Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 76.9 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.24 mmol) and 4-fluorophenylboronic acid (55 mg, 0.36 mmol), Pd(Ph3P)2Cl2 (20 mg), and aq Cs2CO3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (80 mg, 80%). 1H NMR (CDCl3): δ=1.49 (m, 3H), 2.13 (m, 1H), 2.32 (m, 1H), 2.50 (m, 1H), 2.69 (m, 2H), 2.89 (m, 1H), 5.00 (m, 2H), 5.75 (m, 2H), 6.91-7.10 (m, 6H), 7.15 (m, 1H), 7.22 (m, 2H), 7.38 (m, 2H), 7.48 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:60])[C@@H:11]([NH:52]C(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:60])[C@@H:11]([NH2:52])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:39])([CH3:40])[CH3:41])=[C:31]([CH3:50])[CH:30]=3)[CH2:27][CH3:28])=[CH:20][C:19]=2[CH3:51])=[CH:16][CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](N)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (0.25 mL) was added to a solution of (S)-t-butoxycarbonylamino-[4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]acetic acid methyl ester (Example 166-(2); 20.3 mg, 0.0273 mmol) in dichloromethane (1.3 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (12.0 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([OH:18])=O)[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([NH:44][CH2:43][CH2:42][O:41][CH3:40])=[O:18])[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Reactant: COCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCNC(=O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (70 mg, 0.23 mmol), CDI (75 mg, 0.46 mmol) and DIPEA (0.1 mL) in dry THF (3 mL) was stirred at 60° C. for 1 h and then treated with 2-methoxyethylamine (0.1 mL). After additional 2 h at 60° C., the mixture was concentrated under reduced pressure, the residue suspended in water (5 mL) and the solid collected by filtration and washed with water to give 1-(4-bromophenyl)-N-(2-methoxyethyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxamide EXAMPLE 3. LC-MS (ES+): m/z 363/365 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.41 (s, 3H), 3.57 (t, J=4.9 Hz, 2H), 3.67 (app. q, J=4.9 Hz, 2H), 6.34 (br s, 1H, CONH), 6.60 (s, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.88 (s, 1H), 9.32 (br s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: BrCCCBr
Reactant: COc1cc(C#N)ccc1O
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2 CO3 (12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[CH:17]=[C:16]([Cl:19])[CH:15]=[C:14]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:32])[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:12]([C:13]=34)=[C:11]2[C:33]([O:35]C)=[O:34])(=O)=O)C=CC=CC=1.CO.[OH-].[Na+].Cl>C1COCC1>[Cl:19][C:16]1[CH:15]=[C:14]2[CH2:20][CH2:21][CH:22]([CH2:23][C:24](=[O:32])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]3=[C:11]([C:33]([OH:35])=[O:34])[NH:10][C:18]([CH:17]=1)=[C:13]23
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC1CCc2cc(Cl)cc3[nH]c(C(=O)O)c1c23)Nc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.7 %

Procedure:
A solution of methyl 1-benzenesulfonyl-7-chloro-3-phenylcarbamoylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (140 mg, 0.268 mmol) in a mixture of THF (3 mL), MeOH (3 mL), and 5N NaOH (3 mL) was stirred for 22 h at room temperature, acidified to pH 1 with 1N HCl, and, extracted with 1:1 THF/ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was rinsed with dichloromethane and dried in vacuo to give 64 mg of the title compound (63%): 1H NMR (DMSO-d6) δ5 12.92 (bs, 1H), 11.44 (s, 1H), 9.86 (s, 1H), 7.60 (d, 2H, J=7.3 Hz), 7.30 (t, 2H, J=7.3 Hz), 7.16 (s, 1H), 7.03 (t, 1H, J=7.3 Hz), 6.85 (s, 1H), 3.89 (m, 1H), 3.06 (mt, 1H, J=12.6 Hz), 2.79 (md, 1H, J=16.8 Hz), 2.68 (dd, 1H, J=14.2, 4.3 Hz), 2.50 (m, 1H), 2.06 (md, 1H, J=12.2 Hz), 1.85 (m, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: Nc1nnc(-c2cc(Cl)cc(Cl)c2)c(-c2ccc(F)cc2)n1
Yield: 27.8 %

Procedure:
6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.11 g, 17.6%) was prepared from 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.5 g, 1.18 mmol) and 3,5-dichloro phenylboronic acid (0.47 mg, 2.4 mmol) according to the general procedure of Example 1.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:25][CH:24]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[NH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:27][CH:28]=2)[CH2:13]1
Reactant: O=C(NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Yield: 63.3 %

Procedure:
To 3-benzyloxycarbonylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (3.3 g) are added acetic acid (40 ml) and 10% Pd-C (0.4 g) and the reaction mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. One hour thereafter, the catalyst is removed by filtration and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.6 g) as white powder, m.p. 207-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:21]([CH2:23][C:24]([NH:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:6]([Cl:8])[CH:7]=1)=[O:25])#[N:22]
Reactant: N#CCC(=O)O
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.3 %

Procedure:
To a solution of (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (60 mg, 0.19 mmol) in dimethylformamide (1 mL) was added cyanoacetic acid (25 mg, 0.29 mmol), hydroxybenzotriazole (39.73 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (56.17 mg, 0.29 mmol) and N,N-diisopropylethyl amine (0.06 mL, 0.31 mmol) in the same order. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured onto water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulphate, filtered and the solvent was removed under rotary evaporator. The product was purified by silica gel column chromatography using dichloromethane and methanol (1.5-2%) as eluant to yield 2-cyano-N-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]acetamide (8.7 mg, 12%).
Reaction SMILES: [C:1]([N:9]([C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].CO>[C:1]([N:9]([C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cccc(N(C(=O)c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(N(C(=O)c2ccccc2)c2ccccc2)c1
Yield: 87.4 %

Procedure:
The ester (600 mgs, 1.9 mmol) in 4N sodium hydroxide (20 ml) and methanol (20 ml) was stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in water (10 ml) and acidified with 5N hydrochloric acid. The acidic solution was extracted with dichloromethane (3 ×50 ml), and the combined organics dried and evaporated to afford 3-(N-benzoylanilino)phenylacetic acid as an oil (550 mgs); δH (CDCl3) 3.59 (2H, s, CH2CO2H), 6.83-7.29 (10H, m, ArH), 7.42-7.48 (3H, m, ArH), 8.09 (2H, d, J 7.2 Hz, ArH).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]2[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:33][CH:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([NH:10][CH2:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][S:36]([CH:34]([CH3:35])[CH3:33])(=[O:38])=[O:37])[CH2:4][CH2:5]2)[N:20]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CN)CC2)nc2ccccc12
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)NC[C@H]1CC[C@H](CNc2nc(N(C)C)c3ccccc3n2)CC1
Temperature: 4 °C
Reaction time: 12 h

Procedure:
To a suspension of trans-N2-(4-aminomethyl-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step A of example 15 (227 mg, 0.72 mmol) in CH2Cl2 (4 mL) was added diisopropylethylamine (263 μL, 1.51 mmol). The mixture was cooled at 4° C. and a solution of 2-propanesulfonyl chloride (108 mg, 0.76 mmol) in CH2Cl2 (1 mL) was added below 5° C. The reaction mixture was stirred at ambient temperature for 12 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 66% EtOAc in hexane) to give trans-propane-2-sulfonic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide (135 mg, 45%) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:11]2[CH:10]=[C:9]([CH2:12][N:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]4[C:34](=[O:35])[CH:33]=[N:32][C:31]5[N:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:30]4=5)[CH2:23][CH2:22]3)C(=O)OC(C)(C)C)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[O:1]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][N:29]4[C:34](=[O:35])[CH:33]=[N:32][C:31]5[N:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:30]4=5)[CH2:25][CH2:26]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 87 mg of tert-butyl (3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and chloroform and water were added thereto. The aqueous layer was separated and adjusted to pH 13.1 with a 20% aqueous sodium hydroxide solution. Chloroform was added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 54 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one as a yellowish brown oily substance.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=O>Cl.C(O)CC>[N:19]1([C:9]2[N:8]=[CH:7][C:6]([NH2:5])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:10]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CCCO
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N
Temperature: 25 °C

Procedure:
A suspension of2.93 g (8.28 mmol)2,2-dimethyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-propionamide in 80 ml 3 N hydrochloric acid solution and 5 ml 1-propanol was heated to 90-95° C. overnight. The reaction mixture was cooled to room temperature, washed with three 20 ml portions diethyl ether and filtered over celite. The filtrate was diluted with 20 ml water and was adjusted to pH 7-8 by addition of 28% sodium hydroxide solution under ice cooling. The product was extracted with four 100 ml portions of dichloromethane. The combined organic layers were washed with 50 ml brine, dried (magnesium sulfate) and evaporated to give 2.31 g (quantitative) of the title compound as a white foam.
Reaction SMILES: [CH:1](=[N:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[C-:17]>C(O)C>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[CH:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=NCc1ccccc1)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1N=CN(Cc2ccccc2)C1c1ccccc1
Yield: 99.9 %

Procedure:
25.7 g (0.1305 mol) of benzylidenebenzylamine were dissolved in ethanol, and 15.2 g (0.1305 mol) of ethyl isocyanoacetate were added dropwise. The solution was heated under reflux for 16 h. Removal of the solvents and drying gave 40.2 g of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[N:17]([CH:25]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]=3[N:16]=2)=[N:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH:25]1([N:17]2[C:15]3[N:16]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=4)[N:12]=[CH:13][C:14]=3[CH:19]=[C:18]2[C:20](=[O:24])[N:21]([CH3:22])[CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCCCC4)c3n2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a solution of 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (146 mg, 0.33 mmol, 1.0 eq) in THF (1.5 mL) was added LiOH (94.7 mg, 4.0 mmol, 12 eq) in 1.5 mL of water. The mixture was stirred at room temperature for 48 h. The reaction mixture was cooled to 0° C. in an ice bath and was acidified with 1N HCl until pH was about 1-2. The solid precipitate was filtered and washed to give the title compound as a light pink solid (52 mg, 0.124 mmol, 37%) and used as is; alternatively it can be extracted out with 20% Isopropanol in dichloromethane) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br s, 1H) 10.38 (br s, 1H) 8.87 (s, 1H) 8.81 (d, J=2.01 Hz, 1H) 8.53 (d, J=9.03 Hz, 1H) 8.19 (dd, J=9.03, 2.01 Hz, 1H) 6.67 (s, 1H) 4.44 (br s, 1H) 3.07 (d, J=13.05 Hz, 6H) 2.54-2.60 (m, 2H) 1.87-1.98 (m, 2H) 1.75-1.87 (m, 2H) 1.59-1.75 (m, 4H) 1.49 (m, 2H). MS (m/z, MH+): 423.5
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br-:17]>>[Br:17][CH:10]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: [Br-]
Product: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Yield: 48 %

Procedure:
According to the procedure of Example 7, Part C, ethyl 3-(3-cyanophenyl)-3-oxopropionate (3.2 g, 14.7 mmol) was converted into the crude bromide, which was purified by flash chromatography (elution with 4:1 hexanes/ethyl acetate) to afford 2.1 g (48%) of the title compound. MS(H2O, GC/MS) 296/298 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Temperature: 25 °C

Procedure:
A solution of 4-Nitrophenol (10 g, 72 mmol) dissolved in acetonitrile (100 ml was charged with potassium carbonate (24.9 g, 180 mmol) and 1-bromo-3-chloropropane (113.2 g, 720 mmol). The mixture was heated and stirred at reflux overnight. The reaction was cooled to room temperature, the solids filtered off and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCC[C@H](CC(=O)OC)c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a flask containing 27.1 (0.900 g, 2.99 mmol) and cesium carbonate (1.27 g, 3.88 mmol) in 8 mL of DMF was added benzyl bromide (0.43 mL, 3.59 mmol), and the resulting mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (0 to 20% EtOAc/Hexanes) to provide 27.2 (1.00 g, 86% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:18](C([O-])=O)(C([O-])=O)[C:19]([O:21]C)=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:29]([CH3:31])[CH3:30])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[C:19]([OH:21])(=[O:20])[CH3:18].[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:29]([CH3:31])[CH3:30])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)[O-])(C(=O)[O-])C1CCCc2nc(C(C)C)n(Cc3ccc(I)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(CC(=O)O)CCC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 132.4 %

Procedure:
To a stirred solution of Intermediate 89 (11.1 g) in Ethanol (150 mL) was added 2M Aqueous Sodium Hydroxide (36.4 mL). The reaction mixture was then stirred at 80° C. and under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, glacial acetic acid (41.6 mL, 727 mmol) added and allowed to stir at 120° C. and under nitrogen for 2 h. The reaction mixture was concentrated under vacuum. The white solid was suspended and stirred in ether (500 mL) for 5 mins. The white solid was filtered off under vacuum. The solid was suspended in EtOAc (500 mL) and the suspension was refluxed for 45 mins. The white solid was hot filtered under vacuum and washed with EtOAc (100 mL). The filtrate was concentrated under vacuum to give the title compound as a white solid (6.8 g). LC/MS MH+ 439, Rt 1.90 min (5 min run).