Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH2:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(CNC)n1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(CN(C)S(=O)(=O)c2ccc(Br)cc2)n1
Reaction time: 18 h
Yield: 66.8 %

Procedure:
4-Bromobenzenesulfonyl chloride (2.1 g, 8.2 mmol) was added to a solution of ethyl 2-(methylaminomethyl)thiazole-4-carboxylate (1.5 g, 7.5 mmol) and triethylamine (2.1 ml, 1.5 g, 15 mmol) in dichloromethane (30 ml) and the mixture was stirred for 18 h. The mixture was diluted with ethyl acetate and washed with 1N potassium hydrogen sulphate, water and brine, dried and reduced. Chromatography (35% EtOAc/65% hexanes) afforded ethyl 2-(N-(4-bromobenzenesulphonyl)-N-methylaminomethyl)thiazole-4-carboxylate (2.1 g, 67%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([C:11](=[O:13])[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[N:12]=[C:3]1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CCl)nc(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(COc2ccc(C=O)cc2)nc(=O)c2ccccc21
Yield: 61.8 %

Procedure:
The title compound (364 mg, 65%) was prepared from 2-chloromethyl-1-methyl-4-oxo-1,4-dihydroquinazoline (416 mg, 2.0 mmol) and 4-hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence of K2CO3 (276 mg, 2.0 mmol) as base by a similar procedure to that described in preparation 13.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[C:12](O)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([O:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)C(=O)O
Yield: 92 %

Procedure:
Reflux a mixture of 2-hydroxy-propionic acid (480 ml, 85% in water) and sulfuric acid (2 mL) in acetic acid (2500 mL) and toluene (300 mL) for overnight. After removal of solvent under vacuum, purify the residue by distillation to give 2-acetoxy-propionic acid (550 g, 92%) as colorless oil. 1H NMR (CDCl3, 400 MHz): δ 9.27 (brs, 1H), 5.10 (m, 1H), 2.13 (s, 3H), 1.53 (d, J=7.2, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].N#N.I[CH2:16][CH3:17]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH2:16][CH3:17])[C:7]=12
Reactant: CCI
Reactant: Clc1nccc2cc[nH]c12
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine (11 mmol) in dry DMF (20 mL) was cooled on an ice bath, NaH (143 mmol) was added portion wise under N2. The mixture was allowed to stir at room temperature for 1 hr. Upon cooling to 0° C., iodoethane (26 mmol) was added and the mixture was reacted for further 3 his. After quenching with H2O (20 mL), the mixture was diluted with diethyl ether and extracted with ether (4×50 mL). The organic layers were combined, washed with brine, dried with MgSO4 and filtered. The solvent was evaporated to give 7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridine as orange oil. MS (ESI+) m/z 181.0533 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH2:26][OH:27])([CH2:24][OH:25])[C:21](O)=[O:22])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:4]=2[CH:3]=1.C(O)C.O.C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH2:21][OH:22])([CH2:24][OH:25])[CH2:26][OH:27])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:4]=2[CH:3]=1
Reactant: O=C(O)C(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: OCC(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of an optically active form (28.3 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionic acid in tetrahydrofuran (40 ml) were successively added dropwise at room temperature a 0.93M solution (225 ml) of borane-tetrahydrofuran complex in tetrahydrofuran and a 1.09M solution (32 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture, ethanol (57 ml) was added dropwise at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (150 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. A solution of the obtained residue in ethanol (50 ml) was cooled to 0° C., sodium borohydride (2.3 g) was added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted again with ethyl acetate (50 ml). The combined organic layer was successively washed with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 9/1) to give the title compound (21.6 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26]C(=O)OC(C)(C)C)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:42]>>[ClH:42].[NH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:19]=[N:18][CH:17]=[CH:16][N:15]=4)=[O:13])[C:4]=23)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(pyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.060 g, 0.12 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was purified by reverse phase HPLC (0 to 50% ACN in water, Gilson system). The resulting product was then dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide hydrochloride (0.019 g, 33% yield). 1H NMR (400 MHz, D2O) δ 8.69 (s, 1H), 8.57-8.56 (m, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 3.70-3.62 (m, 1H), 3.55-3.50 (m, 1H), 3.42-3.39 (m, 1H), 3.31-3.29 (m, 1H), 2.83-2.80 (m, 1H), 2.19-2.16 (m, 1H), 1.92-1.89 (m, 1H), 1.73-1.69 (m, 1H), 1.49-1.47 (m, 1H); LCMS (APCI+) m/z 416, 418 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[O:15][N:14]=1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[CH2:18]([C:16]1[O:15][N:14]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[N:17]=1)[CH2:19][CH3:20]
Reactant: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCCc1nc(C2Cc3ccccc3N2)no1
Yield: 56.1 %

Procedure:
A solution of compound 89 (0.0035 mole) in ethanol (60 ml) was treated with 3M NaOH (60 ml), and the reaction mix was heated to 55–60° C. for 5.5 hours. The reaction was rapidly cooled in an ice bath, diluted with DCM, and treated with cold distilled water. The layers were separated and the aqueous fraction was extracted three times with DCM. The organic fractions were combined, washed once with 1M NaOH, and dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep column chromatography, yielding 0.45 g of 2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3yl)-1H-indole.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[NH3:6]>>[CH3:1][Si:2]([NH:6][Si:2]([CH3:5])([CH3:4])[CH3:1])([CH3:5])[CH3:4]
Reactant: N
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)N[Si](C)(C)C

Procedure:
In a summary of the process shown in FIG. 1, liquid trimethylchlorosilane (TMCS) and gaseous ammonia are fed to the first of a set of two or more reactors where they combine to form "crude" HMDS and an ammonium chloride by-product slurry. As set forth below, the first stage of the set of two or more reactors is a high shear vessel in which the TMCS and ammonia mixture is subjected to continuous high shear agitation in a recirculating reactor loop. Ammonium chloride produced as a by-product is in a "prilled" form in the resultant slurry. The slurry is then optionally fed to a second high shear reactor to insure that a complete reaction of all TMCS occurs. Then, the slurry is passed to a centrifuge where the ammonium chloride crystals are removed. In the centrifuge, HMDS is removed from the solid ammonium chloride particles in the centrifuge cake by displacement of the HMDS with a non-reactive wash. Suitable washes may be hydrocarbons or a buffered saturated ammonium chloride water solution. The HMDS liquid filtrate passes on to a mix tank where solid sodium amide is added.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[N:3]=[CH:2]1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>CN(C=O)C>[Si:18]([O:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCc1c[nH]cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
A solution of 2-(1H-imidazol-4-yl)ethanol (1.24 g, 11.1 mmol) in DMF (10 mL) was treated with imidazole (1.51 g, 22.1 mmol) and TBDPSCl (3.12 mL, 12.2 mmol) and the mixture was stirred at RT for 2 h. The mixture was then poured onto H2O and extracted with AcOEt. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/heptane 0:100 to 100:0) gave the title compound (1.6 g). UPLC-MS: MS 351.2 (M+H+); UPLC rt 1.02 min.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][C:43]([F:46])([F:45])[F:44].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:42][C:43]([F:46])([F:45])[F:44])[N:18]=3)[N:15]=2)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(F)(F)F)c4cc(F)ccc34)nc12
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a mixture of N-tert-Butyl-2-(6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 0.12 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 10 mL of DMF was added 2-iodo-1,1,1-trifluoroethane (0.5 mL, 5.07 mmol). The reaction mixture was heated to 80° C. for 3 hours. After cooling to room temperature, 50 mL of water were added, and the mixture was extracted with ethyl acetate (2×50 mL), combined organics dried with sodium sulphate, filtered and concentrated to give N-tert-butyl-2-(6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, crude). LCMS: (M+H)+=565; (M+Na)+=587. Crude material used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[F:14][C:15]([F:27])([F:26])[S:16]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[H-].[Na+]>>[F:26][C:15]([F:14])([F:27])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: OCc1ccc(SC(F)(F)F)cc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=S(=O)(c1ccc(OCc2ccc(SC(F)(F)F)cc2)cc1)C(F)(F)F
Yield: 66.7 %

Procedure:
4-(Trifluoromethylthio)benzyl alcohol (300 mg, 1.44 mmol) was coupled with 4-(trifluoromethylsulfonyl)chlorobenzene (370 mg, 1.51 mmol) using sodium hydride (65 mg, 60% dispersion in oil, 1.58 mmol) to give 400 mg of 4-trifluoromethylthiobenzyl 4-trifluoromethylsulfonylphenyl ether as a white solid. 1HNMR (360 MHz, DMSO-d6) δ 8.06 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.39 (s, 2H, OCH2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].Cl[C:20]1[C:25](CC=O)=[C:24]([CH3:29])[CH:23]=[CH:22][C:21]=1[S:30]([O-:33])(=[O:32])=[O:31].C1C[O:37][CH2:36][CH2:35]1>O.C(OCC)C>[S:30]([O:33][CH2:35][C:36]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:37])([C:21]1[CH:20]=[CH:25][C:24]([CH3:29])=[CH:23][CH:22]=1)(=[O:31])=[O:32]
Reactant: C1CCOC1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(Cl)c1CC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(=O)Nc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of p-aminobenzoic acid (92 mg, 0.67 mmol) and NaOH (27 mg, 0.67 mmol) in water (6 ml) was stirred at room temperature for 10 min until all of the solid material had dissolved. Na2CO3 (59 mg, 0.5561 mmol) was then added and the mixture cooled to 0° C. A solution of 2-chloro-2-oxoethyl-4-methylbenzenesulfonate (4, 200 mg, 0.8044 mmol) in THF (2 ml) was injected rapidly and the resulting solution allowed to warm to room temperature and stirred for 2 h. Then reaction mixture was poured into a separating funnel containing diethyl ether. The phases were separated and the aqueous phase washed with a further portion of diethyl ether. The aqueous phase was acidified to pH 1 by addition of 1N HCl solution and the product extracted into ethyl acetate. The ethyl acetate was washed twice with 1N HCl solution and the organic phase was dried (Na2SO4), filtered and the solvent removed in vacuo. The resulting pale orange solid was recrystallized from chloroform/MeOH (20:1) affording 5 as a white powder (146 mg, 62%). δH (400 MHz, DMSO) 2.37 (3H, s, Me), 4.70 (2H, s, CH2), 7.46 (2H, d, J=8 Hz, ArH), 7.59 (2H, d, J=8.6 Hz, ArH), 7.82 (2H, d, J=8 Hz, ArH), 7.87 (2H, d, J=8.6 Hz, ArH), 10.39 (1H, s, NH), 12.72 (1H, CO2H); δc (100.6 MHz, DMSO) 21.8, 68.0, 119.4, 126.4, 128.5, 130.9, 131.1, 132.7, 142.7, 146.0, 164.4, 167.5; MS (ES+) 349.7 (100%, [M+H]+), 371.7 (40%, [M+Na]+); MS (ES−) 347.9 (100%, [M−H]−); HRMS [M−H]− requires 348.05473, found 348.05334.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[N:16](C=C)[N:17]=[CH:18][C:3]=12.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[NH:16][N:17]=[CH:18][C:3]=12
Reactant: C#CCN1CCc2nc3c(cnn3C=C)c(N)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C#CCN1CCc2nc3[nH]ncc3c(N)c2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
To a mechanically stirred solution of 4-amino-7,8-dihydro-6-(prop-2-ynyl)-1-vinyl-1H-pyrazolo[3,4-b][1,6]napthyridin-5(6H)-one (1.91 g.) in dry acetonitrile (35 ml.) under a nitrogen atmosphere was added freshly prepared 6N aqueous HCl (11.65 ml.) at room temperature. The resulting suspension was heated under reflux for three hours, followed by cooling to room temperature and addition of water. The reaction mixture was made basic with aqueous saturated sodium carbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered through diatomaceous earth and concentrated to give 4-amino-7,8-dihydro-6-(prop-2-ynyl)-1H-pyrazolo[3,4-b][1,6]napthyridin-5(6H)-one as a white solid (1.24 g.) (72% yield) which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2C=CC=C[CH:11]=2)[N:5]([CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[CH3:23][CH:24]([N:26]=[C:27]=[O:28])[CH3:25]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.ClCCl>[CH3:23][CH:24]([NH:26][C:27](=[O:1])[OH:28])[CH3:25].[CH3:23][CH:24]([NH:26][C:27](=[O:1])[OH:28])[CH3:25].[N:20]1[CH:21]=[CH:22][C:17]([C:4]2[N:5]3[C:6](=[C:7]([CH2:8][OH:9])[C:3]=2[CH2:2][OH:1])[CH2:10][CH2:11][CH2:16]3)=[CH:18][CH:19]=1
Reactant: CC(C)N=C=O
Reactant: Cn1c(-c2ccccc2)c(CO)c(CO)c1-c1ccncc1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: CC(C)NC(=O)O
Product: OCc1c(CO)c(-c2ccncc2)n2c1CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
A mixture of the titled diol compound of Example VIII (1.6 g), 2-propylisocyanate (1.23 g) and dibutyltin diacetate (2 drops) in anhydrous dichloromethane (50 mL) was stirred at room temperature under an argon atmosphere for 15 hours. The mixture was concentrated in vacuo and the residue was subjected to flash chromatography to give the titled carbamate compound as an amorphous white powder (0.66 g) having a melting point of 160°-162° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:15].C(=O)(O)[O-].[Na+].Cl>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2nc(O)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)ccc2c1

Procedure:
A solution of quinoline2,6-diol (1 eq) in THF (0.25 M) was treated with POCl3 (1.1 eq) and a drop of DMF. Crushed ice was added to the reaction mixture and EtOAc was added and neutralized with a solution of sodium bicarbonate. The mixture was brought back to pH 6-7 with 1N HCl and ethyl acetate layer was separated, washed with water and brine to provide title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].C(N(CC)CC)C.Br[CH:13]([CH2:19]Br)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[NH:1]1[CH2:2][CH2:3][S:4][CH2:19][CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(Br)CBr
Reactant: NCCS
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A warm solution of 2-aminoethanethiol (10.0 g, 0.130 mol) and triethylamine (36 mL, 0.260 mol) in chloroform is added over 5 minutes to a solution of ethyl 2,3-dibromopropionate (33.9 g, 0.130 mol) in a chloroform/toluene (1:1.6) solution. The reaction mixture is stirred at room temperature for 2.5 hours, filtered and concentrated in vacuo to obtain an orange liquid. The liquid is vacuum distilled to give the title product as a colorless liquid, bp 121°-124° C. at 3 mm Hg.
Reaction SMILES: [CH:1]1([C:7](=O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[C:14]1([C@@H:20]2[CH2:22][C@H:21]2[NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]1([CH:7]([NH:23][C@@H:21]2[CH2:22][C@H:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(=O)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 1-cyclohexylethanone (95 mg, 0.751 mmol) in 1,2-dichloroethane (DCE) (40 mL) and acetic acid (0.052 mL, 0.901 mmol) was added [(trans)-2-phenylcyclopropyl]amine (100 mg, 0.751 mmol). The reaction mixture was stirred for 2 hour at room temperature, then sodium triacetoxyborohydride (477 mg, 2.252 mmol) was added and the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was quenched with saturated NH4Cl. Water (20 mL) followed by dichloromethane (40 mL) were added. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The solid was suspended in diethylether, sonicated and filtered. trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine (48 mg, 0.187 mmol, 24.95% yield) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.11-9.35 (m, 1H), 8.80-9.03 (m, 1H), 7.27-7.42 (m, 2H), 7.13-7.27 (m, 3H), 3.23 (br. s., 1H), 2.91 (d, J=2.78 Hz, 1H), 2.57 (ddd, J=3.54, 6.44, 9.98 Hz, 1H), 1.68-1.87 (m, 4H), 1.57-1.68 (m, 2H), 1.46-1.57 (m, 1H), 1.26-1.42 (m, 1H), 1.18-1.24 (m, 3H), 0.95-1.18 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 244.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19].[C:20](#N)C.CCOCC>C(OC)(OC)OC>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:20]=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[CH:14][C:13]=1[F:19]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CC#N
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCOCC
Solvent: COC(OC)OC
Product: CC1(C)OC(=O)C(=CNc2ccc(Br)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (36.4 g, 253 mmol) in trimethyl orthoformate (125 mL) was stirred at 100° C. for 1.5 h. This mixture was cooled to 80° C. and 4-bromo-3-fluoroaniline (40 g, 211 mmol) was added using ACN to aid in transfer. Heated to 100° C. for 3.5 h. The reaction mixture was cooled to RT and poured into Et2O (750 mL) and stirred for a few minutes. Filtered resulting solid, washing with Et2O and dried to yield 5-(((4-bromo-3-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (61.41 g, 178 mmol, 85% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ ppm 11.25 (d, J=14.4 Hz, 1H), 8.59 (d, J=14.4 Hz, 1H), 7.67-7.85 (m, 2H), 7.42 (dd, J=8.6, 2.0 Hz, 1H), 1.68 (s, 6H).