Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:13]([O:15]C(C)(C)C)=[O:14])[C:6](=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([CH3:12])[O:3]1.[H][H]>C(OCC)(=O)C.CO>[CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([CH3:12])[O:3]1
Reactant: [H][H]
Reactant: COC(=O)C=C1CC(C)OC1(C)C(=O)OC(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC1CC(C)OC1(C)C(=O)O
Yield: 93.8 %

Procedure:
2,5-Dimethyl-3-methoxycarbonylmethylene-2-tetrahydrofuroic acid, t-butyl ester (28 mg, obtained from Step A) was dissolved in 0.25 mL of ethyl acetate and 0.25 mL of methanol. This mixture was hydrogenated under a balloon of hydrogen at room temperature for 1.25 h. The reaction mixture was filtered over a pad of celite, and the crude product obtained after removal of volatiles was purified via a silica gel SepPak, providing 21 mg of the desired compound cleanly (75% yield), homogeneous by TLC (Rf=0.2 in 10/1 hexane/ethyl acetate)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1.[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26]([N:35]5[CH2:38][CH2:37][CH2:36]5)=[O:27])[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: C1CNC1
Product: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)N1CCC1

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate and azetidine, and in the same manner as in Example 59, the title compound was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([C:13]4[C:33]([F:34])=[CH:32][C:16]5[NH:17][C:18]([O:20][CH:21]6[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]6)=[N:19][C:15]=5[C:14]=4[F:35])=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([C:13]4[C:33]([F:34])=[CH:32][C:16]5[NH:17][C:18]([O:20][CH:21]6[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]6)=[N:19][C:15]=5[C:14]=4[F:35])=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3[nH]2)CC1
Agent: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{[5-(1-cyclopropyl-1H-indol-5-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.046 g, 0.96 mmol) was dissolved in 1 mL of THF and treated with 37 mg of KOTMS (0.037 g, 0.288 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was then diluted with EtOAc and washed with 2 N HCl. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: calculated for C25H23F2N3O3 451.46, observed m/e 451.92 (MAI)+ (Rt 2.42/4 min). 1H NMR (500 MHz, CD3OD): δ7.62 (d, 1H), 7.56 (brs, 1H), 7.25-7.20 (m, 2H), 7.00-6.92 (br, 1H), 6.42 (d, 1H), 4.92 (m, 1H), 3.41 (m, 1H), 2.37 (m, 1H), 2.34-2.27 (m, 2H), 2.15-2.07 (m, 2H), 1.73-1.55 (m, 4H), 1.13-1.08 (m, 2H), 1.03-0.98 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncn2c(-c3cccc(Cl)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c1NCC=C2c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 5.39 g of 4-(m-chlorophenyl)-imidazo[1,5-a]pyrimidine-8-carboxamide (Example 14) in 100 ml of glacial acetic acid, was added in portions 2.8 g of sodium cyanoborohydride at room temperature under nitrogen. The mixture stirred at room temperature for 2 hours. The solvent was evaporated in vacuo to give an oil, and this was dissolved in dichloromethane, then washed with saturated sodium bicarbonate solution, The organic layer was separated, dried over anhydrous sodium sulfate and filtered through a short column of hydrous magnesium silicate. Evaporation of the solvent gave a yellow solid which was recrystallized from acetonitrile to give 3.25 g of the desired product as a yellow solid, mp 182°-184° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.[CH3:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C(#N)C>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:7]1[CH2:6][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN1CCCC1
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: C1CCNCC1

Procedure:
A stock solution of 1 molar piperidine acetate was prepared by mixing one equivalent of glacial acetic acid in an appropriate volume of water and slowly adding one equivalent 1-methylpyrrolidine. The pH of the stock solution is 7. The stock solution was diluted in an appropriate volume of water or acetonitrile to working concentration.
Reaction SMILES: N1CCCCC1.[Br:7][CH:8]([C:14](Br)([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:15][F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10].O>CCOCC>[Br:7][C:8](=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:15][F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(Br)C(Br)(CF)c1cccc(OC)c1
Solvent: CCOCC
Solvent: O
Solvent: C1CCNCC1
Product: CCOC(=O)C(Br)=C(CF)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
Piperidine (0.22 ml) is added to a solution of ethyl 2,3-dibromo-3-(3'-methoxyphenyl)-4-fluorobutyrate (0.80 g) in ether (10 ml). The reaction mixture is stirred at room temperature for 3 hours and water is added. Ether extraction gives essentially pure ethyl 2-bromo-3-(3'-methoxyphenyl)-4-fluoro-2-butenoate (0.65 g).
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:14]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([NH:28][C:29]3[N:34]=[C:33]([N:35]([CH:45]4[CH2:47][CH2:46]4)[CH2:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)[C:32]4=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]4[N:30]=3)[C:21]=2[Cl:53])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:18][CH2:17][C:16]([NH:15][C@@H:14]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([NH:28][C:29]3[N:34]=[C:33]([N:35]([CH:45]4[CH2:47][CH2:46]4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[C:32]4=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]4[N:30]=3)[C:21]=2[Cl:53])[CH2:10][C@H:9]1[OH:8])=[O:19]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CCl)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CCl)[C@H](O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)-2-chloroacetamide (43 mg, 0.055 mmol) in THF (1 mL) was added TBAF (1M in THF, 0.112 mL, 0.112 mmol) and the reaction solution was stirred at room temperature overnight. LCMS showed completion of reaction. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0.5-4% methanol/dichloromethane) to give (+/−)-2-chloro-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)acetamide (22 mg) as a white solid.
Reaction SMILES: CC([CH:5]1[CH2:10][CH:9]([C:11]2[C:19]3[C:14](=[C:15]([C:21]([NH2:23])=[O:22])[CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:27].C(OCC)C>CO.O1CCOCC1>[ClH:27].[Br:20][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([C:21]([NH2:23])=[O:22])[CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl-4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-1-piperidinecarboxylate (which may be prepared according to WO2005067923A1, 74 g) was dissolved/suspended in methanol (300 mL) and to this was added 4N HCl in dioxane (200 mL). The reaction mixture was stirred for 2 hours. Diethyl ether (400 mL) was added and the solid was collected by filtration. This was washed with diethyl ether (300 mL) and dried in vacuo to give the title compound (66.53 g) as pale yellow solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@@H:14]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1>C(O)C>[ClH:3].[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C@@H:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:19][CH:20]=1)([OH:26])=[O:25]
Reactant: CCOC(=O)c1ccc(NC(=O)[C@H](Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C(O)c1ccc(NC(=O)[C@H](Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.6 %

Procedure:
2N NaOH (2.6 ml) was added to solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (120 mg) in ethanol (10 ml) and the whole was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. A small amount of water was added to the residue, and the whole was concentrated under reduced pressure. The above procedure was repeated 3 times to remove ethanol. The residue was dissolved in 1N HCl (20 ml), and diluted with water (20 ml). Then, the solution was washed 3 times with ethyl acetate (10 ml). The aqueous layer was concentrated under reduced pressure. A small amount of water was added, and the whole was concentrated under reduced pressure. The concentrating steps were repeated 3 times to evaporate excess HCl. The residue was dried under reduced pressure in a desiccator. After ethanol was added, the insoluble materials were removed by filtration. The combined filtrates were concentrated under reduced pressure and dried to obtain (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (84 mg).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[F:35][C:36]([F:46])([F:45])[C:37]1[N:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1>ClCCl>[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([NH:44][CH2:43][C:40]1[CH:41]=[N:42][C:37]([C:36]([F:46])([F:35])[F:45])=[CH:38][CH:39]=1)=[O:33]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccc(C(F)(F)F)nc1
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and (6-(trifluoromethyl)pyridin-3-yl)methanamine (0.033 g, 0.186 mmol) were combined and stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (s, 1H), 7.53-7.61 (m, 2H), 7.22-7.30 (m, 10H), 6.50-6.56 (m, 1H), 4.32 (d, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 452 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8](O)=[O:9])[CH:7]=1.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:9])=[CH2:24]
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (0.20 g, 0.48 mmol), O-(2-vinyloxyethyl)-hydroxylamine (55 mg, 0.53 mmol), EDCI (102 mg, 0.53 mmol), HOBt (72 mg, 0.53 mmol) and DIPEA (90 μL, 0.53 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (200 mg, 83%). LCMS (Method B): RT=3.41 min, [M+H]+=501.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH:7]1([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH2:9][CH2:8]1.C(N(CC)CC)C.[O:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:7]1([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([C:41]([CH:40]5[CH2:38][CH2:39]5)=[O:37])[C:4]([CH:1]5[CH2:3][CH2:2]5)=[O:5])[CH:24]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH2:9][CH2:8]1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reactant: C1CCOC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N(C(=O)C1CC1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reaction time: 0.33 h

Procedure:
Cyclopropanecarbonyl chloride (51 mg) was added to a solution of 100 mg of N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide and 49 mg of triethylamine in tetrahydrofuran at 0° C. After 20 minutes of stirring, silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), after which water was added to the residue to obtain 19 mg of the target substance as a white solid.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26].CO.C(Cl)Cl>CS(C)=O>[CH2:23]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:25][CH3:26]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCCCN
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: CCCCNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 75 °C
Yield: 12.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41.5 mg, 0.140 mmol) and butan-1-amine (0.042 mL, 0.420 mmol) in DMSO (1.0 mL), heating at 75° C. for 45 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6.28 mg, 0.018 mmol, 13% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br. s.), 7.88 (1H, d, J=7.4 Hz), 7.56 (1H, d, J=8.0 Hz), 7.27-7.36 (2H, m), 7.13 (1H, d, J=1.6 Hz), 6.94 (1H, br. s.), 3.52 (2H, q, J=6.7 Hz), 3.44 (2H, td, J=6.7, 2.0 Hz), 2.87 (2H, t, J=6.7 Hz), 2.53 (3H, s), 1.72 (2H, quin, J=7.4 Hz), 1.47 (2H, sxt, J=7.3 Hz), 0.94 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](N)=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>O.CO.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:24])=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12
Reactant: Nc1ccc2c(c1)[nH]c(=O)c1c(N)n(-c3ccccc3)nc12
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1c2c(=O)[nH]c3cc(O)ccc3c2nn1-c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture, which is cooled to 0° C., of 3,7-diamino-2-phenyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg), concentrated sulfuric acid (0.7 ml) and water (4 ml) was added dropwise a solution of sodium nitrite (46 mg) in water (1 ml), stirred at 0° C. for 30 minutes, at 90° C. for 1 hour and at room temperature for one night. The reaction mixture was neturalized by adding 5% sodium hydrogen carbonate, and ethyl acetate and methanol were added thereto. The insoluble materials were filtered off. The filtrate was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography to obtain the target compound (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH3:21])[CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]#[C:14][CH2:13][N:12]([CH3:11])[CH3:21])=[N:6][S:5](=[O:10])[N:4]=1
Reactant: CN(C)CC#CCCCCN
Reactant: COC1=NS(=O)N=C1OC
Product: COC1=NS(=O)N=C1NCCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5--thiadiazole-1-oxide (1.57 g) and 7-(dimethylamino)hept-5ynylamine (1.5 g) were reacted to give a solution of 3-methoxy-4-[7-dimethylaminohept-5-ynylamino]-1,2,5-thiadiazole-1-oxide. Reaction with ammonia gas and purification as in Example 1 gave the title compound (1.8 g), m.p. 154°-5° C. (recrystallisation from isopropanolethyl acetate).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[NH:6][C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.C(Cl)Cl.CO>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2[nH]c(C)nc2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(cc1Br)nc(C)n2COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a mixture of 5-bromo-6-methoxy-2-methyl-1H-benzo[d]imidazole (400 mg, 1.659 mmol) in DMF (3 mL) was added 60% wt NaH (80 mg, 1.991 mmol) at 0° C. The mixture was stirred from 0° C. to room temperature for 0.5 hours, then 2-trimethylsilylethyoxymethyl chloride (SEMCl, 0.352 mL, 1.991 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours then quenched with water and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (10-100% EtOAc/Heptane then 0-10% DCM/MeOH) to afford the title compound (310 mg, 50.3% yield) as an oil. MS (M+1)=373.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[BH4-].[Na+].CC(C)=O.[BH4-]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[CH:13]([OH:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: OC1C(=Cc2cccnc2)N2CCC1CC2

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 m water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (3 g, 14.0 mmol) was dissolved in 200 ml methanol and sodium borohydride (3 g, 79.6 mmol) was added in portions (exothermic reaction) with vigorous stirring. After 1 hr of continued stirring, acetone (100 ml) was slowly added to neutralize the remaining borohydride reagent. The mixture was evaporated to dryness and the resulting residue suspended in water (200 ml) and extracted three times with 200 ml portions of chloroform. The chloroform phases were combined, dried over MgSO4, and rotary evaporated to give a clear oil; crystallization of the free base gave a quantitative yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a white precipitate. 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7 mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol) under a nitrogen atmosphere at 0° C., the reaction was than brought to room temperature and stirred for one additional hour. Rotary evaporation at 60° C. produced a viscous oil which, when suspended in ether, afforded 3-chloro-2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octane dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). This chloroquinuclidine (0.3 g, 15 mmol) was dissolved in ethanol (50 ml) and wet Rainey nickel (0.5 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 6 hrs followed by filtration through a pad of Celite filter aid and additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane as a clear oil that solidified upon cooling (0.2 g, 70%). This material (120 mg) was dissolved in 50 ml methanol followed by the careful addition of 0.1 g 10% palladium on charcoal. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 28 hrs followed by filtration through a pad of Celite filter aid and additional washing of the pad with methanol. Evaporation of the solvents afforded a white residue which was crystallized from ethanol-ether to give the desired material, 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane, as a white solid (99 mg, 81%).