Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][CH2:11][Si](C)(C)C)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O[K])(C)(C)C>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CC#Cc1nc(Br)cnc1N
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(Br)cnc2[nH]1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
To a solution of 5-bromo-3-(3-trimethylsilanyl-prop-1-ynyl)-pyrazin-2-ylamine (1.66 g, 66% purity, 5.84 mmol) in 25 mL of THF was added a solution of tBuOK in THF (1M, 11.7 mL, 11.7 mmol) slowly at RT. The reaction mixture was heated to reflux for 2 days, then cooled to RT, diluted with EtOAc, quenched with H2O, filtered through a pad of celite, and washed with H2O and EtOAc. The organic layer was separated, washed with H2O and brine, dried (MgSO4), and concentrated to give 598 mg of 2-bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine as a brown solid (48% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.O.[H][H].[CH2:13]1[C@@H:21]2[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][NH:14]1>[C].[Ru].C(O)(C)(C)C>[CH2:1]1[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:13][NH2:14]
Reactant: c1ccc2c(c1)CNC2
Reactant: [H][H]
Reactant: C1CC[C@H]2CNC[C@H]2C1
Agent: [Ru]
Solvent: O
Solvent: CC(C)(C)O
Product: C1CC[C@H]2CNC[C@@H]2C1
Product: CC1CCCCC1CN
Yield: 3.8 %
Yield: 0.1 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 129 g of isoindoline, 516 g of 50% water-containing tert-butyl alcohol and 26 g of 5% ruthenium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 30 kg/cm2 and a temperature of 130° C. After a 6 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 96.0%. In addition, 0.1% of trans-hexahydroisoindoline and 3.8% of 2-methylcyclohexylmethylamine is formed. After concentrating the reacted solution, the residue is purified by distillation to give 123.2 g of cis-hexahydroisoindoline (yield 91%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:47][C:48]1[CH:49]=[C:50]([C:65]2[CH:66]=[CH:67][C:68]([C:71](O)=[O:72])=[N:69][CH:70]=2)[CH:51]=[C:52]([NH:54][C:55]2[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=2)[CH:53]=1>O.CN(C=O)C>[CH3:47][C:48]1[CH:49]=[C:50]([C:65]2[CH:66]=[CH:67][C:68]([C:71]([N:3]3[CH2:4][CH2:5][O:1][C:2]3=[O:6])=[O:72])=[N:69][CH:70]=2)[CH:51]=[C:52]([NH:54][C:55]2[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=2)[CH:53]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)O)nc2)c1
Reactant: O=C1NCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)N3CCOC3=O)nc2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
DMF (800 μL), 1,3-oxazolidin-2-one (28 mg, 0.32 mmol), triethylamine (67 μL, 0.48 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (100 mg, 0.19 mmol) were added to 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxylic acid (60 mg, 0.16 mmol) and the reaction was stirred for 60 hours at room temperature. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10-80% acetonitrile/water with 0.1% TFA) and then chromatography on silica gel (10-100% acetone gradient in hexanes) to afford 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]carbonyl}-1,3-oxazolidin-2-one. MS ESI calc'd for C21H17F3N5O3 [M+H]+ 444. found 444. 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.87-8.77 (m, 2H), 8.13 (dd, J=2.2 Hz, 8.1, 1H), 8.02 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.31-7.21 (m, 2H), 4.49 (t, J=7.8 Hz, 2H), 4.11 (t, J=7.8 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].[Br:34]Br.O>C(O)(=O)C>[Br:34][C:8]1[CH:9]=[C:10]([C:12]2[C:24]3[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=3[C:19]([Br:27])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]=1[OH:28]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(C4CCCC4)c3)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a suspension of 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 4.4 mmol) and potassium acetate (4.4 g, 44.3 mmol) in glacial acetic acid (60 mL) was added dropwise over a period of 17 minutes a solution of bromine (0.27 mL, 5.3 mmol) in glacial acetic acid (8 mL). The thick reaction mixture was diluted with glacial acetic acid (20 mL). After stirring at room temperature for 2 h the reaction mixture was poured into water (500 mL). The solution was extracted once with diethyl ether (250 mL), and then with diethyl ether (100 mL). The combined extracts were washed twice with water (100 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (98:2), followed by trituation with petroleum ether gave the title compound as a white solid (1.2 g, 52%): mp 189.5-191° C.; (DMSO-d6): δ 9.19 (s, 1H), 8.18 (d, 1H), 7.65-7.61 (m, 1H), 7.50-7.47 (m, 2H), 7.33 (d, 1H), 7.11 (d, 1H), 3.42 (quintet, 1H), 2.43 (s, 3H), 2.00-1.97 (m,2H ), 1.69-1.46 (m, 6H), 1.60 (s, 3H); MS(EI): [M+], 2 bromine isotope pattern, 528 (46%), 530 (100%), 532 (52%); Anal. Calc. for C25H22Br2OS: C, 56.62, H, 4.18, N, 0.00. Found: C, 55.78, H, 4.12, N, 0.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:23][OH:24])=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)C[CH2:31][C:30]1=O.C[Si](C#C)(C)C.[OH-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH:31]=[CH:30][O:24][N:23]=3)=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: O=C1CCC(=O)N1Br
Agent: C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1c(-c2ccon2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.55 g (1.5 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime is dissolved in 30 ml of dry DMF and combined with 0.3 g (1.7 mmol) of N-bromosuccinimide (dissolved in 5 ml of DMF). The reaction mixture is stirred for 10 minutes at room temperature and then 1.5 eq. of trimethylsilylacetylene and 1 ml of triethylamine are added. After 4 hours of agitation at room temperature, 5 ml of 1-molar sodium hydroxide solution is added and subsequently agitation is continued for another hour. The solution is poured into ice water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent drawn off. The resultant product is purified by column chromatography on silica gel with ethyl acetate as the eluent. Melting point: 123°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH3:11].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCBr
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of 4-fluorobenzenethiol (80 g, 0.625 mol) and bromoethane (71.88 g, 0.666 mol) in DMF (1.25 L) under nitrogen atmosphere, Cs2CO3 (213.75 g, 0.666 mol) was added. The reaction mixture was stirred at 25° C. overnight. TLC (petroleum ether) indicated the reaction was complete. The mixture was diluted with water (800 mL), extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with water (500 mL×2) and brine (500 mL), dried over Na2SO4 and concentrated in vacuum to give ethyl(4-fluorophenyl)sulfane (60 g, 61.5%) as a colorless oil. A mixture of ethyl(4-fluorophenyl)sulfane (60 g, 0.38 mol), acetic acid (1 L) and 30% H2O2 (180 mL) was stirred at reflux under N2 overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was poured into water (500 mL). Then NaHSO3 (200 g) was add. The mixture was extracted with ethyl acetate (500 mL×3), dried over Na2SO4 and concentrated in vacuum to remove the remaining acetic acid. Then the residue was poured into saturated aq. NaOH (800 mL) and extracted with ethyl acetate (500 mL×3) again. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound (66 g, 92.4%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (210 mg, 1.0 mmol), tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (255 mg, 1.04 mmol) and triethylamine (296 μL, 2.12 mmol) in isopropyl alcohol (1 mL) was stirred at 80° C. for 2 h. The solvent was evaporated under reduced pressure and the resulting residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to give the sub-title compound as a yellow oil (318 mg, 74%). LCMS calc. for C20H31N4O5 (M+H)+ m/z=407.2. found 407.2.
Reaction SMILES: [C:1](=[O:3])=[O:2].[NH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]>>[C:1](=[O:3])([OH:2])[NH2:4].[NH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]
Reactant: O=C=O
Solvent: OCCNCCO
Product: NC(=O)O

Procedure:
78 l of CO2 (3.48 mol) (saturation) were introduced into 1000 g of diethanolamine (9.52 mol), the reaction temperature rising from 25° C. to 70° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1>O1CCCC1.C(OCC)(=O)C>[CH2:8]([O:23][C:21]([CH:19]1[CH2:20][C:17](=[O:16])[CH2:18]1)=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CC(C(=O)OCc2ccccc2)C1

Procedure:
Triethylamine (2.0 mL) and benzyl bromide (1.2 mL) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., vol. 53, pp. 3841-3843 (1981)) (995 mg) in tetrahydrofuran (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and was sequentially washed with 1N aqueous HCl, saturated aqueous sodium hydrogencarbonate, and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6), to thereby give the title compound (886 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH:12]=[O:13].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].[CH3:22]N(C=O)C>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:11]/[C:6]1[N:7]([CH3:22])[C:8]2[C:4]([C:5]=1[CH:12]=[O:13])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: Cc1[nH]c2ccc(F)cc2c1C=O
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Product: CN(C)/C=C/c1c(C=O)c2cc(F)ccc2n1C
Temperature: 80 °C
Yield: 62 %

Procedure:
5-fluoro-2-methyl-1H-indole-3-carbaldehyde (50 mg, 0.28 mmol) was dissolved in 3 mL dry DMF, followed by the addition of N,N-dimethylformamide dimethyl acetal (124 mg, 138 μL, 1.04 mmol). The reaction mixture was heated to 80° C. for 4 h and turned from light yellow to dark red over the course of the reaction. The crude reaction was concentrated in vacuo, dissolved in 0.5 mL DMSO/MeOH, and purified by reverse phase HPLC (5-95% water/acetonitrile gradient over 60 minutes) to obtain 2-((E)-2-(dimethylamino)vinyl)-5-fluoro-1-methyl-1H-indole-3-carbaldehyde as a pale yellow solid (40 mg, 62% yield). 1H NMR (400 mHz, DMSO-d6) δ 9.73 (s, 1H), 7.73 (dd, J=9.8, 2.6 Hz, 1H), 7.39 (m, 2H), 6.96 (dt, J=9.2, 2.6 Hz, 1H), 5.20 (d, J=13.1 Hz, 1H), 3.66 (s, 3H), 2.99 (s, 6H). Mass and purity were confirmed by LC/MS using an acetonitrile gradient with 5 mM ammonium formate pH 6.5. Theoretical (M+H)+ m/z for C14H15FN2O=247.12; Found 247.06.
Reaction SMILES: CO[C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1.[N:19]#[C:20][NH2:21]>CO>[C:20]([NH:21][C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1)#[N:19]
Reactant: N#CN
Reactant: COC(=N)CCCCc1cc(CN(C)C)ccn1
Solvent: CO
Product: CN(C)Cc1ccnc(CCCCC(=N)NC#N)c1
Reaction time: 8 h

Procedure:
Methyl-5-(4-dimethylaminomethyl-2-pyridyl)pentanoimidate is added to a methanol solution of cyanamide. After standing overnight N-cyano-5-(4-dimethylaminomethyl-2-pyridyl)pentanoamidine is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].C([Mg]Br)C(C)C.[C:35](=O)=[O:36]>O1CCCC1>[OH:36][CH2:35][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: O=C=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Agent: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CO)c(Cc3ccccc3C(F)(F)F)sc21
Reaction time: 2 h

Procedure:
5-Bromo-1-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.6 g, Example 1c)) was dissolved in tetrahydrofuran (150 ml) at room temperature under an atmosphere of nitrogen. To this solution was added isobutyl magnesium bromide (4.9 mls, 2M in tetrahydrofuran). After 30 mins carbon dioxide gas was passed through the reaction and stirred for 2 hrs. The reaction mixture was then concentrated in vacuo and redissolved in ethanol (100 ml). Concentrated HCl (1 ml) was added and the reaction was heated at reflux for 36 hrs. The reaction was then concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The resultant gum was purified via chromotography eluting with 3:2 isohexane/diethyl ether to yield the sub title compound as a brown oil (2.3 g)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].C[O-].[Na+].[Cl-:11].[NH4+:12]>CO>[ClH:11].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH2:12])=[NH:7]
Reactant: [Cl-]
Reactant: N#Cc1nccs1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1nccs1
Temperature: 25 °C

Procedure:
To a stirred solution of thiazole-2-carbonitrile (1.5 g, 14 mmol) in 5 mL of dry MeOH was added dropwise a solution of sodium methoxide (0.74 g, 14 mmol) in 10 mL of dry methanol. The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. After that, ammonium chloride (1.5 g, 28 mmol) was added in one portion and the reaction mixture was stirred overnight. The undissolved material was removed by filtration and the filtrate was concentrated to afford thiazole-2-carboxamidine hydrochloride (Compound A1) as a grey solid which was used directly in the next step without further purification. MS: calc'd 128 (MH+), measured 128 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1.[CH:15](OCC)=[O:16].[C:20](O)(=[O:22])C>CCCCCC.O1CCCC1>[CH:15]([CH:9]([C:7]1[N:8]=[C:4]([NH:3][CH:20]=[O:22])[S:5][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:16]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCOC=O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C=O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogen, 14 g (0.29 mmol) of 50% NaH in oil was washed with 2×40 ml of hexane and then suspended in 90 ml of anhydrous tetrahydrofuran (THF). To this slurry at 0° C. was added dropwise a solution of ethyl 2-(2-amino-4-thiazolyl)acetate (27 g, 0.145 mmol) in 290 ml of anhydrous THF, followed by ethyl formate (21.5 g, 0.29 mmol), and the mixture stirred at room temperature for 18 hours. The pH of reaction mixture was adjusted to 7 by the addition of 50% aqueous acetic acid and the mixture extracted with 250 ml ethyl acetate. The aqueous layer was further extracted with 2×50 ml of 1:1 THF:ethyl acetate. The extracts were combined, dried over Na2SO4 and evaporated to a solid, which was recrystallized from ethyl acetate to yield purified title product, 17.8 g (50.7%); m.p. 179°-180° C.; 1H-nmr (CDCl3 -d6 -DMSO) 1.33 (t, 3H), 4.16 (q, 2H), 7.50 (s, 1H), 8.00 (s, 1H), 8.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:10]1[N:9]=[C:8]([CH:11]2[CH2:12][C:13](=[O:15])[CH2:14]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC(c2ncc3c(Cl)nccn23)C1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(c2nc(Br)c3c(Cl)nccn23)C1
Temperature: -4 °C
Reaction time: 0.08 h

Procedure:
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (47.7 g, 215 mmol) was dissolved in DMF (200 mL) under an atmosphere of nitrogen and cooled to −4° C. N-Bromosuccinimide (40.3 g, 226 mmol) was dissolved in DMF (140 mL) and slowly added to the reaction mixture. After 5 min, water (400 mL) was added and the resulting solid isolated by filtration and washed with solid with water to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 3.45-3.53 (m, 2H), 3.58-3.67 (m, 2H), 4.08-4.16 (m, 1H), 7.45 (d, 1H, J=5.2 Hz) and 8.30 (d, 1H, J=4.8 Hz).
Reaction SMILES: ON1C2C(=CC=CC=2)C([CH:13]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1=O.Cl.[H][H].[OH-:32].[Na+]>O1CCOCC1.[Pd].CCOCC>[C:17]1([N:26]2[CH2:25][CH2:24][N:23]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:20](=[CH:21][CH:22]=3)[NH:23][C:13](=[O:32])[CH2:14][CH2:15]4)[CH2:28][CH2:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC(C(CCCc2ccccc2)N2CCNCC2)c2ccccc2N1O
Reactant: [OH-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1CCc2cc(CCCCN3CCN(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C

Procedure:
1.57 Grams of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl-butyl]-3,4-dihydrocarbostyril and 0.2 g of palladium black were suspended in 100 ml of dioxane, then 10 ml of concentrated hydrochloric acid was added thereto and the mixture was catalytically hydrogenated under 1.5-3.0 kg/cm2 of hydrogen gas at 80°-90° C. The catalyst was removed by filtration and the filtrate was dried under a reduced pressure. To the residue thus obtained were added 10N-NaOH and ether and the mixture was stirred at a room temperature for 30 mintues. The crystals formed were collected by filtration and separated by a silica-gel chromatography, then recrystallized from isopropanol-diisopropyl ether to obtain 6-[4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydro-carbostyril. Yield: 0.60 g (40%). Colorless prism-like crystals. Melting point: 151°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][NH:13][CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+].C(Cl)[Cl:31]>CO.C=O>[Cl-:31].[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3ccc(Br)cc31)CCNC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Product: [Cl-]
Reaction time: 1 h
Yield: 88 %

Procedure:
7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.24 g, 4.68 mmol) was dissolved in a mixture of MeOH (20 mL) and CH2Cl2 (5 mL) and formaldehyde (0.56 mL, 37% aqueous solution) was added. After stirring for 1 h, NaBH(OAc)3 (1.98 g, 9.34 mmol) was added and the mixture stirred for a further 10 minutes. The mixture was diluted with methylene chloride (50 mL), washed with saturated Na2CO3 solution, concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient (s, 2H), ylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.15 g, 88%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:51])[CH2:48][NH:49][CH3:50])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:49]([CH3:50])[CH2:48][C:47]([OH:46])=[O:51])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 234B and N-methylglycine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.20-13.15 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.12 (s, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (m, 3 H), 3.01 (s, 2 H), 2.91 (s, 3 H), 2.81 (s, 1 H), 2.40 (m, 4 H), 2.27 (t, 1 H), 1.58-1.79 (m, 4 H); MS (ESI+) m/z 660 (M+H)+.