Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[CH2:24][CH3:25].CNCCN.ClC1C=CC=C(Cl)C=1[C:34]([NH:36][C:37]1C=CC=C2[C:46]=1[N:45]=[CH:44]C(CC)=C2CNCCNC)=[O:35].C(N1C=CN=C1)(N1C=CN=C1)=O>COCCOC.CN1CCN(C)C1=O.O>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([CH2:24][CH3:25])=[C:3]2[CH2:2][N:36]1[CH2:37][CH2:46][N:45]([CH3:44])[C:34]1=[O:35])=[O:23]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CNCCNC
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Agent: CNCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCN(C)C1=O
Solvent: COCCOC
Solvent: O
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CN1CCN(C)C1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (150 mg) and N-methylethylenediamine (141 mg) in 1,2-dimethoxyethane was stirred for 2 hours at 70° C. The mixture was partitioned between dichloroethane and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give a residue containing 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-[(2-methylaminoethyl-amino)methyl]quinoline. To the solution of the obtained residue in 1,3-dimethyl-2-imidazolidinone was added 1,1'-carbonyldiimidazole (309 mg), and the mixture was stirred for 30 minutes at 70° C., for 1 hour at 100° C. and for 1 hour at 150° C. Water was added to the mixture, and the resulting precipitates were collected by filtration. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) and crystallized from isopropyl alcohol to give 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(3-methyl-2-oxoimidazolidin-1-ylmethyl)quinoline (28.6 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:14]=[O:15])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N=C=O)cc1

Procedure:
To a solution of 1.5 g (9.08 mmol) 4-amino-benzoic acid ethyl ester in 16 ml of THF was added 0.621 ml (5 mmol) of trichloromethyl chloroformate. The reaction mixture was stirred under reflux for 1 h and then concentrated under reduced pressure to dryness. The crude 4-Isocyanato-benzoic acid ethyl ester was used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[C:64]([CH:69]=[C:70]([O:72][CH3:73])[CH:71]=1)[C:65]([O:67][CH3:68])=[O:66]>ClCCl>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:60][CH2:61][C:62]3[CH:63]=[C:64]([CH:69]=[C:70]([O:72][CH3:73])[CH:71]=3)[C:65]([O:67][CH3:68])=[O:66])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1cc(CN)cc(OC)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)OC)c3)cn2)C1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (50 mg, 0.14 mmol) and HATU (63 mg, 0.17 mmol) in dry dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.075 mL, 0.42 mmol) at 20-25° C. The mixture was stirred for 10 min, then methyl 3-(aminomethyl)-5-methoxybenzoate hydrochloride was added (33 mg, 0.14 mmol) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 1 hour. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (10 mL), washed with water (2 times with 10 mL), and dried over NaSO4. The organics were concentrated under reduced pressure to obtain methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoate (65 mg, 87%).
Reaction SMILES: CCN(CCN[C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])CC.CCN(C(C)C)C(C)C.CN(C([O:46][N:47]1[N:55]=[N:54][C:49]2[CH:50]=[CH:51][CH:52]=[N:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:25][C:26](=[O:27])/[C:18]/2=[CH:17]\[C:13]1[NH:14][C:15]([CH3:16])=[C:11]([C:9]([O:46][N:47]2[C:48]3=[N:53][CH:52]=[CH:51][CH:50]=[C:49]3[N:54]=[N:55]2)=[O:10])[C:12]=1[CH3:29]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
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: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
15 (10 g, 33.3 mmol) was suspended in DMF (50 ml, 5 P.) and stirred for 5 minutes. DIPEA (9.0 mL, 54.5 mmol) was then added and the mixture was stirred for 10 minutes. HATU (13.95 g, 36.7 mmol) was added and the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight. The intermediate (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (15b) (12 g, 86.5 percent yield) with 86.8% HPLC purity as a yellow powder was got. 1H NMR (300 MHz, DMSO-d6): δ 2.61 (s, 3H, H-31), 2.68 (s, 3H, H-16), 6.87 (m, 1H, H-2), 7.01 (m, 1H, H-6), 7.64 (m, 1H, H-10), 7.85 (m, 1H, H-3), 8.73 (dd, J=1.5, 1.2 Hz, 1H, H-28), 8.83 (dd, J=1.2, 1.5 Hz, 1H, H-27), 13.11 (s, 1H, NH). To a 15b (10.0 g, 23.9 mmol) DMF solution was added N,N-diethylethane-1,2-diamine (7; 3.33 g, 28.7 mmol), the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight to give Sunitinib (8.38 g, 88% yield) with 77.6% HPLC purity.
Reaction SMILES: II.[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C@@H:20]2[C:34](=[O:35])[NH:33][C@H:32]([CH2:36][S:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:31](=[O:57])[NH:30][C@H:29]([CH:58]([CH3:60])[CH3:59])[C@@H:28]([OH:61])[CH2:27][C:26](=[O:62])[O:25][C@H:24](/[CH:63]=[CH:64]/[CH2:65][CH2:66][S:67]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:23][C:22](=[O:87])[NH:21]2)=[CH:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CO>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C@@H:20]2[C:34](=[O:35])[NH:33][C@@H:32]3[CH2:36][S:37][S:67][CH2:66][CH2:65][CH:64]=[CH:63][C@@H:24]([O:25][C:26](=[O:62])[CH2:27][C@H:28]([OH:61])[C@@H:29]([CH:58]([CH3:60])[CH3:59])[NH:30][C:31]3=[O:57])[CH2:23][C:22](=[O:87])[NH:21]2)=[CH:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)C[C@@H]1O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](Cc3cn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N2)OC(=O)C[C@@H]1O
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](Cc3cn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N2)OC(=O)C[C@@H]1O

Procedure:
To a solution of iodine (107.2 mg, 0.42 mmol) in CH2Cl2/MeOH (9:1, 143 mL) was added dropwise a solution of 6B (48.4 mg, 0.0041 mmol) in CH2Cl2/MeOH (9:1) (70 mL) over 30 min, the reaction mixture was then allowed to stir for a further 30 min after which time sodium thiosulfate (26 mL, 0.05 M) was added. The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×20 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography on silica gel (eluent 0:100-1:99-3:97 MeOH/CH2Cl2) which gave 7B (13 mg, 0.019 mmol, 46%) as a white solid: Rf 0.18 CH2Cl2/MeOH (97:3); [α]28D=−1.9 (c 0.36, CHCl3); IR (thin film) 3379 (br), 3343 (br), 2974 (m), 2931 (m), 1732 (s), 1662 (s), 1538 (m), 1519 (m), 1453 (m), 1371 (s), 1333 (m), 1310 (m), 1271 (m), 1255 (s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:3]=2)[CH:19]=[N:18]1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Temperature: 90 °C
Yield: 68 %

Procedure:
A mixture of 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (0.50 g, 2.246 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.467 g, 2.246 mmol), and Cs2CO3 (1.463 g, 4.49 mmol) in dioxane/H2O (5:1, 6 mL) was sparged with argon, treated with Pd(PPh3)4 (0.260 g, 0.225 mmol), sparged again with argon and heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration, rinsed with dioxane and the filtrate concentrated to dryness. The material was treated with EtOAc, the solid collected via filtration, rinsed with EtOAc and H2O and dried to obtain product. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4, concentrated to dryness, triturated with EtOAc and the solid collected via filtration and combined with the above-isolated product to afford 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (410 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, J=1.1 Hz, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.78 (d, J=2.9 Hz, 1H), 7.30-7.25 (m, 2H), 6.48 (d, J=8.9 Hz, 1H), 5.94 (s, 2H), 3.88 (s, 3H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Into a 1-Neck round-bottom flask 4-(Hydroxymethyl)piperidine (6.53 g, 56.7 mmol), Potassium carbonate (7.84 g, 56.7 mmol), Acetonitrile (50 mL, 1000 mmol), and [A] 4-Fluoronitrobenzene (4.00 g, 28.3 mmol)were added. The reaction was heated at 60° C. overnight. The reaction content was poured into ice water and stirred for 30 minutes. The solid was filtered, washed with water and dried under vacuum to give [1-(4-Nitro-phenyl)-piperidin-4-yl]-methanol as an off-white solid (5.20 g, 78%). NMR 1H (DSMO-d6)-8.02 (d, 2H, J=9.40 Hz), 7.00 (d, 2H J=9.49 Hz), 4.50 (bs, 1H), 4.07 (bd, 1H, J=13.33 Hz), 3.27 (d, 1H, J=5.84 Hz), 2.94 (t, 2H), 1.80-1.95 (m, 3H), 1.02-1.13 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:11]2[CH:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[CH2:3]1.[OH-].[K+]>C(O)CCC.O>[CH3:1][C:2]1([CH3:24])[N:11]2[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[CH2:3]1
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(C)(C)CN3C
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CN1CC(C)(C)N2c3c(cccc31)C1CNCCC12
Temperature: 120 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (8 mg, 0.02 mmol) in n-butanol (5 mL) at rt was added KOH (50 mg, 0.89 mmol) and stirred at 120° C. for 20 hours. The solution was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford the title compound (5 mg, 81%). MS [M+H]+258.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:5][CH:4]([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:3]1.Br[CH2:17][C:18]1[CH:37]=[CH:36][C:21]2/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[O:25][CH2:26][C:20]=2[CH:19]=1>>[F:15][C:2]1([F:1])[CH2:3][CH:4]([C:6]2[N:7]([CH2:17][C:18]3[CH:37]=[CH:36][C:21]4/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=5[O:25][CH2:26][C:20]=4[CH:19]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:5]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: FC1(F)CC(c2nc3ccccc3[nH]2)C1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC(F)(F)C4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 96.9 %

Procedure:
[step 3] Using 2-(3,3-difluorocyclobutyl)-1H-benzo[d]imidazole (57 mg, 0.27 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (100 mg, 0.28 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (127 mg, 96%) was obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O-:41].[Na+]>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12]([O:41][CH3:40])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 105 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol (61.9 mg, 0.108 mmol, Intermediate 37) and sodium methoxide (0.0313 g, 0.579 mmol) were charged to a microwave vial with dry toluene (0.57 mL) and heated to 105° C. for 4 hours. The mixture was allowed to cool to room temperature, then filtered through Celite® and rinsed with dichloromethane. The filtrate was concentrated to dryness and purified by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.46 (d, J=4.0 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.84 (dd, J=2.5, 0.5 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.68-7.63 (m, 2H), 7.56-7.52 (m, 2H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 7.33 (dd, J=6.5, 4.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.25-7.20 (m, 3H), 6.42 (dd, J=2.4, 1.8 Hz, 1H), 4.29 (s, 2H), 4.08 (s, 3H); MS m/e 567.2 [M+H]+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:19]1[CH:18]=[N:17][C:16]([O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[N:21][CH:20]=1
Reactant: Oc1ccccc1O
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccccc1Oc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a mixture of 6.0 grams (0.055 mole) catechol and 7.0 grams of potassium carbonate stirring in 45 ml of dimethylformamide, 7.0 grams of 2,5-dichloropyrimidine was added and the mixture stirred at room temperature overnight followed by heating at 80° for 4 hours. Excess water was added to the reaction mixture, and the aqueous mixture extracted with 300 ml of ethyl ether. The ether extract was washed with H2O (2X), brine, dried (magnesium sulfate), filtered, and the solvent removed to yield a yellow oil which slowly crystallized. From a 1-chlorobutane/cyclohexane mixture, the crude solid was recrystallized to give 6.0 grams of product, m.p. 131°-139°; ir (Nujol): 2.90-3.30 (OH), 12.80, 13.30 microns.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7](O)=[N:6][C:5]=1[CH3:13].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>O=P(Cl)(Cl)Cl>[Cl:16][C:7]1[C:8]([C:10]#[N:11])=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:14])=[C:5]([CH3:13])[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C#N)c(O)nc1C
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(C#N)c(Cl)nc1C
Temperature: 110 °C
Yield: 137 %

Procedure:
A mixture of methyl-5-cyano-6-hydroxy-2-methylnicotinate (2.0 g, 10.41 mmol), POCl3 (40 mL) and PCl5 (1.08 g, 5.2 mmol) was heated to 110° C. for 24 h. The reaction mixture was concentrated under reduced pressure and quenched with ice-water. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford methyl 6-chloro-5-cyano-2-methylnicotinate (1.5 g, yield 68%). 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 3.96 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH3:22].[CH:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:25]([O:24][C:21]([CH:22]=[CH:29][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: COc1nc(Cl)nc(OC)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of anhydrous i-Pr2NH (1.76 ml, 12.49 mmol) in anhydrous THF (30 ml) stirred at 0° C. under nitrogen, was slowly added a solution of n-BuLi (5.36 ml, 13.40 mmol, 2.5 M in hexane). After 30 min, LDA was cooled to −78° C. and t-butyl acetate (1.64 ml, 12.18 mmol) was added dropewise. After 30 min, a solution of methyl 4-formylbenzoate (1.00 g, 6.09 mmol) in anhydrous THF (10 ml) was slowly added. After 2 h, a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.604 g, 9.14 mmol) in anhydrous THF (10 ml) was added. Then, the temperature was allowed to warm up to room temperature overnight. A suspension appeared. The reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/hexane:10/90→15/85) to give the title product VI (785 mg, 3.00 mmol, 49% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ(ppm): AB system (δA=8.04, δB=7.57, J=8.4 Hz, 4H), 7.60 (d, J=15.4 Hz, 1H), 6.46 (d, J=15.8 Hz, 1H), 3.93 (s, 3H), 1.54 (s, 9H). 13C NMR (75 MHz, CDCl3) δ(ppm): 166.72, 166.01, 142.31, 139.18, 131.33, 130.26, 127.99, 122.87, 81.11, 52.46, 28.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=O)[C:6]=2[CH:14]=1.[O:15]1[C:24]2[CH:23]=[C:22]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:21]=[CH:20][C:19]=2[O:18][CH2:17][CH2:16]1.CO>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][N:37]3[CH2:36][CH2:35][CH:34]([N:26]([CH2:25][C:22]4[N:21]=[CH:20][C:19]5[O:18][CH2:17][CH2:16][O:15][C:24]=5[CH:23]=4)[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:39][CH2:38]3)[C:6]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)sc2ccc(Cl)cc21
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 101.3 %

Procedure:
(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetaldehyde (0.10 g, 0.44 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (0.154 g, 0.44 mmole) (for a synthesis see WO2004/058144 Example 99(h)) were dissolved in chloroform (10 ml) and MeOH (1.5 ml) and treated with acetic acid (8 drops) and (polystyrylmethyl)trimethylammonium cyanoborohydride (Novabiochem) (4.1 mmol/g, 0.87 g), and the mixture stirred at rt for 60 h. The reaction was filtered and evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0-12% MeOH/DCM gave 1,1-dimethylethyl {1-[2-(5-chloro-2-oxo-1,3-benzthiazol-3(2H)-yl)ethyl]-4-piperidinyl}(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)carbamate as an oil (0.25 g, 100%). MS (ES+) m/z 561 and 563 (MH+). This was dissolved in DCM (10 ml) and treated with trifluoroacetic acid (3 ml) at rt for 18 h then evaporated to dryness. The residue was partitioned between 10% potassium carbonate in water (30 ml) and 10% MeOH in DCM (3×30 ml). The organics were dried, filtered and evaporated to dryness. Chromatography on silica gel eluting with a gradient of 0-10% 2M ammonia in MeOH/DCM gave the free base of the title compound as an oil (0.138 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([C:7]1[N:8]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:9]2[C:10]([C:19]=1[NH2:20])=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1c(N)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a solution of (2-cyano-4-trifluoromethylphenylamino)acetic acid tert-butyl ester 5B (11.7 g, 39.0 mmol) in anhydrous THF (60 mL) and anhydrous DMF (60 mL) at 0° C. was added potassium tert-butoxide (8.74 g, 78.0 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and benzyl chloroformate 5C (10 g, 58.7 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Ethyl acetate (500 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-amino-1-benzyloxycarbonyl-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5D (5.96 g, 13.7 mmol).