Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)C(=O)OC(C)(C)C)[CH3:2].[OH-].[Na+].C(Cl)Cl>CO.Cl>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)[CH3:2]
Reactant: CCN(CCN1CCOc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCNCCN1CCOc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C

Procedure:
Under positive argon pressure, an orange suspension of tert-butyl ethyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)carbamate (4 g, 9.29 mmol) in MeOH (30 mL) and 1N HCl (30 mL) was refluxed for 1 hour. The mixture was then cooled to room temperature, transferred to an ice bath, and 1N NaOH (75 mL) was then added. The solution turned a milky green colour with a black suspension. The mixture was then treated with CH2Cl2 (50 mL) and stirred for half an hour. After this time, the mixture was transferred to a separatory funnel and the product was extracted into CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using the following sequence of eluents: EtOAc; 1:99 (2M NH3 in MeOH):CH2Cl2; 2.5:97.5 (2M NH3 in MeOH):CH2Cl2; and 5:95 (2M NH3 in MeOH):CH2Cl2. A brown solid was obtained (2 g, 65.1%). 1H-NMR (CDCl3) δ 7.40-7.37 (m, 2H), 7.07-7.04 (m, 1H), 6.75-6.72 (m, 1H), 6.52-6.50 (m, 2H), 4.82 (brs, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.39-3.31 (m, 4H), 2.86 (t, J=6.3 Hz, 2H), 2.71 (q, J=6.9 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (95); HPLC purity: 94.1% by area.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:14][CH2:12][CH3:13])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CCN
Product: CCNc1nc(Cl)ccc1C(=O)O
Yield: 62 %

Procedure:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a solution of ethylamine (70% in water) was stirred at ambient temperature for 72 hours. The excess amine was then evaporated off under reduced pressure, and an aqueous solution of acetic acid at 10% was added until the product precipitates. The beige solid was spin-filter-dried, rinsed with cold water and dried in an oven. 10.5 g of the expected product were obtained.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]Cl)[C:17]=1[CH3:24].[OH-].[Na+]>C(O)C>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:17]=1[CH3:24]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCCCl)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCCCl)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
12.3 g of crude 2-mercaptobenzimidazole, 20 g of 4-(2-chloroethoxy)-2-chloromethyl-3-methylpyridine hydrochloride and 11 g of sodium hydroxide were dissolved in 300 ml of ethanol to obtain a solution. This solution was stirred at 60° C. for 2 hours and distilled under a reduced pressure to remove the ethanol. The obtained residue was chromatographed over a silica gel column and eluted with 40% ethyl acetate in hexane and then with ethyl acetate to obtain 15.5 g of the title compound as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3CC2CC2)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 3, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and cyclopropylmethyl bromide to afford the desired product as a colorless foam (54%). MS (ISP): 516.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])(C[Si](OC(C)C)(C)C)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[C:37](=O)(O)[O-:38].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])([CH2:37][OH:38])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccccc1F)[C@@H](C)n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Temperature: 50 °C
Yield: 57.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxy dimethylsilyl)-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (1 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which an 30% aqueous solution of hydrogen peroxide (2 ml) and sodium bicarbonate (157 mg) were added. The mixture was heated at 50° C. for 4 hours, then cooled and extracted with ethyl acetate (100 ml). The extract was washed with water (30 ml), an aqeous solution of Na2S2O3 (30 ml×2) and a saturated aqueous solution of sodium chloride (30 ml) successively, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/4) and recrystallized from diethyl ether (20 ml) to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) as a colorless crystalline powder.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1>[Pd].C(O)C>[F:21][C:18]([F:19])([F:20])[C:12]1[CH:13]=[C:14]([NH2:15])[CH:9]=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cncc(C(F)(F)F)c1
Reaction time: 6 h
Yield: 99.4 %

Procedure:
A Parr hydrogenation flask was charged with 10% Palladium on carbon, 50% wet (0.050 g, 0.023 mmol) and ethanol (10 mL). Triethylamine (1.0 ml, 3.09 mmol), 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (0.70 g, 3.09 mmol) and an additional 10 mL of ethanol were added. The flask was purged of air, charged with 48 psi of hydrogen, and shaken for 6 h. The reaction mixture was purged of hydrogen in vacuo and filtered through Celite®, washing with EtOAc (20 mL) and EtOH (20 mL). The filtrate was concentrated in vacuo and the product partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with sat aq NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo to provide 5-(trifluoromethyl)pyridin-3-amine (498 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.14 (m, 1 H), 8.00 (s, 1 H), 7.13 (m, 1 H), 5.84 (s, 2 H); MS (ESI) m/z 163.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:20][NH:21][C:22]([NH2:24])=[S:23].C(O)(=O)C.C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:9]=[N:20][NH:21][C:22]([NH2:24])=[S:23])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=S)NN=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(Br)cc1

Procedure:
1.0 g of 2-(4-bromophenyl)-3-(5-nitro-2-furyl) acrolein and 0.31 g of thiosemicarbazide are heated at reflux for 30 minutes in 25 cc of methanol with 0.3 g of glacial acetic acid and 1.0 g of sodium acetate. Upon cooling, the title compound is obtained as yellow brown crystals having a M.P. of 230°-237°.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][Cl:23])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(C#CCCCCl)n[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
To a nitrogen degassed solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (250 mg, 0.786 mmol) in anhydrous N,N-dimethylformamide (6 mL) under nitrogen atmosphere at room temperature was added copper(I) iodide (30 mg, 0.158 mmol), bis(triphenylphosphine)palladium(II)dichloride (62 mg, 0.088 mmol) and finally triethylamine (0.219 mL, 1.572 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes and then a solution of 5-chloro-1-pentyne (161 mg, 1.572 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added. The reaction mixture was stirred at 60° C. for 80 minutes. The reaction was evaporated in-vacuo to yield a brown oil. The oil was partitioned between water/brine (1:1) and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid. The solid was absorbed onto Florisil, loaded onto a 50 g silica cartridge and purified by chromatography using a 0-100% ethyl acetate in cyclohexane gradient over 60 minutes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a pale yellow solid (172 mg).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:33][O:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:37][CH2:36][CH2:35][O:34][CH3:33])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COCCO
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: COCCOc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CC(F)(F)C3)C2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and 2-methoxyethanol. White solid (37%). MS (EI): 546.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]([O-:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2- dioxo-3,3-dimethylpentyl-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3):d 0.87 (t,3H); 1.22, 1.25 (s,3H each); 1.77 (dm,2H); 2.02 (m,2H); 2.17 (m, 1H); 2.25 (m,1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])#[N:2].[H][H].[ClH:19]>[Pt]=O.C(O)C.C(OCC)(=O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc2n(c1CC#N)CCCC2
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2n(c1CCN)CCCC2

Procedure:
Methyl 3-(Cyanomethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate 101e was hydrogenated with platinum oxide catalyst under 50 psi of hydrogen in ethanol and ethyl acetate in the presence of hydrogen chloride overnight at room temperature to give 101f (380 mg, 1.74 mmol) which was used in directly in the next step.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(OC(C)(C)C)=O>Cl.C(O)C>[ClH:20].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nn1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(OC[C@@H]2CCN2)nn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 811 mg sample of 3-(1-BOC-2(S)-azetidinylmethoxy)-6-chloropyridazine, prepared as in Example 13a above, was dissolved in 10 mL of satd HCl in ethanol cooled to 0° C., and the reaction was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the oily residue was dried under high vacuum for 4 hours to provide a solid. The solid was triturated with ether, collected, and recrystallized three times from ethanol/ether to give 118 mg of the title compound. mp 150-151° C. MS (DCI/NH3) m/e: 200 (M+H)+. 1H NMR (DMS-d6, 300 MHz) δ: 9.31 (br s, 1H), 7.87 (d, J=9.2 Hz, 1H, 7.44 (d, J=9.2 Hz, 1H), 4.84-4.63 (m, 3H), 3.98-3.83 (m, 2H), 2.59-2.36 (m, 2H). Anal. Calc. for C8H11N3OCl2 : C, 40.70; H, 4.70; N, 17.80; Found C, 40.58; H, 4.59; N, 17.58.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28]=[C:29]=[S:30])[CH3:27]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:29]([NH:28][CH2:26][CH3:27])=[S:30])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CCN=C=S
Solvent: CC#N
Product: CCNC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 52 μl (2 molar equivalents) of ethyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 92 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=73%) which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (3.0 g, 13.4 mmol) was dissolved in tetrahydrofuran (67 mL), and oxalyl chloride (1.35 mL, 15.8 mmol) and N,N-dimethylformamide (20 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride. To a solution of 3-amino-4-fluorophenol (1.62 g, 12.8 mmol) in tetrahydrofuran (20 ml) was added a suspension of sodium hydrogen carbonate (3.22 g, 38.3 mmol) in water (40 mL), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise at 0° C. a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride produced above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added ethyl acetate (100 mL), and the aqueous layer was separated. The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate/n-hexane to give the title compound (4.13 g, 97%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1

Procedure:
4-(4-Nitrobenzoylamino)-2-nitrobenzoic acid was prepared as described in Example 3 from 20.0 g (0.11 mol) of 4-amino-2-nitrobenzoic acid and 22.4 g (0.121 mol) of 4-nitrobenzoyl chloride. The product was reprecipitated from THF/H2O.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+]>>[CH3:1][C@H:2]1[C@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C

Procedure:
The mother liquor of 17 from above is treated with 1N—NaOH to obtain the free base which is then crystallized with D-(+)-O,O′-Dibenzoyl tartaric acid as described above to give the antipode 20.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:4]1[NH:3][CH:2]([CH3:1])[N:7]=[C:6]2[N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:9]([CH3:11])=[CH:10][C:5]=12
Reactant: Cc1cc(C)c(-n2c(C)cc3c(=O)[nH]c(C)nc32)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-n2c(C)cc3c2=NC(C)NC=3Cl)c(C)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of compound (5) (18.3 g, 65.0 mmol) in POCl3 (30 mL) was refluxed for 3 hours, cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate, dried, and concentrated under vacuum. The residue was chromatographed (elution with 10% ethyl acetate in hexanes) to afford 16.3 g (84%) of compound (6) as a tan powder.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]I.[OH-].[Na+].O>CN(C=O)C>[CH3:31][N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]1[CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14][CH2:13]2)[CH:16]=[CH:17][C:18]=1[N+:28]([O-:30])=[O:29]
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1)c1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Yield: 86.4 %

Procedure:
A solution of 5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (2.0 g, 5.00 mmol), methyl iodide (0.31 ml, 5.00 mmol) and sodium hydroxide (0.26 g, 6.5 mmol) in 25 ml DMF was stirred at 0° C. for 2 hours. 100 ml water was added to the mixture to quench the run, and the mixture was extracted with ethyl acetate (2×20 ml). The extraction was washed with water (3×30 ml) and dried over anhydrous sodium sulfate. N-methyl-5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (1.8 g, 90%) was obtained after remove of solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.38 (s, 3H), 3.37-3.87 (m, 8H), 6.72 (m, 4H), 6.84 (m, 1H), 7.21 (m, 2H), 7.45 (m, 5H), 8.07 (d, J=9.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 40.5, 47.7, 47.9, 111.1, 114.6, 115.3, 119.8, 127.6, 129.1, 129.2, 129.6, 130.7, 135.6, 137.3, 145.4, 148.4, 155.1, 171.0.
Reaction SMILES: [C:1](=[O:4])([O-])N.[CH3:5][O:6][C:7]1[C:12]2[N:13]=[C:14]([NH:16][C:17](=[O:19])[OH:18])[S:15][C:11]=2[CH:10]=[CH:9][CH:8]=1>>[CH3:5][O:6][C:7]1[C:12]2[N:13]=[C:14]([NH:16][C:17](=[O:18])[OH:19])[S:15][C:11]=2[C:10]([N:13]2[CH2:14][CH2:1][O:4][CH2:11][CH2:12]2)=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(NC(=O)O)nc12
Reactant: NC(=O)[O-]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)O)nc12
Yield: 58 %

Procedure:
Carbamate formation using the same procedure as for (4-methoxy-benzothiazol-2-yl)-carbamic acid methyll ester yields the product as off-white solid in 58% yield. MS: m/e=324 (M+H+).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1C#N
Temperature: 60 °C
Yield: 97 %

Procedure:
To 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) in methanol (30 mL) was added sodium methylate in small portion (2 mol eq, 0.26 g). The reaction mixture was heated at 60° C. overnight. The solvent was distilled under reduced pressure and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give 28c as a pale yellow oil (0.48 g, 2.33 mmol, 97% Yield). 1HNMR (DMSO, 200 MHz) δ 4.04 (s, 3H), 7.71 (d, 1H, J=6), 8.59 (d, 1H, J=6).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[C:13]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:12][N:11]=[C:10]2[NH:18][CH:19]=[CH:20][C:9]=12>CN1C(=O)CCC1>[CH:15]([O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:9]2[CH:20]=[CH:19][NH:18][C:10]2=[N:11][CH:12]=1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)Oc1cnc2[nH]ccc2c1F
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 200 °C
Yield: 48.8 %

Procedure:
Piperazine (222 mg, 2.6 mmol) was added to 4-fluoro-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.26 mmol) in NMP (1 mL), and the reaction was heated to 200° C. for 1 hour under microwave irradiation. The reaction was concentrated to dryness under high vacuum and then purified by chromatography (SP4, 12+M, water/ACN 100/0→40/60, 20CV) to yield 5-isopropoxy-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (33 mg, 49% yield) as an oil.