Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.O.O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[O-:21].[Na+].[C:26]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)#[N:27].O.CCOCC>CN(C=O)C>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[O:21][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:26]#[N:27])=[CH:29][CH:30]=1
Reactant: [O-]c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1ccc(COc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 7.24 g (19.92 mmol) of sodium 3-(2-quinolinylmethyloxy)phenoxide pentahydrate and 4.68 g (23.90 mmol) of p-cyanobenzyl bromide in 34 ml of dry DMF is stirred at 75° C. under nitrogen for 2 days. The reaction mixture is cooled to room temperature, then poured into 400 ml of 3:1 H2O/Et2O, shaken, and the phases separated. The aqueous layer is extracted and washed with 1:1 brine/H2O and brine. The ether solution is dried over 1:1 Na2SO4MgSO4, filtered and concentrated. The crude product is recrystallized from 70% EtOAc/hexane to obtain 4-(3-(2-quinolinylmethyloxy)phenoxy-methyl)benzonitrile. (M.P. 112.5° C.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].N1C=CC=CC=1.[C:25]([O:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])[CH3:26]>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[NH:18][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=2[O:28][C:25](=[O:27])[CH3:26])=[N:11][CH:12]=1
Reactant: CC(=O)Oc1cc(F)ccc1C(=O)Cl
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-2-amino-N-(5-chloropyridin-2-yl)benzamide (5.32 g, 20 mmol) was added to a solution of 2 mL dry pyridine and 2-acetoxy-4-fluorobenzoyl chloride (21 mmol) in 100 mL dry methylene chloride under dry nitrogen with magnetic stirring. The reaction was allowed to stir overnight at room temperature and then was diluted with 500 mL of methylene chloride. The methylene chloride solution was washed with cold 1 M HCl, cold saturated NaHCO3, and brine; and then was dried over sodium sulfate. The solvent was evaporated, and the crude product was crystallized from acetone to give 2:92 g of off-white product.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25]([CH2:27][C@@H:28]([OH:35])[CH2:29][C:30](OCC)=[O:31])#[N:26].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:25]([CH2:27][C@@H:28]([OH:35])[CH2:29][C:30](=[O:31])[CH2:9][C:8]([N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])#[N:26]
Reactant: CC(=O)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CC[C@@H](O)CC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diphenylacetamide (211 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -10° C. to -5° C. The mixture is stirred at -0° C. to 20° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared anion. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6 -cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide which is not isolated. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil. Proton nuclear magnetic resonance spectroscopy
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.[OH:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:20][O:21][CH3:22])[CH2:17][CH:18]=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:17][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:15])[CH2:20][O:21][CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: COCC(O)(CC=O)c1ccccc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaB(OAc)3 (0.98 g), and acetic acid (0.27 mL) were added in the given order to a solution of 3-hydroxy-4-methoxy-3-phenyl-butyraldehyde (0.90 g) in tetrahydrofuran (20 mL) at ca. 10-15° C. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Then, water (50 mL) and 1 M aqueous NaOH solution (20 mL) were added and the resulting mixture was stirred for another 30 min. The mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. After drying (MgSO4), the solvent was removed to give the title compound which was submitted to the subsequent reaction step without further purification. Yield: 1.80 g (quantitative).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N+:25]([O-])([O-:27])=[O:26].[K+].N>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[C:8]([N+:25]([O-:27])=[O:26])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1cc(C#N)ccc21
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
Powdered carbamate 143 (1.00 g, 2.9 mmol) was added portionwise to stirred conc. H2SO4 (10 mL) at 0° C., and the mixture was warmed to room temperature for 10 min. The resulting solution was cooled to −5° C. and treated dropwise with a solution of KNO3 (324 mg, 3.2 mmol) in cone. H2SO4 (2 mL). After siting for a flirter 5 min at 0° C., the mixture was poured into ice/water and neutralized with dilute aqueous NH3. The resulting solid was purified by chromatography on silica gel, eluting with CH2Cl2, followed by recrystallization from CH2Cl2, then EtOAc, to give 1-(chloromethyl)-7-cyano-5-nitro-1,2-dihydro-3H-benzo[e]indole (144) (522 mg, 62%) as a red solid: mp 237-238° C.; 1H NMR [(CD3)2SO] δ 8.55 (d, J=1.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.74 (dd, J=8.8, 1.5 Hz, 1H), 6.87 (s, 1H), 4.29-4.21 (m, 1H), 3.94-3.85 (m, 2H), 3.80 (dd, J=11.1, 8.1 Hz, 1H), 3.75 (dd, J=10.6, 3.1 Hz, 1H). Anal. (C14H10ClN3O2) C, H, N, Cl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[C:11]#[CH:12])=[CH:5][CH:4]=1.ClC(Cl)=N[C:30]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[CH:32][CH:31]=1.CC1C=CC(CN2CCNCC2)=CC=1.C([Li])CCC.COC1C=CC=CC=1C=C(Br)Br>C(OCC)C.O1CCCC1.CCCCCC>[CH3:35][O:34][C:33]1[CH:36]=[CH:37][CH:30]=[CH:31][C:32]=1[C:12]#[C:11][C:10](=[N:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(N=C(Cl)Cl)cc1
Reactant: C#CC(=Nc1ccc(OC)cc1)N1CCN(Cc2ccc(C)cc2)CC1
Agent: COc1ccccc1C=C(Br)Br
Agent: Cc1ccc(CN2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(N=C(C#Cc2ccccc2OC)N2CCN(Cc3ccc(C)cc3)CC2)cc1

Procedure:
1-(2-Methoxyphenyl)-3-(4-methoxyphenylimino-3-[4-(4-methylbenzyl)-1-piperazinyl]propyne can be prepared by working as in Example 11 but starting with a solution of N-dichloromethylene-p-anisidine (20.6 g) in ethyl ether (200 cc) to which a solution of 4-(4-methylbenzyl)piperazine (38.4 g) in tetrahydrofuran (150 cc) is added. The solution obtained after filtration is added in the course of 30 minutes at a temperature of about -70° C. to a solution of 2-(2-methoxyphenyl)ethynyllithium obtained by adding, in the course of 20 minutes, at a temperature of about -70° C., a 1.6M solution (126 cc) of butyllithium in hexane to a solution of 2-methoxy-β,β-dibromostyrene (29.5 g) in tetrahydrofuran (300 cc). 1-(2-Methoxyphenyl)-3-(4-methoxyphenylimino)-3-[4-(4-methylbenzyl)-1-piperazinyl]propyne (30.6 g), m.p. 83° C., is thereby obtained.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.CCOC(C)=O.CCN(CC)CC>CCO.CCOC(C)=O>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A mixture of cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-nitro-benzyl)-amine (16f) (0.16 g, 0.39 mmol) and SnCl2/2H2O (0.35 g, 1.55 mmol) in EtOH/EtOAc (20 ml, 7:3) was heated to reflux for 1.5 h (monitored by TLC, Hex/EtOAc/Et3N 5:5:0.4). After removal of the solvent, the residue was diluted with 10% NaHCO3 and EtOAc and stirred vigorously for 30 min. After filtration the organic phase was separated and the aqueous phase was extracted with EtOAc (20 ml×2). The combined organic phase was dried over Na2SO4. After removal of the solvent, flash chromatography gave 16o, cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-amino-benzyl)-amine (0.087 g, 60%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[O:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:18]=[C:17]4[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:34]=3)=[N:12][N:13]=2)=CC=1>C(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>[O:42]1[CH2:41][CH2:40][N:39]([C:35]2[N:34]=[C:33]([C:17]3[C:16]4[C:20](=[CH:21][CH:22]=[C:14]([C:11]5[O:10][C:9]([NH2:8])=[N:13][N:12]=5)[CH:15]=4)[N:19]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=4)(=[O:25])=[O:24])[CH:18]=3)[CH:38]=[CH:37][CH:36]=2)[CH2:44][CH2:43]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(N5CCOCC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(N4CCOCC4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Yield: 44 %

Procedure:
The solution of N-(4-methoxybenzyl)-5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.21 g, 0.33 mmol) in CHCl3 (2 mL) and TFA (2 mL) was heated at 80° C. for 12 h. Then the reaction mass was evaporated to dryness and ice cold H2O (10 mL) was added and basified with saturated NaHCO3 solution to pH 8. A white colored solid precipitated out which was collected by filtration and dried under vacuum to give 5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.075 g, 44.1%). MS (ESI, pos. ion) m/z: 517 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.94 (s, 1H), 8.51 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.42-7.36 (m, 3H), 7.18 (s, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.77-3.75 (m, 4H), 3.57-3.56 (m, 4H), 2.3 (s, 3H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>O1CCCC1.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29](/[CH:30]=[C:19](/[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)\[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: COc1ccc(C=O)cc1OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C\c1ccc(OC)c(OC)c1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
n-Butyllithium (1.6M hexane solution, 99.2 ml) was dropped into a solution of diisopropylamine (23.4 ml, 166.6 mmol) in tetrahydrofuran (320 ml). The obtained mixture was stirred at 0° C. for 30 minutes. A solution of ethyl 3-pyridylacetate (24.0 ml, 158.9 mmol) in tetrahydrofuran (20 ml) was dropped into the resulting mixture at -70° C. and the obtained mixture was stirred at 0° C. for 15 minutes. A solution of 3,4-dimethoxybenzaldehyde (27.6 g, 166.0 mmol) in tetrahydrofuran (100 ml) was dropped into the mixture at 0° C. The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ether. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated. The oily residue was purified by flash column chromatography (ethyl acetate/hexane=3:2) to give the title compound as a pale yellow oil (18.19 g, yield: 37%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CSC(CCCCN)CCCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CSC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.219 g ethyl 8-amino-4-[3-(3-pyridyl)propyl]-3-thia-octanoate in 1.5 mL methylene chloride is added a few crystals of 4-dimethylaminopyridine followed by 60 mcL triethylamine and 0.068 g p-chlorobenzenesulfonyl chloride. The mixture is stirred at room temperature for 18 hours, diluted with ether and washed with saturated aqueous sodium bicarbonate. The ether layer is dried, filtered and evaporated to leave an amber oil which is chromatographed using 3:2 ethyl acetate, hexane to give ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-3-thia-octanoate as an oil; NMR (CDCl3): delta 8.0 (d,2H), 7.55 (d,2H), 3.15 (s,2H); such being the compound of formula X wherein X represents sulfur, Ar represents p-chlorophenyl, Het represents 3-pyridyl and R1 represents ethoxy.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:14](N)[CH2:15][NH2:16].Cl.C>C(=S)=S>[CH2:1]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC#N
Reactant: NCCN
Agent: Cl
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NCCN1
Temperature: 125 °C

Procedure:
18.32 g (100 mmoles) of undecyl cyanide, 8.5 ml (127 mmole) of ethylenediamine and 0.5 ml of carbon disulfide were mixed and heated in an oil bath at 125° C. for 24 hours. The reaction mixture was cooled, treated with dilute hydrochloric acid and treated with charcoal. The light yellow filtrate was basified and extracted with ethyl acetate, the organic extracts dried over magnesium sulfate and concentrated. The residue was Kugelrohr distilled and then recrystallized from toluene. Yield 13.7 g (61.1%), m.p. 82° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]([OH:23])=[C:17]([C:19]([O:21]C)=O)[N:18]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C(O)(=O)C.O>C(O)(C)C>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:19]([C:17]2[N:18]=[C:13]([C:10]([NH:9][C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)=[O:8])([CH3:11])[CH3:12])[NH:14][C:15](=[O:24])[C:16]=2[OH:23])=[O:21])=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(C(C)(C)NC(=O)c2nnc(C)o2)[nH]c(=O)c1O
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)[nH]2)o1
Temperature: 82.5 °C

Procedure:
Methyl 2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylate [V(a); 40 gms] was suspended in isopropyl alcohol (400 ml) and 4-fluorobenzyl amine (30 gms) was added to the above mixture. The reaction mixture was stirred at 80 to 85° C. After completion, reaction mass was cooled to 60° C. and acetic acid (1600 ml) and water (400 ml) was added. The resultant crystalline product was filtered and washed with mixture of water and isopropyl alcohol (1:1) and dried to give N-(4-fluorobenzyl)-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido) propan-2-yl)-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxamide VI).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][N:10]=1.O.C(O)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C>[N:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:11]1[N:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[N:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Brc1ccncc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: Clc1cc(Cl)nc(-c2ccccn2)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
nButyllithium (1.5 M in hexanes/1.53 mL, 2.3 mmol) was added dropwise to a solution of 4-bromopyridine (200 μL, 2.08 mmol) and in diethyl ether (20 mL)−78° C. After 30 minutes, the reaction mixture was warmed to −30° C. and 4,6-dichloropyrimidine (283 mg, 1.9 mmol) was added. The reaction mixture was allowed to warm to 0° C. over 60 min after which water (2 mmol) and acetic acid (4 mmol) were added followed by DDQ (431 mg, 1.9 mmol). After 30 minutes, the reaction mixture was diluted with diethyl ether (30 mL) and washed three times with aqueous 3M NaOH. the organic layer was dried over MgSO4. Filtration and removal of volatiles under reduced pressure yielded a brown gummy solid which was purified by flash chromatography to afford 2-pyridyl-4,6-dichloropyrimidine as a white solid (0.261 mg, 61%). 1H NMR: (CDCl3) δ 7.40, 1H, s; 8.23, 2H, d; 8.80, 2H, d.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cnccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
4-Bromonicotinonitrile (1.0 g, 5.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.9 g, 7.1 mmol) using the method in Example 51. Purification by chromatography on silica gel eluting with dichloromethane gave 4-(2-fluoro-5-nitrophenyl)nicotinonitrile as a white solid: δH (400 MHz, CDCl3) 7.44-7.52 (2H, m), 8.38-8.47 (2H, m), 8.95 (1H, d, J 5), 9.06 (1H, s).
Reaction SMILES: [I:1][C:2](=[C:5]([I:7])[I:6])[CH2:3][OH:4].[CH:8](O)=[O:9]>>[CH:8]([O:4][CH2:3][C:2]([I:1])=[C:5]([I:7])[I:6])=[O:9]
Reactant: OCC(I)=C(I)I
Reactant: O=CO
Product: O=COCC(I)=C(I)I
Reaction time: 3 h

Procedure:
2.0 g of 2,3,3-triiodoallyl alcohol and 30 ml of formic acid were refluxed, with stirring, for 3 hours. After cooling the mixture, the crystals which precipitated were collected by filtration, dissolved in ethyl acetate, adsorbed in a dry silica gel chromatography column and eluted with 3:1 by volume mixture of hexane and ethyl acetate, to give 1.8 g of the desired Compound No. 81 in the form of crystals melting at 84°-85° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH2:49]([N:56]1[CH2:61][CH2:60][C@@H:59]([CH3:62])[C@@H:58]([NH:63][CH3:64])[CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:49]([N:56]1[CH2:61][CH2:60][C@@H:59]([CH3:62])[C@@H:58]([N:63]([CH3:64])[C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CN[C@H]1CN(Cc2ccccc2)CC[C@H]1C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@H]4CN(Cc5ccccc5)CC[C@H]4C)ncnc32)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 163.4 %

Procedure:
To a clean, dry, nitrogen-purged reactor were charged 4-chloro-7-(4-methyl-benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (25.12 g, 0.082 mol), bis-(3R,4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine di-p-toluoyl-L-tartaric acid (40.31 g, 0.041 mol), potassium carbonate (34.2 g, 0.245 mol), and water (125.6 ml). The mixture was heated to 95-105° C. for a minimum of 10 hours, then cooled to 45-55° C. Acetonitrile (25 ml) was charged and the slurry was held at 45-55° C. for a minimum of 1 hour. The mixture was further cooled to 20-30° C. and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with water (50 ml). After drying, 32.8 g (82.1%) of the title compound were isolated.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[Br:24]NC(=O)CCC(N)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[Br:24]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1Br
Temperature: 23 °C
Reaction time: 24 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-bromosuccinamide (146 mg, 0.822 mmol), and DMF (4 mL) were allowed to stir at 23° C. After 24 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate: hexane 1:1) to afford 6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (27): Mass Spectrum (CI) 385 (MH+Br81).