Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:49])([F:48])[F:47])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1COCC1.CO.O.[OH-].[Li+].O>>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:46]([F:47])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:50][CH2:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)O)CC3)c3c2C(=O)N(C)C3)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-ethoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 245, 23.4 mg, 0.031 mmol) was taken up in THF (0.042 mL, 0.52 mmol) and MeOH (0.042 mL, 1.0 mmol). This was treated with a solution of lithium hydroxide, monohydrate (6.57 mg, 0.16 mmol) in H2O (0.042 mL, 2.30 mmol) and allowed to stir at rt for 30 hrs. The reaction was concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM] to afford 22.3 mg (99%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 4.54 (s, 1H), 4.05-4.21 (m, 6H), 3.29 (s, 2H), 3.20 (s, 3H), 2.60-2.69 (m, 1H), 2.38-2.48 (m, 1H), 2.15 (d, J=11.87 Hz, 2H), 1.91-1.98 (m, 2H), 1.56-1.77 (m, 4H), 1.43 (t, J=6.95 Hz, 3H), 1.30 (t, 6H). MS (ES+): m/z 720.22/721.25 (100/98) [MH+]. HPLC: tR=1.54 min (Micromass TOF: polar—3 min)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:13]12>>[OH:10][C:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]([C:15](=[O:16])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[NH:12][CH3:11])[N:2]=1
Reactant: O=c1[nH][nH]c2cccnc12
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CNc1ccccc1C(=O)n1nc(O)c2ncccc21
Yield: 84.8 %

Procedure:
Pyrazolo[4,3-b]pyridine-3(2H)-one was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 84.8% yield; m.p. 221°-223° C.,
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3cccc(C#N)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-cyanophenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 262; HRMS: calcd for C18H15NO+H+, 262.12264; found (ESI, [M+H]+), 262.1219.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Nc1cncc(Br)c1
Product: CS(=O)(=O)Nc1cncc(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and N-(5-bromopyridin-3-yl)methanesulfonamide (prepared according to the method described in WO2008141065), the title compound was obtained as a beige solid after purification.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])[N:15]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.[O:35]1CCOCC1>O.O=[Os](=O)(=O)=O>[CH:1]([C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])[N:15]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:12]2=[N:13][CH:14]=1)=[O:35]
Reactant: C[Si](C)(C)CCOCn1c(-c2cccc(C(=O)O)c2)cc2nc(/C=C/c3ccccc3)cnc21
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2cccc(C(=O)O)c2)cc2nc(C=O)cnc21
Yield: 100 %

Procedure:
(E)-3-(2-Styryl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoic acid (0.940 g, 1.99 mmol; prepared using D from Preparation #V.1 with (E)-styrylboronic acid), OsO4 (2.5 wt % in t-BuOH, 1.00 mL, 0.080 mmol) and NaIO4 (1.71 g, 7.97 mmol) were added to a stirred mixture of 1,4-dioxane (10 mL) and water (2 mL) at rt. After about 4.5 h the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to provide 3-(2-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoic acid (0.792 g, 100%): LC/MS (Table 2, Method c) Rt=1.45 min; MS m/z 398 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[CH3:16]I>C1COCC1>[CH3:16][O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.5 g, 2.67 mmol) in THF (20 mL) at 0° C. was added NaH (60%, 0.077 g, 3.2 mmol) and the mixture was stirred for 15 min. Methyl iodide (0.2 mL, 3.2 mmol) was slowly added and the reaction was stirred for 18 h at ambient temperature. The reaction was quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic extracts were washed with water (6 mL), brine (8 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by FCC eluting with DCM to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:32][C@@H:33]1[CH2:37][NH:36][C@H:35]([CH2:38][O:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)[CH2:34]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:36]3[CH2:37][C@@H:33]([O:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:22]=4)[CH2:34][C@H:35]3[CH2:38][O:39][C:40]3[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (141 mg, 0.50 mmol), methyl 4-((2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinylmethoxy)benzoate (189 mg, 0.50 mmol), EDC•HCl (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol) and triethylamine was stirred at room temperature for 16 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was separated and purified by chromatography on a thin-layer silica gel column with (chloroform/acetone (5/1)), whereby the title compound (312 mg, 97%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:22]([O:25]C)=[N:23][N:24]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=2)([CH3:3])[CH3:2]>CC(O)=O.Br>[CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:22](=[O:25])[NH:23][N:24]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([CH2:15][N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COc1nnc2c(NC(C)C)nc3cc(CN4CCOCC4)ccc3n12
Agent: Br
Solvent: CC(=O)O
Product: CC(C)Nc1nc2cc(CN3CCOCC3)ccc2n2c(=O)[nH]nc12
Temperature: 23 °C

Procedure:
A solution of isopropyl-(1-methoxy-7-morpholin-4-ylmethyl-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-amine (32 mg) in AcOH (0.5 mL) and 48% HBr (0.5 mL) was heated at 50° C. for 2.5 hrs. After cooling to 23° C., the solution was concentrated. The resulting residue was concentrated from toluene, and then triturated with MeOH/EtOAc. The resulting solid was isolated by filtration, and then concentrated from MeOH to afford a light yellow solid. MS (M+H)+=341.3.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C:6]([Cl:19])([Cl:18])[C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2.Cl>CO>[Cl:18][C:6]([Cl:19])([C:7]12[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][C:9]([OH:17])([CH2:15]3)[CH2:8]1)[CH2:16]2)[C:5]([OH:20])=[O:4]
Reactant: COC(=O)C(Cl)(Cl)C12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cl)(Cl)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C

Procedure:
A 500 ml round-bottomed flask was charged with methanol (200 ml) and 1 N NaOH (194 ml, 194 mmol, approximately 1.36 equivalents relative to input dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid methyl ester (Formula VIII)). The resulting solution was cooled in an ice bath until the temperature was <9° C. The cold bath was removed and dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid methyl ester (Formula VIII)(41.68 g, 142.1 mmol) was added. The resulting suspension was allowed to stir at ambient temperature under argon. After stirring for approximately 6 hours, an additional portion of methanol (10 ml) was used to rinse down the vessel walls. After stirring for approximately 17 hours, the reaction mixture was filtered to remove a small amount of particulate material. The resulting solution was transferred to a 2-liter three-necked flask equipped with a mechanical stirrer. Water (900 ml) was used to dilute the reaction mixture and to compete the transfer. The resulting solution was acidified by the addition of concentrated HCl (38 ml, approximately 456 mmol). A white solid quickly formed. The mixture was gently stirred for approximately 20 minutes and then placed in an ice bath. After gently stirring for approximately 90 minutes, the stirrer was stopped and the mixture was allowed to stand in the ice bath for an additional 2 hours. The resulting suspension was filtered and the filtercake was washed with ice cold water. The bulk of the water was removed from the solid by pulling air through the filtercake. The material was then dried under vacuum at ambient temperature for 22 hours to give dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid (Formula IX) as a colorless powdery solid: 39.19 grams (98.7% yield); mp 238° C. (dec).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[N:17]([CH2:26][CH2:27][O:28]C[Si](C(C)C)(C(C)C)C(C)C)[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[N:17]([CH2:26][CH2:27][OH:28])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: CC(C)[Si](COCCn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NCC#N)cc2ccc(Cl)cc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(Cl)cc2n1CCO
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 140 mg (0.25 mmol) of 6-chloro-1-{2-[(triisopropylsilanyl)-methoxy]-ethyl}-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide dissolved in 20 mL THF was added 66 mg (0.25 mmol) of tetrabutylammonium fluoride (1.0 M in THF). The reaction mixture was stirred at room temperature for several hours, concentrated, and purified by column chromatography eluting with 70% ethyl acetate in hexane to provide 50 mg of 6-chloro-1-(2-hydroxy-ethyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide. HPLC: 98% pure, yield: 50%, MS: 403 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl.Cl.[C:17]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:44])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:35])[CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)CCC>[C:17]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:2]2[S:3][C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)[CH2:28][CH2:27]1)=[O:44]
Reactant: Cc1nc(Br)sc1C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)OC(C)(C)C
Yield: 28.6 %

Procedure:
tert-Butyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (247 mg, 0.739 mmol), the compound (199 mg, 0.369 mmol) obtained in Example 11c, triethylamine (180 μL) and 4.0 mL of n-butanol were used to give the title compound (70 mg; yield, 29%) as a colorless oily substance according to the same procedure as in Example 104b.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[C:19]([CH3:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[C:19]([CH3:25])=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1c(O)cccc1Cl
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Cl)cccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 40.9 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-chloro-2-methylphenol (26 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-chloro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (15 mg, 41%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.55-7.65 (m, 3H), 7.16 (d, J=8.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 5.22 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15]C3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C#CC2CC3(CCN(C([O:39][C:40](C)(C)C)=O)CC3)ON=2)C=CC=CC=1.COC1C(=C)CN(C(OC(C)(C)C)=O)C1.C(Cl)(Cl)[Cl:60]>>[Cl:60][C:5]1[CH:6]=[C:1]([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH:18]([O:39][CH3:40])[CH2:17][NH:16][CH2:15]3)[O:11][N:10]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Agent: C=C1CN(C(=O)OC(C)(C)C)CC1OC
Product: COC1CNCC12CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with the compound of Example 125 and using chloroform as the solvent. The crude residue was used without further purification in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH2:22].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COCCOc1ccc2c(Cl)c(C#N)cnc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COCCOc1ccc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2c1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
A mixture of 4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (262 mg, 1.0 mmol), 2,4-dichloroaniline (195 mg, 1.2 mmol) and pyridine hydrochloride (140 mg, 1.2 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for 30 minutes. The reaction mixture is cooled to room temperature partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with a 1:1 mixture of saturated sodium bicarbonate and 5 N sodium hydroxide. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography, eluting with a gradient of 1:1 ethyl acetate:hexane to all ethyl acetate provides 103 mg of 4-[(2,4-dichlorophenyl)amino]-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 144-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>C1COCC1.CO.O>[CH2:13]([C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[C:3]([C:1]#[N:2])[N:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)OC)cc(C#N)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(C(=O)O)cc(C#N)n1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-cyano-6-ethylisonicotinate (0.233 g, 1.23 mmol, Eq: 1.00) was diluted in THF (12.1 ml) and MeOH (1.46 ml). At 2-3° C., 1M LiOH in water (1.53 ml, 1.53 mmol, Eq: 1.25) was added dropwise (over 3 min) The RM was stirred at 2-3° C. for 30 minutes. Control with TLC: the reaction was finished. The reaction mixture was acidified with 1M HCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo. White solid. MS (EIC): 174.9 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([O:15]C)=[O:14].O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([OH:15])=[O:14]
Reactant: COC[C@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H]1CCCN1Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-5-methylbenzoate (120 mg, 0.43 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (180 mg, 4.3 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 264 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:3].[C:19](ON1C(=O)CCC1=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:19]([NH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:2]([OH:4])=[O:3])[CH:6]=2)=[CH:18][CH:17]=1)([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2cccc(C(=O)O)c2)cc1)OCC1c2ccccc2-c2ccccc21
Yield: 47.5 %

Procedure:
A solution of 4-(3-carboxyphenyl)benzylamine hydrochloride (20 g, 0.075 mol) in 10% Na2CO3 (350 mL) and dioxane (100 mL) was cooled to 0° C. with stirring. A solution of Fmoc-OSu (30.7 g, 0.091 mol) in dioxane (100 mL) was added in one portion and the reaction mixture was stirred at RT for 3 h. Acidified with 1.5 N aqueous solution of HCl and extracted with EtOAc (3×400 mL). The organic layer was washed with water (3×500 mL), brine dried over Na2SO4 and concentrated, purification by column chromatography using dichloromethane/methanol (9:1) to give N-Fmoc-4-(3-carboxyphenyl)benzylamine (16 g). This was further purified by recrystallization from THF/PetEther gave the title pure product (8 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([NH:12][C:13]3[CH:44]=[CH:43][C:16]([C:17]([N:19]([CH3:42])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])=[O:18])=[CH:15][C:14]=3[O:45][CH3:46])=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl-].C[CH:49]=[N+:50]=[CH:51]C.Cl[CH2:54]Cl>O>[CH3:49][N:50]([CH2:51][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([NH:12][C:13]2[CH:44]=[CH:43][C:16]([C:17]([N:19]([CH3:42])[C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[O:34])=[O:18])=[CH:15][C:14]=2[O:45][CH3:46])=[O:11])[NH:1][CH:2]=1)[CH3:54]
Reactant: CC=[N+]=CC
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]ccc12
Reactant: ClCCl
Agent: [Cl-]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]cc(CN(C)C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(indol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (93 mg) in dichloromethane (6.0 ml) was added N,N-dimethylmethylene- ammonium chloride (41.7 mg) at 0° C. and the mixture was stirred at ambient temperature for 1 hour. The resulting mixture was diluted with water and the aqueous solution was extracted with dichloromethane. Drying, filtering and removal of solvents afforded 4-[(3-dimethylaminomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (90 mg) as a colorless syrup.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[I:12]Cl>C(Cl)Cl>[I:12][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: ClI
Reactant: Nc1ccccc1C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(I)cc1C(F)(F)F
Reaction time: 12 h
Yield: 42.5 %

Procedure:
2-Trifluoromethylphenylamine (30 mg, 0.21 mmol) and ICl (1.1 eq, 0.24 mmol, 38.97 mg) were added into methylene chloride. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to step 2 of Example 8 to give a title compound (25.6 mg, 42.48%).