Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20].[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N+:28]([C:27]1[CH:22]=[CH:23][C:24]([O:20][C:19]([C:3]2[CH:4]=[C:5]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[OH:1])=[O:21])=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)COc1cc(C(=O)O)c(O)c2ccccc12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c(O)c2ccccc12
Yield: 65.9 %

Procedure:
335 g (1.15 mol) of 1-hydroxy-4-ethoxycarbonylmethyloxy-2-naphthoic acid and 160 g (1 mol) of p-nitrophenol were added to 1 liter of toluene, and the mixture was stirred while keeping the temperature at 80° C. 130 mols of thionyl chloride were added dropwise over 30 minutes. After stirring for 30 minutes more, the mixture was cooled. The precipitated crystals were filtered off and dried to obtain 271 g (57% yield) of 1-hydroxy-4-ethoxycarbonylmethyloxy-2-naphthoic acid 4-nitrophenyl ester. Melting point: 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C(OC([N:37]1[CH2:40][CH:39]([N:41]2[CH:45]=[C:44](I)[CH:43]=[N:42]2)[CH2:38]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[NH:37]1[CH2:40][CH:39]([N:41]2[CH:45]=[C:44]([C:18]3[CH:19]=[C:20]4[C:12]([CH:10]([C:3]5[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=5[Cl:1])[CH3:11])=[CH:13][NH:14][C:15]4=[N:16][CH:17]=3)[CH:43]=[N:42]2)[CH2:38]1
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Temperature: 90 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100.0 mg, 0.230 mmol), 3-(4-iodopyrazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (88.3 mg, 0.253 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (95.3 mg, 0.689 mmol) and 4:1 dioxane/H2O (8 mL) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel, extracting with DCM and water. The organic layer was concentrated in vacuo, redissolved in dioxane, and 4M HCl in dioxane (1 mL) was added. The solution was heated to 45° C. for 3 h. The solvents were removed on the corrosive pump, and the material was dry-loaded onto silica gel for column chromatography, eluting with 3-6% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 1.88 (d, J=7.3 Hz, 3 H), 3.90-3.98 (m, 2 H), 4.08-4.15 (m, 2 H), 5.20-5.34 (m, 2 H), 7.18 (t, J=8.6 Hz, 1 H), 7.36 (d, J=1.3 Hz, 1 H), 7.36-7.48 (m, 2 H), 7.65 (s, 1 H), 7.95 (s, 1 H), 8.32 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 430.10 (100) [MH+]. HPLC: tR=2.25 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=O.[OH-].[Na+]>C(O)C.O>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[CH:12]=[CH:11][C:4]([C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])=[O:5]
Reactant: CC(=O)c1c(Cl)cccc1Cl
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1c(Cl)cccc1Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(32) To a solution of the 2,6-dichlorobenzaldehyde (438 mg, 2.50 mmol) and 2,6-dichloroacetophenone (473 mg, 2.50 mmol) in 3.7 ml of ethanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 2 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 465 mg (53.8%) of white, cottony needles: mp 130-130.4° C. (lit. mp 124-125° C., Kaiser, et al., Monatshefte fur Chemie, 1997, 128, 1247-1254). 1H NMR (250 MHz) δ 7.43-7.17 (m, 7 H), 7.10-7.03 (d, 1 H); 13C NMR (62.7 MHz) 193.0, 141.7, 137.5, 135.3 134.4, 132.1, 131.8, 131.0, 130.6, 129.0, 128.3 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][O:27][C:26]2[CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=[CH:33][C:25]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:34]([C:31]2[CH:32]=[CH:33][C:25]3[O:24][CH2:29][CH2:28][O:27][C:26]=3[CH:30]=2)=[O:35])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc4c(c3)OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid (46%). MS 480 (MH+).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24](OC)=[O:25])=[CH:6][CH:5]=2.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.C([O-])(O)=O.[Na+].[ClH:40]>>[ClH:40].[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]([NH:34][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][O:33]1)=[O:25])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Reactant: NCC1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC1CCCO1)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Yield: 27 %

Procedure:
Starting materials: methyl 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxylate and tetrahydrofurfurylamine, but heated at reflux for 2 h. The cooled mixture was poured into a saturated NaHCO3 solution and concentrated in vacuo. The residue was suspended in methanol/dichloromethane, (1:1), silica gel (˜2 g) was added and the mixture was re-concentrated in vacuo. The resulting residue was purified on a silica gel column using dichloromethane/methanol, (100:1 to 25:2 and 1% ammonia solution in water (25%)), as the eluent to give the base. Yield: 27%: 1H NMR (DMSO-d6, 300 MHz) δ 14.75 (br s, 1H), 11.37 (br s, 1H), 10.69 (s, 1H), 8.50 (t, J=5.51 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 4.25 (s, 2H), 4.02-3.60 (m, 6H), 3.44-3.22 (m, 4H), 3.20-3.03 (m, 2H), 1.95-1.78 (m, 4H), 1.70-1.55 (m, 1H); MS (ES) m/z 437 (M++1). The base was transferred to the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C1COCC1>[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]([OH:29])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: Cc1cc(=O)oc2ccc(C#N)cc12
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2oc(=O)cc(CC(O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (56 mg, 0.325 mmol) in dry THF (12 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (0.6 mL). After 30 minutes 2,4-dichlorobenzaldehyde (105 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-60% ethyl acetate in hexanes to yield 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-6-carbonitrile as a white powder.
Reaction SMILES: CN(C)C([O:5][C@H:6]1[CH2:10][N:9]([C:11](OCCCCCCCC)=O)[C@H:8]([CH2:22][CH2:23][O:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:31][C:30]1[C:25]([O:24][CH2:23][CH2:22][C@@H:8]2[CH2:7][C@@H:6]([OH:5])[CH2:10][N:9]2[CH3:11])=[C:26]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1c(F)cccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H](O)C[C@H]1CCOc1c(F)cccc1CCc1ccccc1
Yield: 52.6 %

Procedure:
984 mg of (2R,4R)-4-dimethylcarbamoyloxy-2-{2-[6-fluoro-2-(2-phenylethyl)phenoxy]ethyl}-1-octyloxycarbonylpyrrolidine [prepared as described in step (a) above], 20 ml of tetrahydrofuran and 200 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 319 mg (yield 53%) of the title compound as an oily substance.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]O)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.CCN(S(F)(F)[F:37])CC.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:37])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCCO)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCCF)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a suspension of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-[(6-hydroxyhexyl)oxy]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.14 g) obtained in Example 183 in dichloromethane (10 ml) was added DAST (0.10 ml) at −78° C. The reaction mixture was slowly allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as a white powder (0.02 g, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:31][CH3:32])[CH:21]=3)[CH:16]=2)[CH:12]=[CH:11][N:10]=1.[Br:38][C:39]1[C:47]2[C:42](=[N:43][CH:44]=[N:45][C:46]=2Cl)[NH:41][N:40]=1>>[Br:38][C:39]1[C:47]2[C:42](=[N:43][CH:44]=[N:45][C:46]=2[N:28]2[CH2:27][CH2:26][N:25]([C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:31][CH3:32])[CH:21]=4)[CH:16]=[C:15]([C:13]4[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH2:7][CH2:6][C:5]5[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:14]=4)[CH:24]=3)[CH2:30][CH2:29]2)[NH:41][N:40]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCNCC3)c2c1
Product: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c2c1

Procedure:
4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]pyrimidin-2-amine was synthesized according to General Procedure E except N-(3,4-dimethoxyphenethyl)-4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)pyrimidin-2-amine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. 4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]pyrimidin-2-amine 179 was isolated as a yellow solid. M.p.=130-133° C. 400 MHz 1H NMR (DMSO-d6) δ: 13.07 (br s, 1H), 8.39 (m, 3H), 7.98 (m, 2H), 7.73 (s, 1H), 7.27 (s, 1H), 6.91 (s, 1H), 6.85 (s, 2H), 6.44 (m, 1H), 4.02 (s, 3H), 3.80-3.76 (m, 8H), 3.41-3.39 (m, 4H), 2.95 (m, 2H), 2.84 (m, 2H); Experimental Elemental Analysis (1.73 equivalents of water and 0.38 equivalent of diethyl ether)=56.44% C, 4.74% H, 16.68% N; Calculated Elemental Analysis 56.44% C, 5.50% H, 16.68% N; LCMS (m/z): 697 [M+H].
Reaction SMILES: [C:1]([CH2:3][N:4]([CH2:9][CH2:10][C:11]#[N:12])[CH2:5][CH2:6][CH2:7][OH:8])#N.N.[H][H]>[Ni].C(O)C>[OH:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][NH:12][CH2:1][CH2:3]1
Reactant: [H][H]
Reactant: N#CCCN(CC#N)CCCO
Agent: [Ni]
Agent: N
Solvent: CCO
Product: OCCCN1CCCNCC1

Procedure:
100 grams (0.598 mole) of cyanomethyl-(2-cyano-ethyl)-(3-hydroxy-propyl)-amine, 800 ml of ethanol, 67 grams of ammonia and 26 grams of Raney-nickel were heated in an autoclave during 2 hours under 80 to 100 bar hydrogen pressure at 70° C. (at the beginning) to 120° C. (toward the end). Subsequently the reaction mixture was worked up as described under (b). There were obtained 52 grams (55% of theory) as a final product.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]([O:11]CC)=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CCO.O>[CH:1]([C:4]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1noc(C(=O)O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
Ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate (10.42 mmol, 1.919 g) was dissolved in EtOH (20 ml). Sodium hydroxide pellets (12.50 mmol, 0.500 g) were dissolved in cold water (10 ml) and solution slowly added. The resulting solution was heated at 60° C. for 1.5 h. EtOH was removed under vacuum. The residue was diluted with tert-butyl methyl ether. The mixture was acidified under cold conditions by adding 2 N HCl solution. The mixture was stirred overnight and washed with DCM. Water phase was evaporated precipitating the product. 1.673 g of the title compound was obtained. 1H-NMR (400 MHz, D2O): δ 1.33 (d, 6H), 3.10-3.25 (m, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C)C(=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[N:27][C:26]([NH:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[N:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: NCCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cnc(Cl)nc2)cc1
Solvent: CC(=O)N(C)C
Product: Nc1ccccc1NC(=O)c1ccc(-c2cnc(NCCCN3CCCCC3)nc2)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide (Method 53, 80 mg, 0.19 mmol) in N,N-dimethylacetamide (3.5 ml) was added 3-aminopropylpiperidine (108 mg 0.76 mmol). The reaction mixture was stirred at 50° C. for 20 hours, before being allowed to cool. The reaction mixture was partitioned between water and ethyl acetate, before being filtered under gravity, through a Varian Chem Elut (CE1010) diatomaceous earth column. The resulting solution was then concentrated under reduced pressure and purified by flash column chromatography, eluting with methanol/dichloromethane (0-20%), to give the title compound, which was used without further purification; Mass Spectrum: M+H+ 531.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[O:11]([CH2:3][CH2:2][Br:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccccc1
Reaction time: 6 h
Yield: 86.8 %

Procedure:
In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130° C. over 30 minutes with stirring. The reaction solution was further stirred for 6 hours. After completion of the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried with anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105° C. to 107° C. at 6 mmHg in a yield of 85%.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37].Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[F:27])[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(N)Cc1ccc(F)cc1F
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: CC(C)(Cc1ccc(F)cc1F)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Reaction of 0.89 g (2.49 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.40 g (2.16 mmol) of 2-(2,4-difluorophenyl)-1,1-dimethylethylamine in the manner described for Example 8(d). Yield: 0.80 g (62%, hydrochloride); melting point 245° C.-247° C.
Reaction SMILES: [C:1]12[C:9](=[O:10])[O:8][C:6](=[O:7])[C:2]=1[CH2:3][CH2:4][CH2:5]2.Cl.[CH3:12][O:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1.CCN(CC)CC>C1COCC1>[C:6]([C:2]1[CH2:3][CH2:4][CH2:5][C:1]=1[C:9]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([O:13][CH3:12])=[O:20])=[O:10])([OH:8])=[O:7]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)C1=C(C(=O)O)CCC1
Temperature: 10 °C

Procedure:
2.76 (20 mmol) of 1-cyclopentene-1,2-dicarboxylic anhydride was dissolved in 50 ml of THF at 25° C. under a nitrogen atmosphere. The solution was cooled to 10° C. and 3.31 g (20 mmol) of L-proline methyl ester HCl was added, followed by 2.78 ml (20 mmol) Et3N, which produced a slight exothermic reaction. The mixture was heated at reflux for 12 hours, cooled and the solvent removed under reduced pressure. The residue was dissolved in methylene chloride and the solution was washed with 1N hydrochloric acid and brine. The organic phase was then dried over magnesium sulfate and evaporated in vacuo to afford the title compound which crystallized from methylene chloride/ether as an off-white solid (4.20 g; 79%). TLC (90:10/CH2Cl2 :MeOH): Rf =0.35. 1 H NMR δ: 8.15-8.42(bs,1H); 4.35-4.60(m,1H); 3.38-3.76(m,5H); 2.48-2.98(m,4H); 1.70-2.32(m,6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[CH:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[C:29][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1cc(C#CCN(C)C)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 5.6 %

Procedure:
5-Bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50 mg, 0.125 mmol), 1-dimethylamino-2-propyne (194 μL, 0.14 mmol), trimethylacteylene (20 μL, 0.14 mmol), Pd(PPh3)2Cl2 (1.9 mg, 0.003 mmol) and copper iodide (1.0 mg, 0.006 mmol) were stirred together at 120° C. for 30 minutes. The reaction was cooled and partitioned between aqueous NaHCO3 and EtOAc, and the organic was washed with 1N HCl and then basified with 1N NaOH, extracting with EtOAc. The solvent was removed under reduced pressure and purified on silica (2% ammonia in MeOH/EtOAc) to afford 2.8 mg (6%) of a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 2H), 7.29 (d, 2H), 7.20 (d, 2H), 4.78 (s, 2H), 4.22 (s, 2H), 3.49 (s, 2H), 2.74 (s, 3H), 2.38 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Cc1cccnc1CNCc1ncccc1Cl
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1Cl

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and 3-chloro-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil. Using General Procedure A: Reaction of (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 2-{[(3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 2.12 (s, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 3.97 (s, 2H), 4.22 (s, 2H), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.13 (dd, 1H, J=7.8, 4.8 Hz), 7.32 (d, 1H, J=6.9 Hz), 7.52-7.63 (m, 2H), 7.71 (d, 1H, J=8.1 Hz), 7.94 (d, 1H, J=1.5 Hz), 8.30 (d, 1H, J=4.5 Hz), 8.42 (dd, 1H, J=4.8, 1.5 Hz).