Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].F[C:10]1[CH:38]=[CH:37][C:13]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:38]=[CH:37][C:13]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=2)=[O:15])=[CH:12][CH:11]=1)[CH3:7]
Reactant: CNCCCN(C)C
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(F)cc3)ccc2C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(N(C)CCCN(C)C)cc3)ccc2C)cc1OC
Temperature: 130 °C
Yield: 34.1 %

Procedure:
N-(3-Dimethylaminopropyl)-N-methylamine (0.325 g) was added to a stirred mixture of N-[5-(4-fluorobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.38 g), potassium carbonate (0.39 g) and DMSO (5 ml). The mixture was stirred and heated to 130° C. for 10 days. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated to give an oil which was purified by column chromatography on silica gel using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether and the resultant solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.16 g), m.p. 164-165° C.; NMR Spectrum: (DMSOd6) 1.6 (m, 2H), 2.16 (s, 3H), 2.2 (s, 6H), 2.3 (t, 2H), 2.94 (s, 3H), 3.4 (t, 2H), 3.83 (s, 6H), 6.72 (d, 2H), 7.06 (d, 1H), 7.18 (d, 1H), 7.55 (m, 2H), 7.63 (m, 1H), 7.79 (d, 2H), 7.84 (d, 2H), 9.71 (br s, 1H), 9.8 (br s, 1H); Mass Spectrum: M+H+ 505; Elemental Analysis: Found C, 65.9; H, 7.0; N, 10.4; C29H36N4O4 1.3H2O requires C, 66.0; H, 7.4; N, 10.6%.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N:13]1([C:22]2[N:27]=[C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=4)[O:32][CH2:31][CH2:30]3)[C:25]([NH2:40])=[CH:24][N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>C1COCC1>[N:13]1([C:22]2[N:27]=[C:26]3[C:25]([NH:40][C:1](=[O:2])[N:28]3[C@H:29]3[C:38]4[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=4)[O:32][CH2:31][CH2:30]3)=[CH:24][N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: Nc1cnc(-n2cnc3ccccc32)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cnc(-n3cnc4ccccc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (0.2 g) was added to a solution of the above amine in THF (10 mL). The resulting mixture was stirred at RT overnight, silica gel was added, then the solvents were removed under reduced pressure and purified via column chromatography, elution with 5% MeOH/DCM, to yield the titled product (28 mg), MH+=403, 1H NMR (CDCl3) δ 10.6 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.8 (m, 2H), 7.3 (m, 2H), 7.0 (m, 1H), 6.7 (m, 1H), 5.9 (dd, 1H), 4.7 (m, 1H), 4.4 (t, 1H), 2.7 (m, 1H), 2.3 (m, 1H) ppm, 19F NMR δ −135.7 (m). Chiral HPLC—no evidence of other enantiomer, Method; Chiralcel™ OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) isocratic 15% (0.05% TFA/EtOH) 85% (0.05% TFA/Hex), Rt=19.5 min (R)-enantiomer, Rt=22.4 min (S)-enantiomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18].[N+](=[CH2:22])=[N-]>CCOCC>[CH3:22][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)Cc1ccccc1Nc1c(C)cccc1Cl
Reaction time: 2 h

Procedure:
To a solution of 10 g of [o-(3-chloro-o-toluidino)-phenyl]-acetic acid (M.P. 124°-125°) in 100 ml of ether are slowly added dropwise 100 ml of 2% ethereal diazomethane solution. The solution is allowed to stand for 2 hours at room temperature, and then concentrated to dryness at 40° under 11 Torr. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 40 ml of 2 N sodium hydrogen carbonate solution and water, dried over sodium sulphate, and concentrated at 40° under 11 Torr. The residue is crystallised from benzine. The obtained [o-(3-chloro-o-toluidino)-phenyl]-acetic acid methyl ester melts at 47°-48°.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)=[CH:10][C:11](=[O:15])[O:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: C#CC(O)(CC)CC
Reactant: [N-]=[N+]=NCc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-fluorophenyl)-2H-chromen-2-one (343 mg, 0.78 mmol) and 3-ethyl-1-pentyn-3-ol (80 mg, 0.71 mmol) in THF (7 mL) N,N-diisopropylethylamine (622 uL, 3.6 mmol) and copper iodide (204 mg, 1.07 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 10:90) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.89 (s, 1H), 7.7-7.6 (m, 1H), 7.53 (d, 1H), 7.45-7.32 (m, 4H), 7.27 (d, 1H), 6.42 (s, 1H), 5.79 (s, 2H), 3.78 (s, 1H), 2.0-1.74 (m, 4H), 0.78 (t, 6H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[C:11]([C:13]1[CH:35]=[CH:34][C:16]([O:17][C:18]2[CH:19]=[C:20]([NH2:33])[CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)=[CH:15][CH:14]=1)#[N:12]>>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]2[CH:21]=[C:20]([NH:33][C:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:6]3)=[O:10])[CH:19]=[C:18]([O:17][C:16]3[CH:34]=[CH:35][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH:23]=2)=[CH:26][CH:27]=1)#[N:32]
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Product: C[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1

Procedure:
Following the procedure of Example 107(e) trans-4-methyl-cyclohexanecarboxylic acid 0.21 g (1.52 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (0.50 g, 1.52 mmol) were used to afford 0.65 g of the required product. Percentage purity (LCMS): 85.4%, (M+1)=451.1+1.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:34](=[O:35])[CH2:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)CCc2ccc(Cl)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-(4-Chlorophenyl)propionyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[β-(4-chlorophenyl)propionyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: CS(O[CH:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][N:8]([CH3:18])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=O)=O.[NH:25]1[CH2:30][CH2:29][C:28]2([CH2:34][S:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]2=3)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:18][N:8]([CH2:7][CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N:25]1[CH2:30][CH2:29][C:28]2([CH2:34][S:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]2=3)[CH2:27][CH2:26]1)[S:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: c1ccc2c(c1)SCC21CCNCC1
Reactant: CN(CC(OS(C)(=O)=O)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC(c1ccccc1)N1CCC2(CC1)CSc1ccccc12)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
N-(2-Methanesulfonyloxy-2-phenylethyl)-N-methylbenzenesulfonamide (128 mg, 0.346 mmol), spiro(benzo[b]thiophene-3(2H),4'-piperidine) (142 mg, 0.693 mmol), and sodium carbonate (167 mg, 1.04 mmol) were combined in 1.0 mL of dry DMF. The mixture was stirred under nitrogen 1 h at room temperature and 1.5 h at 40° C., then slowly warmed to 65° C. and maintained at that temperature for 5 h. After cooling to room temperature and stirring overnight, the mixture was partitioned between 50 mL of ethyl acetate and 25 mL of saturated aqueous sodium bicarbonate. The organic layer was washed with 25 mL of brine, dried over sodium sulfate and concentrated. Purification by preparative TLC, eluting with 5% ethyl ether in dichloromethane, gave 103 mg of the title compound as a viscous oil. 1NMR (400 MHz, CDCl3): δ 7.77 (d, 2H, J=8 Hz), 7.58 (tt, 1H, J=8, 1 Hz), 7.51 (t, 2H, J=8 Hz), 7.39-7.28 (m, 3H), 7.23 (d, 2H, J=8 Hz), 7.17-7.03 (m, 4H), 3.77 (t, 1H, J=7 Hz), 3.71 (dd, 1H, J=13, 7 Hz), 3.30 (dd, 1H, J=13, 7 Hz), 3.12 (d, 1H, J=11 Hz), 3.08 (d, 1H, J=11 Hz), 2.94 (bd, 1H, J=12 Hz), 2.84 (bd, 1H, J=12 Hz), 2.65 (s, 3H), 2.34 (td, 1H, J=12, 3 Hz), 1.99 (td, 1H, J=12, 3 Hz), 1.96-1.73 (m, 4H). Mass spectrum (ESE): m/z=479 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:37]([F:42])[CH:36]=1)[CH3:32]
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid ethyl ester (CAS Reg. No. 73792-12-8) in the presence of DMAP to give the title compound as yellow oil. MS: m/e=538.4 [M+H+].
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14]
Reactant: C[Si](C)(C)CCOC(=O)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)CN
Yield: 89.1 %

Procedure:
To a solution in ethyl acetate (20.0 mL) of the compound (634 mg) obtained in step (1) above, 20% palladium hydroxide/carbon (63.0 mg) was added. The mixture was stirred at room temperature for an hour in a hydrogen atmosphere. After passing the reaction mixture through Celite (registered trademark), the filtrate was concentrated under reduced pressure to give the titled compound as a pale yellow oil (320 mg).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:8]2[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Yield: 74.5 %

Procedure:
Compound 114 (1.0 g, 2.82 mmol) was suspended in 3 N HCl (15 mL) and the suspension heated to reflux for 30 min. Following neutralization with saturated aqueous Na2CO3 solution, the precipitated product was collected by filtration, washed with water (70 mL), and dried under vacuum. The residue was crystallized from MeOH to give the product (655 mg, 2.1 mmol, 74%) as a solid, mp 220-221° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (9, s), 5.91 (2, br s), 6.60 (2, d, J=7.0 Hz), 7.45 (2, d, J=7.0 Hz), 13.95 (1, br s); 13C NMR (125 MHZ, DMSO) δ 29.3, 36.0, 112.6, 127.3, 127.7, 152.5, 166.1, 166.6; MS (LCQ, ESI+) Calculated for C12H17N4O2S2 313.1. found 313.0 (M+H)+. HRMS (FAB+, m/z) Calculated for C12H17N4O2S2 313.0793. found 313.0793 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[CH:7]=[C:6]1[CH3:18].[OH-].[Na+].O.Cl>C(O)C>[C:14]([C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[C:6]([CH3:18])[N:5]2[CH2:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[Cl:1])=[CH:9][CH:10]=1)([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2cc(C)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 79.8 %

Procedure:
A mixture of 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-methylindole (0.630 g), aqueous 10% sodium hydroxide solution (2.7 g), water (1.8 g) and ethanol (7.0 g) is refluxed for 2.5 hours. After cooled, this is processed with 10% HCl to have a pH of 4, and the crystal formed is taken out through filtration and dried to obtain 6-carboxy-1-(2-chlorobenzyl)-2-methylindole (31) (0.480 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[C:13]([C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O>[C:24]([C:22]1[CH:21]=[C:19]([NH:20][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)[CH:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:23]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnc(Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of ethyl 2-chloropyrimidine-5-carboxylate (335 mg), 3,5-di-tert-butylaniline (370 mg), and K2CO3 (600 mg) was heated at 110° C. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=10:1) to give white crystals of ethyl 2-[N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (574 mg, 90%).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:25][C:26]([C:28]2([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:33][CH2:32][N:31]([C:34]3[C:35]4[CH:42]=[CH:41][NH:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH:6]=1>C(O)C>[NH2:14][CH2:13][CH2:12][CH:11]([NH:25][C:26]([C:28]1([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:29][CH2:30][N:31]([C:34]2[C:35]3[CH:42]=[CH:41][NH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH2:32][CH2:33]1)=[O:27])[C:8]1[CH:7]=[CH:6][C:5]([Cl:4])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN2C(=O)c3ccccc3C2=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
Hydrazine monohydrate (10.32 μL) was added to a stirred suspension of tert-butyl 4-(1-(4-chlorophenyl)-3-(1,3-dioxoisoindolin-2-yl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 37) (14 mg) in ethanol (1.0 mL) under argon. The resulting suspension was stirred at room temperature for 3 days. The mixture was filtered and was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Pure fractions were evaporated to dryness to afford tert-butyl 4-(3-amino-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate as a white powder (5.00 mg, 44.5%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5].[N-:16]=[N+:17]=[N-:18].[Na+].[I-].[Na+]>O>[N:16]([CH2:2][CH2:3][C:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])=[N+:17]=[N-:18]
Reactant: O=C(CCBr)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A 5 L round bottom three-necked flask, equipped with a heating mantle, an overhead stirrer, and a thermometer, was charged with 150 gm bromoethylglucose (525 mmol). The oil was dissolved in 2 L water and treated with 68.3 gm sodium azide (1.05 mol, 2 equiv.; 65 gm/mol; Alfa-Aesar) followed by 7.9 gm sodium iodide (52.5 mmol, 0.08 equiv.; 149.89 gm/mol; Alfa-Aesar) and the solution warmed to 50 C and stirred overnight. The solution was cooled to room temperature and concentrated to dryness on the rotovap. The solid residue was digested with 3×500 mL of 5:1 vol. CHCl3:MeOH at 40 C. The combined organic portions were filtered and evaporated to dryness to afford azidoethylglucose (86 gm) as an off-white solid. TLC (20% MeOH/DCM; char with H2SO4): single spot, indistinguishable from the starting material.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([O:16]C)[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([F:18])=[CH:10][CH:9]=3)[CH3:2].Cl>C(O)(=O)C>[CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15]([OH:16])[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([F:18])=[CH:10][CH:9]=3)[CH3:2]
Reactant: CCc1nnc2c(OC)nc3cc(F)ccc3n12
Agent: Cl
Solvent: CC(=O)O
Product: CCc1nnc2c(O)nc3cc(F)ccc3n12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 11.3 g (0.046 mole) of 1-ethyl-7-fluoro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 115 ml. of 1N hydrochloric acid and 345 ml. of glacial acetic acid was refluxed for a period of three hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 30 minutes, filtered and the recovered solid product subsequently washed with water and air-dried to ultimately afford 6.6 g. (62%) of pure 1-ethyl-7-fluoro-4-hydroxy[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >300° C. Mass Spectrum: m/e, 232 (P); m/e, 231 (P-1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]([NH:12][C:4]2[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH3:14])=[CH:16][CH:17]=1
Reactant: Nc1cnccn1
Reactant: COC(=O)c1ccc(Cl)nc1N[C@@H](C)c1ccc(F)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cnccn2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2.83 g of methyl (S)-6-chloro-2-[1-(4-fluorophenyl)ethylamino]nicotinate, 870 mg of 2-aminopyrazine, 1.06 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 4.09 g of tripotassium phosphate and 475 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 15 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 3.14 g of the objective compound as orange powder.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.21 g, 0.64 mmol) in acetone (5 mL) was added potassium carbonate (0.12 g, 0.87 mmol) followed by iodomethane (0.20 mL, 0.46 g, 3.2 mmol). The reaction vessel was flushed with nitrogen and sealed. The mixture was stirred at room temperature for 16 h, after which time additional iodomethane (0.20 mL, 0.46 g, 3.2 mmol) and potassium carbonate (0.11 g, 0.80 mmol) were added. Stirring was continued at 40° C. for an additional 20 h. The solvent was then evaporated, and the resulting residue was partitioned between water and ethyl acetate, separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (quantitative) as an oil that was used without further purification. MS (ESI) m/z 343 ([M+H]+); HRMS: calcd for C19H19FN2O3, 342.13804; found (ESI+), 343.14463.