Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Br:10][C:11]1[S:25][C:14]2[S:15][CH2:16][CH2:17][C:18]3[C:19](=[N:20][NH:21][C:22](=[O:24])[CH:23]=3)[C:13]=2[CH:12]=1>>[Br:10][C:11]1[S:25][C:14]2[S:15][CH2:16][CH2:17][C:18]3[C:19](=[N:20][N:21]([CH2:6][C:5]4[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:22](=[O:24])[CH:23]=3)[C:13]=2[CH:12]=1
Reactant: O=c1cc2c(n[nH]1)-c1cc(Br)sc1SCC2
Reactant: ClCc1ccc(Cl)cc1
Product: O=c1cc2c(nn1Cc1ccc(Cl)cc1)-c1cc(Br)sc1SCC2

Procedure:
The reaction and procedure are conducted in the same manner as in Example 36 using 4-chlorobenzylchloride in place of methyl iodide and using 9-bromo-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in place of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as used in Example 36 to give 9-bromo-2-(4-chlorobenzyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 152°-154° C.
Reaction SMILES: [CH2:1]([CH:8]1[NH:12]C(=O)N[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+].C.Cl>>[NH2:12][CH:8]([C:9]([OH:14])=[O:15])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Agent: Cl
Agent: [Na+]
Product: NC(Cc1ccccc1)C(=O)O
Yield: 72 %

Procedure:
95.1 g (0.5 mole) of 5-benzyl-hydantoin are heated to boiling in 350 ml of a 20% sodium hydroxide solution for 30 hours. The reaction mixture is clarified with activated charcoal and acidified with concentrated hydrochloric acid (pH 2). The precipitate (hydrantoinic acid) is filtered off and the phenyl alanine is precipitated from the filtrate as described in Example 11. Thus 59.5 g of the dry desired compound are obtained, yield 72%. Purity: 97.5% (according to HPLC).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)=[O:3].[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C.C1COCC1>[N+:10]([C:8]1[CH:9]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[CH:7]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
3,5-Dinitroacetophenone (3.27 g, 0.0156 mol) was dissolved in a mixture of absolute ethanol (75 ml) and THF (37.5 ml) and the mixture was cooled to −10° C. NaBH4 (0.30 g, 7.9 mmol) was added and the mixture was stirred for 1 h at −10° C. Water (80 ml) and ethyl acetate were added, the phases were separated and the organic phase was washed with water (80 ml) and dried (Na2SO4). The solvents were removed by evaporation and the residue was purified by chromatography on neutral alumina using a mixture of pentane and ethyl acetate (1:1) as the eluent. Yield: 2.52 g (76%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 4 h

Procedure:
A solution of 3-chloro-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (150 mg, 0.42 mmol) in MeOH (1 mL) and NaOMe (2.5 mL, 0.87 mmol, 25-30% in MeOH) was heated at 80° C. After 4 h, solvent was evaporated and the mixture was diluted with water (3 mL), extracted with EtOAc (3×2 mL) and dried over Na2SO4. Evaporation of the solvent followed by purification Combiflash chromatography (SiO2, eluant 30-40% EtOAc/hexanes) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.87-1.95 (m, 2H), 2.07-2.14 (m, 2H), 3.58-3.64 (m, 2H), 3.78-3.86 (m, 2H), 3.97 (s, 3H), 4.90-5.00 (m, 1H), 6.94 (d, 1H), 7.08-7.12 (m, 1H), 7.35 (t, 2H), 7.59-7.65 (m, 2H). MS (+ESI) m/z 354 (MH+).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH:38][CH3:39])[CH2:23][CH2:22]1.Cl>CC(C)=O.C(O)(C)C>[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][N:38]([CH3:39])[C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:23][CH2:22]1
Reactant: CNCCN1CCCCC1CNC[C@H]1CC[C@H](O)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CN(CCN1CCCCC1CNC[C@H]1CC[C@H](O)CC1)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 24 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and trans-2-[2-[[(4-hydroxy-cyclohexyl)methylamino]methyl]-piperidin-1-yl]-N-methyl-ethanamine in a yield of 24% of theory. Colourless, substantially amorphous solid substance with an approximate m.p. 105°-120° C. M.p. of the hydrochloride 210°-213° C. (D.) (acetone/isopropanol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][S-:11].[Na+].C1COCC1.C(OCC)(=O)C>O>[C:8]([C:4]1[N:3]=[C:2]([S:11][CH3:10])[N:7]=[CH:6][CH:5]=1)#[N:9]
Reactant: C[S-]
Reactant: N#Cc1ccnc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nccc(C#N)n1
Yield: 65.7 %

Procedure:
A mixture of 2-chloro-6-cyanopyrimidine (2.20 g, 15.8 mmol), sodium thiomethoxide (1.22 g, 17.3 mmol) and THF (100 ml) was refluxed for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.57 g, 66%) as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:12]4[CH:11]=[N:10][CH:9]=[C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])[CH:13]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1CCCN1Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN5CCCC5C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-methylpyrrolidine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 6 mg of the title compound (16%).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.CC(=[N:11][OH:12])C.F[C:14]1[C:39]([C:40]#[N:41])=[CH:38][CH:37]=[CH:36][C:15]=1[C:16]([NH:18][C:19]1[C:20]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:17]>CN(C=O)C>[NH2:41][C:40]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:15]([C:16]([NH:18][C:19]3[C:20]([NH:25][C:26](=[O:35])[C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:17])[C:14]=2[O:12][N:11]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2F)cc1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc3c(N)noc23)cc1
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a suspension of potassium t-butoxide (92 mg, 0.82 mmol) in DMF (5 mL) was added acetone oxime hydrochloride (60 mg, 0.82 mmol). After 1 h, N1-(2-fluoro-3-cyanobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (290 mg, 0.74 mmol) was added. After another 2 h, potassium t-butoxide (92 mg, 0.82 mmol) and acetone oxime hydrochloride (60 mg, 0.82 mmol) were added. After 12 h, the reaction was concentrated and the residue was dissolved in ethyl acetate and washed with water (2×), brine, MgSO4 dried, and concentrated. The resulting solid was dissolved in ethanol (35 mL), 5% HCl (35 mL) was added, and the mixture was refluxed for 1 h. The reaction was cooled, concentrated to 2 mL, diluted with ethyl acetate (250 mL), and neutralized with satd aq NaHCO3. The organic layer was washed with satd aq NaHCO3 (2×) and brine, MgSO4 dried, concentrated and crystallized to give the title compound as an off-white solid (106 mg, 35%); MS(FD): 402.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3]C=1N1CCC(=O)CC1.N.C(O[C:18]([N:20]1[CH2:25][CH2:24][C:23]([C:46]#[N:47])([NH:26][C:27](=[O:45])[CH:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][CH2:21]1)=O)C.[NH2:48][C:49]1([C:61]#[N:62])[CH2:54][CH2:53][N:52]([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:51][CH2:50]1>CO>[NH2:48][C:49]1([C:61]#[N:62])[CH2:54][CH2:53][N:52]([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:51][CH2:50]1.[C:46]([C:23]1([NH:26][C:27]([CH:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:45])[CH2:24][CH2:25][N:20]([C:18]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:21][CH2:22]1)#[N:47]
Reactant: CCOC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1
Reactant: O=C1CCN(c2ncccn2)CC1
Agent: N
Agent: N#CC1(N)CCN(c2ncccn2)CC1
Solvent: CO
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(c2ncccn2)CC1

Procedure:
4-Amino-4-cyano-1-pyrimidin-2-yl-piperidine was prepared according to the procedure from Example 7, step a, starting with 1-(pyrimidin-2-yl)-4-piperidone with the exception that a 2 M ammonia in methanol solution replaced the 5 M ammonia in methanol solution. (b) The title compound was prepared starting from N-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and 4-amino-4-cyano-1-pyrimidin-2-yl-piperidine according to the procedure from Example 2, step b, except that the compound was purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 30% acetonitrile in water to 100% acetonitrile. MS, m/z 469=M+1.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.C([Mg]Cl)(C)C.C(O)(=O)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1COCC1>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:40]
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Cbz-β-Alanine (5.0 g, 21.6 mmol) is dissolved in THF (10 mL). To this is added dropwise a solution of carbonyl diimidazole (3.5 g, 21.6 mmol) in THF (50 mL) and allowed to stir 16 hrs. This solution is then reduced to ˜30 mL by rotary evaporation. In a separate flask (oven dried), isopropyl magnesium chloride in THF (2M) (16.2 mL, 32 mmol) is added and cooled to 0° C. and hydrogen ethyl malonate (4.28 g, 32.4 mmol) is added dropwise. The contents are allowed to stir at 0° C. for 30 min, allowed to warm to 25° C. and continue stirring for another 30 min, and finally warmed to 40° C. for 30 min. The contents are then cooled to 0° C. and the contents of the first flask are added dropwise. The reaction is allowed to gradually come to 25° C. and continue stirring for 4 hrs. The reaction is poured into 100 mL of ice cold 1 N H3PO4 and allowed to stir for 30 min. The contents are extracted (3×100 mL) with ethyl acetate. The combined organic layers are then washed (3×100 mL) with saturated sodium bicarbonate followed by (3×100 mL) with brine. The organic layer is dried over MgSO4, filtered and reduced to an oil by rotary evaporation to provide 5-benzyloxycarbonylamino-3-oxo-pentanoic acid ethyl ester. The product is used as is without further purification. 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 5H), 5.25 (bm, 1H), 5.06 (s, 2H), 4.17 (q, 2H), 3.42 (m, 5H), 2.78 (t, 2H), 1.25 (t, 3H); MS (ion spray) 294 (M+H)+.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH2:6]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22][CH:23]3[O:25][CH2:24]3)[CH:16]=[N:15][C:14]=2[N:13]([CH2:26][CH2:27][CH2:28][CH3:29])[C:11]1=[O:12])[CH2:7][CH2:8][CH3:9].C(=O)(O)[O-:31].[Na+]>COCCOC.O>[CH2:6]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22][CH:23]([OH:31])[CH2:24][OH:25])[CH:16]=[N:15][C:14]=2[N:13]([CH2:26][CH2:27][CH2:28][CH3:29])[C:11]1=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: O=C([O-])O
Reactant: CCCCn1c(=O)c2c(ncn2CCC2CO2)n(CCCC)c1=O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: COCCOC
Solvent: O
Product: CCCCn1c(=O)c2c(ncn2CCC(O)CO)n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 45 h

Procedure:
0.4 ml of perchloric acid (70% strength) was added dropwise with stirring in 5 minutes to a solution of 7 g of 1,3-dibutyl-7-(3,4-epoxybutyl)xanthine in 300 ml of a mixture of ethylene glycol dimethyl ether/water (volume ratio 3:2) at room temperature. After stirring at room temperature for 45 hours, the mixture was neutralized with sodium bicarbonate and the solution was evaporated. The residue was taken up with methylene chloride and purified by column chromatography on silica gel with a mixture of chloroform and ethanol (volume ratio 8:2) as the mobile phase and by recrystallization from methylene chloride/petroleum ether.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C1OCCOCCOCCOCCOCCOC1.[CH3:27][CH:28]([NH:30][C:31]([CH:33]1[CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34]1)=[O:32])[CH3:29]>C[O-].[Na+].CO.CO.C(#N)C.O>[OH:34][CH:33]([CH:35]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:31]([NH:30][CH:28]([CH3:27])[CH3:29])=[O:32]
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Reactant: Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(C)NC(=O)C(O)C(Oc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Phenol (3.0 g.) was converted into its sodium salt by dissolving in a freshly prepared sodium methoxide-methanol solution (0.7 g. of metallic sodium in 50 ml. of absolute methanol), and subsequent evaporation of the excess methanol under reduced pressure on a rotary evaporator. The solid residue was dissolved in acetonitrile (250 ml.) by stirring with 18-crown-6 (0.9 g.) for 30 minutes at room temperature. N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.) was added to the solution, and the resulting mixture was heated under reflux for 6 hours. After cooling to room temperature, it was filtered. The filtrate was evaporated on a rotary evaporator under reduced pressure to give a resinous material. Water (ca. 200 ml.) was added to the residue, and allowed to stand at room temperature. The white precipitate thus separated was collected on a filter and washed with water. The filter residue was dried in air, then recrystallized from ethanol, giving 2.5 g. of product, m.p. 166°-168°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2sc(N=C(SC)SC)nc12
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A mixture of dimethyl 7-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (150 mg, 0.52 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (132 mg, 0.58 mmol) and cesium carbonate (427 mg, 1.31 mmol) in DMF (3 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (95 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (br. s., 1 H) 8.52 (s, 1 H) 4.16 (s, 3 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.40 (dd, J=14.93, 1.88 Hz, 1 H) 2.70-3.07 (m, 5 H) 2.08-2.27 (m, 2 H) 1.68-1.85 (m, 1 H) 1.48-1.66 (m, 2 H). MS (LC/MS) R.T.=0.90; [M+H]+=347.34.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][N:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=C(O)C1CNC1
Reactant: Cc1cc(C=O)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(CN2CC(C(=O)O)C2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (85.0 mg, 229 μmol), azetidine-3-carboxylic acid (116 mg, 1147 μmol), and acetic acid (106 μL, 1836 μmol) in 1:1 CH2Cl2/MeOH (7.0 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (26 mg, 413 μmol) was then added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo, dissolved in 2 mL DMSO+20 μL trifluoroacetic acid, filtered, and purified by rpHPLC (10-100% acetonitrile/water+0.1% TFA) to provide 1-((3-methyl-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-azetidine-3-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.1 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 8.11 (d, J=8.6 Hz, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.35-7.55 (m, 6 H), 7.27-7.34 (m, 1 H), 7.11 (d, J=8.6 Hz, 1 H), 4.47 (s, 2 H), 4.32-4.42 (m, 4 H), 3.63-3.81 (m, 1 H), 2.67 (s, 3 H), 1.70-1.77 (m, 2 H), 1.36-1.47 (m, 2 H)
Reaction SMILES: [OH:1][C@H:2]1[CH2:12][N:5]2[C:6](=O)[CH2:7][NH:8][C:9](=O)[C@@H:4]2[CH2:3]1>C1COCC1>[CH2:9]1[NH:8][CH2:7][CH2:6][N:5]2[CH2:12][C@H:2]([OH:1])[CH2:3][CH:4]12
Reactant: O=C1NCC(=O)N2C[C@H](O)C[C@@H]12
Solvent: C1CCOC1
Product: O[C@@H]1CC2CNCCN2C1
Reaction time: 1 h

Procedure:
A solution of LiAIH4 in THF (2M in THF, 20 ml, 40 mmol) was added slowly to a solution of (+/−)-(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (prepared according to a published literature procedure: Pharmaceutical Chemistry Journal, Vol 46, No. 2, 96 (2012), 2 g, 11.75 mmol) in THF (60 mL) and the resulting mixture was heated at reflux for 5 h. The reaction was quenched with careful addition of 0.6 ml of water, 0.6 ml of 15% NaOH and 1.2 ml water. Celite and anhydrous magnesium sulfate were then added and the mixture stirred for 1 h. The mixture was filtered and the filtrate was concentrated to give (+/−)-(7R)-octahydropyrrolo[1,2-a]pyrazin-7-ol (0.925 g) which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:49]([N:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([NH:63][CH3:64])=[CH:59][CH:58]=1)[CH2:53][CH2:54][CH3:55])[CH2:50][CH3:51]>CN(C=O)C>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:63]([C:60]2[CH:61]=[CH:62][C:57]([CH2:56][N:52]([CH2:49][CH2:50][CH3:51])[CH2:53][CH2:54][CH3:55])=[CH:58][CH:59]=2)[CH3:64])=[O:20])=[CH:22][CH:23]=1)[CH2:6][C:2]1[NH:3][CH:4]=[CH:5][N:1]=1
Reactant: CCCN(CCC)Cc1ccc(NC)cc1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(N(C)C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The compound (278 mg) obtained in Example 2-2, HOBt (95.9 mg), and DCC (147 mg) were dissolved in anhydrous DMF (11.0 ml), followed by stirring at room temperature for 19 hours. Then, the solution was added with a solution (1.2 ml) of the compound (128 mg) obtained in Example 68-1 in DMF and stirred at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and added with 1 mol/l hydrochloric acid to separate the solution into layers. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to adjust the solution to pH 11. The aqueous layer was extracted with chloroform and the organic layer was then dried with anhydrous magnesium sulfate. After having been treated with hydrochloric acid, the product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (10.2 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9](O)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([NH:35][C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2c3ccccc3oc(=O)c21
Yield: 56 %

Procedure:
Prepared by the method described for Ex. 17 from 4-ethyl-1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.2 g, 0.0077 mole), 1,1'-carbonyldiimidazole (2.4 g, 0.0148 mole) and 5-aminotetrazole monohydrate (0.76 g, 0.0076 mole) in dimethylformamide (30 ml). Recrystallization from dimethylformamide gives pale yellow crystals (1.5 g, 55%), m.p. above 300.
Reaction SMILES: C([NH:5][C:6]1[C:7]2[N:8]([N:16]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)CCC.N>>[NH2:5][C:6]1[C:7]2[N:8]([N:16]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCCCNc1nc2ccccc2n2ncc(C(=O)OCC)c12
Agent: N
Product: CCOC(=O)c1cnn2c1c(N)nc1ccccc12

Procedure:
2,76 g. of the chloro compound of Example 1 c is stirred for 10 hours with 25 ml. of saturated alcoholic ammonia solution at room temperature. The product, 4-aminopyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester, is obtained as a white precipitate which is filtered under suction, treated with water and recrystallized from ethanoldimethylformamide; yield 1.76 g., m.p. 235°-237°.