg, 0.040 mmol) was dissolved in methanol (2 mL) and treated with 4 N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at reflux for 20 minutes. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (14 mg, 0.025 mmol, 63% yield): 1H NMR (400 MHz, d6-DMSO): 8.62 (br s, 1H), 8.46 (s, 1H), 8.18 (dd, 1H), 7.65 (dd, 1H), 7.45 (d, 1H), 7.37 (t, 1H), 7.16-7.08 (m, 1H), 4.25 (dd, 1H), 4.04 (dd, 1H), 3.90 (t, 1H), 3.70 (d, 1H), 2.95 (br d, 1H), 2.52-2.42 (m, 2H), 1.78-1.68 (m, 1H), 1.57 (br t, 1H), 1.47 (br d, 1H), 1.35-1.13 (m, 2H), 1.10-0.96 (m, 1H); MS (EI) for C20H22FIN4O2: 497 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16](C(=O)C(F)(F)F)[CH2:15][CH2:14]1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.[OH-].[Na+].O>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:5]=2)(=[O:10])=[O:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c(N3CCNCC3)c2)cc1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride (0.19 g), prepared as in Example 1 Step 2, in THF (0.5 ml) at 0° C. under argon atmosphere was added dropwise a solution of 4-methoxyphenylmagnesium bromide in THF (0.5M, 2 ml; 1 mmol). After stirring at this temperature for 1 h. A solution of 6N NaOH (0.5 ml) was added and the reaction mixture was stirred at ambient temperature for 20 h. Water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 1-[5-(4-methoxy-benzenesulfonyl)2-methoxy-phenyl]piperazine as a white solid (0.65 g, 36%), MS, MH+ 363.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.[C:11]([S-:16])(=[S:15])OCC.[K+].Cl>CN(C=O)C>[SH:16][C:11]1[S:15][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(S)sc2c1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 4-amino-3-chlorobenzonitrile (12.2 g, 80.2 mmol) from Step 1 of this Example in DMF (60 mL) was added potassium O-ethyl carbonodithioate (28.9 g, 180.7 mmol) at rt. The mixture was refluxed for 4 h. After cooling to rt, the reaction mixture was poured into ice water and acidified with 2N aq HCl. The tan solids were collected and dried in vacuum oven overnight. Then the solids were refluxed with 500 mL of CHCl3 for 10 min. After cooling to rt, the mixture was treated with 200 mL of hexanes and sonicated for 20 min. The pale brown solid was collected by filtration to give 2-mercaptobenzo[d]thiazole-6-carbonitrile (12.9 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 14.16 (br s, 1H), 8.23 (d, J=0.9 Hz, 1H), 7.83 (dd, J=1.3, 8.5 Hz, 1H), 7.31-7.51 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(OCC)(=O)C.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:63]=[CH:62][C:52]2[NH:53][C@@H:54]([CH2:57][C:58]([NH:60][CH3:61])=[O:59])[CH2:55][O:56][C:51]=2[CH:50]=1>C(OCCCC)(=O)C.O>[F:48][C:49]1[CH:63]=[CH:62][C:52]2[N:53]([C:12]([C:9]3[CH:10]=[CH:11][C:5]4[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:14])[C@@H:54]([CH2:57][C:58]([NH:60][CH3:61])=[O:59])[CH2:55][O:56][C:51]=2[CH:50]=1
Reactant: CNC(=O)C[C@H]1COc2cc(F)ccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCCCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C[C@H]1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 80 °C
Yield: 50.9 %

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (9.58 g, 48.0 mmol) was suspended with stirring in n-butyl acetate (48 mL). T3P in ethyl acetate (52.5 mL, 87.5 mmol, 50.0% w/w) was added followed by DIPEA (3.82 mL, 21.9 mmol). The resulting suspension was heated at 80° C. over night. 2-[(3S)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]-N-methylacetamide (Intermediate 13, 10.0 g, 43.7 mmol) was added portion wise over approximately 90 min and then held at 80° C. over night. Water (100 mL) was added and the mixture stirred at 40° C. The organic phase was collected and washed with aqueous sodium hydrogen carbonate (100 mL, 5.25% w/w) at 40° C. The organic phase was cooled to 10° C. and stirred over night. Isopropanol (100 mL) was added and the solid collected by filtration and dried under vacuum at 40° C. The title compound was obtained as an off-white solid (9.29 g, 22.3 mmol, 95.7% w/w, ee 98.4%, 50.9% yield).
Reaction SMILES: [CH2:1]([C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]([CH2:20][CH2:21][CH3:22])=[C:12]2[C:17]=1[CH:16]=[C:15]([I:18])[C:14]([I:19])=[CH:13]2)[CH2:2][CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:20]([C:11]1[C:10]2[C:5]([C:4]([CH2:1][CH2:2][CH3:3])=[C:17]3[C:12]=1[CH:13]=[C:14]([I:19])[C:15]([I:18])=[CH:16]3)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:21][CH3:22]
Reactant: CCCc1c2c(c(CCC)c3cc(I)c(I)cc13)CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCCc1c2ccccc2c(CCC)c2cc(I)c(I)cc12
Yield: 42.4 %

Procedure:
9,10-Dipropyl-2,3-diiodo-5,6,7,8-tetrahydroanthracene (0.259 g, 0.5 mmol), 2,3-dichloro-5,6-dicyanobenzoquinone (0.341 g, 1.5 mmol) and 1,4-dioxane (3 ml) were charged in a reactor. Then, the mixture was refluxed for an hour. After cooling, the precipitates were removed by filtration. The solvent in the mixture was removed in vacuum. Column chromatography (hexane) was performed to give the title compound (0.109 g) as a light yellow solid. The isolation yield was 42%.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[C:6]([C:7]([F:10])([F:8])[F:9])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)c(C(F)(F)F)nn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)c(C(F)(F)F)nn1C
Yield: 62.5 %

Procedure:
3-(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.08 mmol) was treated with 4-fluorophenyl isocyanate (0.01 g, 8.99 μL, 0.08 mmol, 1.1 equiv.) in CH2Cl2 (2.0 mL), in a similar manner as described in Example 1.102, to afford Compound 39 (0.03 g, 0.05 mmol, 64% yield) as a white solid: LCMS m/z (%)=487 (M+H79Br, 100), 489 (M+H81Br, 93). 1H NMR (400 MHz, MeOH-d4) δ: 7.58 (dd, J=10.0, 2.0 Hz, 1H), 7.42 (dd, J=4.0 Hz, 2H), 7.38 (dd, J=10.0, 2.0 Hz, 1H), 7.16 (d, J=12.0 Hz, 1H), 7.03 (dd, J=12.0, 8.0 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.[ClH:20].Br[C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][C:33]3[N:34]=[CH:35][NH:36][CH:37]=3)[CH2:30][CH2:29][N:28]([C:38]([C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][CH:41]=3)=[O:39])[CH2:27][C:26]=2[CH:50]=1>>[ClH:20].[ClH:20].[ClH:20].[NH:36]1[CH:37]=[C:33]([CH2:32][N:31]2[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)=[CH:50][C:26]=3[CH2:27][N:28]([C:38]([C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][CH:41]=3)=[O:39])[CH2:29][CH2:30]2)[N:34]=[CH:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccnc3)cc2C1
Yield: 8 %

Procedure:
Example 67 was prepared as a yellow solid in 8% yield from Compound A of Example 37 and 3-(tributylstannyl)pyridine as described for Compound B of Example 37.
Reaction SMILES: Cl.ClC1C2NC(=O)C=CC=2CCC1.O.N.O.O.O.[OH:19][CH:20]1[C:29]2[NH:28][C:27](=[O:30])[CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[O:19]=[C:20]1[C:29]2[NH:28][C:27](=[O:30])[CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: O=c1ccc2c([nH]1)C(O)CCC2
Agent: Cl
Agent: N
Agent: O=c1ccc2c([nH]1)C(Cl)CCC2
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCCc2ccc(=O)[nH]c21
Reaction time: 3 h
Yield: 83.2 %

Procedure:
110 g (0.5 mol) of 8-chloro-5,6,7,8-tetrahydro-2-quinolone hydrochloride are heated with 500 ml of water to about 90° C. with agitation, thus obtaining after a short time a transparent solution which is then neutralized with 75 ml of concentrated ammonia. After cooling of the solution, 105 g of 8-hydroxy-5,6,7,8-tetrahydro-2-quinolone trihydrate areisolated having a melting point of 192° C., which correspond to a yield of 85.7% of theory. 105 g (0.48 mol) of trihydrate are heated with 2liters of chloroform while stirring, the hydration water is removed in the form of an azeotropic mixture, and the chloroform phase of the distillate is recycled to the flask. After this operation is complete, 350 g of manganese dioxide (precipitated in an active form) are added to the chloroform solution in portions and in such a manner that the reaction temperature does not exceed 40° C. Intense agitation is continued at this temperature for 3 hours. Subsequently, the batch is separated fromthe manganese dioxide, the chloroform is distilled off, and 65 g of light brown 8-oxo-5,6,7,8-tetrahydro-2-quinolone, corresponding to a yield of 83% of theory, are isolated, which after recrystallization from cyclohexanone has a melting point of 253° C. in a closed vial.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+].CO>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]-phenyl]-2methoxypropanoate (1.5 g), 10% aqueous sodium hydroxide solution (7.5 mL) and methanol (23 mL) was stirred for 1.5 hrs at room temperature and then diluted with water (600 mL), washed with dichloromethane (300 mL) and acidified to pH2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (3×300 mL) and the combined ethyl acetate solutions washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate-dichloromethane-hexane to afford the title compound, mp 150°-153° C.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[CH3:6][C:7]1[CH:8]=[C:9]([C:24]2[CH:25]=[C:26]([C:30]3([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:27]=[N:28][CH:29]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1.[NH4+].[OH-]>C1COCC1.O>[OH:36][C:30]1([C:26]2[CH:27]=[N:28][CH:29]=[C:24]([C:9]3[CH:10]=[C:11]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][N:15]=4)[CH:12]=[C:7]([CH3:6])[CH:8]=3)[CH:25]=2)[CH2:31][CH2:32][N:33]([C:2]([NH2:3])=[O:1])[CH2:34][CH2:35]1
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCNCC3)c2)c1
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(C3(O)CCN(C(N)=O)CC3)c2)c1
Temperature: 50 °C

Procedure:
Potassium cyanate (11.9 mg, 0.147 mmol) and HCl (138 μL, 0.138 mmol) was added to the 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidin-4-ol (50.0 mg, 0.092 mmol) in THF (383 μL) and water (1.15 mL) and heated to 50° C. for 4 hours. The reaction mixture was cooled to room temperature and neutralize with aqueous 10% NH4OH. The resulting precipitate was collected by filtration to yield 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidine-1-carboxamide. MS APCI calc'd for C23H24F3N6O2 [M+H]+ 473. found 473. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.82 (d, J=5.2 Hz, 1H), 8.68 (dd, J=2.4 Hz, 6.3 Hz, 2H), 8.02 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.25 (d, J=10.2 Hz, 1H), 7.22 (s, 1H), 5.92 (s, 2H), 3.85 (d, J=16.4 Hz, 2H), 3.09 (t, J=14.5 Hz, 2H), 2.36 (s, 3H), 1.88 (t, J=15.9 Hz, 2H), 1.63 (d, J=14.3 Hz, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=O.[Mg+2].ClCCl.[I:41]Cl>O.C(#N)C>[I:41][C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=[CH:12][C:11]=2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])[CH:8]=1
Reactant: ClI
Reactant: C[Si](C)(C)CCOCn1ncc2c(ccn2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To 65 ml of acetonitrile solution containing 7.0 g (18 mmol) of 1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 18-(a) were added 6.0 g (71 mmol) of sodium hydrogencarbonate and 12.4 g (103 mmol) of anhydrous magnesium sulfate under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. Then, 4.0 g (36 mmol) of s-caprolactam and 35.5 ml (35.5 mmol) of dichloromethane solution containing 1M iodine chloride were added to the mixture, and the mixture was further stirred for 3 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with 5% aqueous sodium hydrogen sulfite solution and then a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=5:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 7.3 g of the title compound as a brownish solid. (Yield: 79%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15](O)=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)Cl.C(Cl)(=O)[C:22](Cl)=[O:23].Cl>Cl[Ti](Cl)(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:22](=[O:23])[CH2:15][CH:10]1[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cccc(C2CCCCC2C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C1CCCCC1CC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Combine 2-(3-methoxy-phenyl)-cyclohexane carboxylic acid (11.50 g, 46.3 mmol), methylene chloride (200 mL), catalytic DMF (4.0 mL) and slowly add oxalyl chloride (4.8 mL, 55.6 mmol), stir at room temperature. After 1.5 hours, at 0° C. add TiCl4 (12.7 mL, 115.78 mmol) and let reaction warm to room temperature. After 3.5 hours, quench reaction with ice water and add 5N HCl. Allow reaction mixture to stir for 30 minutes then extract with ethyl acetate and wash with sodium bicarbonate solution (aq), then Brine. Dry the organic phase with anhydrous sodium sulfate then concentrate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (9.91 g, 93%) as a yellow oil. TLC Rf=0.26 in 5:1 hexanes:ethyl acetate 1H NMR (CDCl3): 8.01 (d, 1H, J=8.8 Hz), 6.83 (m, 1H), 6.72 (m, 1H), 3.86 (s, 3H), 2.89 (m, 2H), 2.45 (m, 2H), 1.60 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:13][O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Br:1])=[CH:3][C:4]=1[F:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(Br)cc1F
Reaction time: 5 h
Yield: 96.6 %

Procedure:
A solution of 4-bromo-2-fluoro-5-nitrophenol (25 g, 106 mmol) in DMF (200 mL) was treated with potassium carbonate (28.9 g, 212 mmol) and methyl iodide (12.8 mL, 212 mmol). The reaction mixture was stirred at 60 C for 5 hours and evaporated in vacuo. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under vacuum to afford the product (25.6 g, 97%) as a yellow solid. LC-MS (ES) (M+H)+ m/z=251.