Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:8]=1)[NH2:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:5][C:4]1[CH:6]=[C:7]([O:9][C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:21]
Reactant: Nc1cc(Cl)cc(Oc2cncnc2)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cc(Oc2cncnc2)c1)c1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 6.2 %

Procedure:
Compound 9 (29 mg, 0.13 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.2 mL) and DMAP (32 mg, 0.26 mmol, 2.0 eq) was added and the reaction stirred for 5 min. 3-Chlorobenzoyl chloride (23 mg, 0.13 mmol, 1.0 eq) was added and the reaction was stirred until determination of completion by LCMS. The reaction was diluted with CH2Cl2, washed with water (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.9 mg (6%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.07 (s, 1H), 8.75 (s, 2H), 7.96 (t, J=1.7 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.68-7.66 (m, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.46 (t, J=2.0 Hz, 1H), 7.05 (t, J=2.0 Hz, 1H); ES-MS [M+1]+: 360.1.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].CO[C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:14]=1>>[CH3:27][CH:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:28])=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)CNCC(C)C
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Product: CC(C)CCCC(C)Oc1ccc(C(=O)N(CC(C)C)CC(C)C)cc1

Procedure:
By the procedure given in Example 37, diisobutylamine is reacted with p-[(1,5-dimethyl-hexyl)-oxy]-benzoic acid methyl ester to produce p-[(1,5-dimethyl-hexyl)-oxy]-N,N-diisobutyl-benzamide (nD24 = 1.4968).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]#[N:17])[C:9](=[O:15])[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=1.[O-]CC.[Na+].[Na]>O.C(O)(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:10](=[O:12])[C:9](=[O:15])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]#[N:17])[C:26]#[N:27])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)C(=O)C(C#N)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Ethyl 3-(p-chlorophenyl)-3-cyanopyruvate (40 g., 0.16 mol.) and 49.8 g. (0.33 mol.) of p-chlorophenylacetonitrile were added to an alcoholic solution of sodium ethoxide [prepared from 7.36 g. (0.32 g.-atom) of sodium and 190 ml. of absolute ethanol] and the resulting soltuion was refluxed for two hours. The reaction mixture was diluted with water, acidified with acetic acid and cooled (ice bath) to yield 2,5-di-(p-chlorophenyl)-3,4-dioxoadiponitrile, m.p. 280°.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)#[CH:2].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([C:3]1[S:7][C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C1COCCN1
Reactant: C#Cc1ccc(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: C#Cc1ccc(CN2CCOCC2)s1
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
To a solution of 5-ethynylthiophene-2-carbaldehyde (88 mg, 0.646 mmol), morpholine (56 uL, 0.646 mmol) in 1,2-dichloroethane (3.0 mL) was added a drop of AcOH. The mixture was stirred for 15 min and then NaBH(OAc)3 (205 mg, 0.969 mmol) was added and stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3 (2×5 mL), brine (5 mL), and the organic layer dried over MgSO4. The solvent was removed and the residue purified by column chromatography (silica gel, hexanes/EtOAc, 3:1) to give the title product (80 mg, 60%); MS ESI [M+H]+ 208.08, calcd for [C11H13NOS+11]+ 207.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@H:19]2[C@@H:10]([N:11]([CH2:26][C:27]([OH:29])=O)[C:12](=[O:25])[C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N:32](CC)CC)C.ClC(OCC)=O.CN>C1COCC1>[CH3:30][NH:32][C:27](=[O:29])[CH2:26][N:11]1[C@H:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:20][C@@H:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]([F:24])([F:22])[F:23])[C:13]=2[C:12]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 2-((3aR,9bS)-2-(tert-butoxycarbonyl)-5-oxo-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-5H-pyrrolo[3,4-c]isoquinolin-4(9bH)-yl)acetic acid (40 mg, 0.1 mmol) in 4 mL of THF at 0° C. was added triethylamine (0.017 mL, 0.12 mmol) and ethyl chloroformate (0.012 mL, 0.12 mmol). The reaction was allowed to stir for 30 min at 0° C. and then there was added methylamine (0.1 mL of a 2.0M solution in THF, 0.2 mmol). The resulting mixture was stirred for 1 h at 0° C. and then was quenched with 10 mL of 1N HCl. The mixture was extracted with ethyl acetate and the organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 30 mg (70%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 428.24 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[NH:4][CH2:3]1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[N:4]([CH2:16][CH2:15][CH2:14][Br:13])[CH2:3]1
Reactant: CC1CNc2ccc(F)cc2O1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(CCCBr)c2ccc(F)cc2O1
Temperature: 70 °C
Yield: 47.2 %

Procedure:
A mixture of 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, 1 eq, 25.74 mmol) obtained in step (iii) above, 1,3-dibromo propane (26.1 ml, 10 eq, 257 mmol) and anhydrous sodium carbonate (8.2 g, 3 eq, 77.2 mmol) in dry DMF (260 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (3.5 g, yield 48%) as viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.[BH4-].[Na+].[CH3:34][OH:35]>>[OH:35][CH2:34][C:2]1[CH:3]=[CH:4][N:1]([C:2]2[C:3]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[CH:4][C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)=[N:6][CH:7]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(-n3ccc(CO)c3)cn2)cn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (37 mg, 0.074 mmol) (Synthesis 107-A) was dissolved in methanol (1.5 mL) and cooled to 0° C. Sodium borohydride (15 mg, 0.396 mmol) was added and the reaction was stirred at 0° C. for 4 h. The solution was evaporated and the residue was partitioned between water and dichloromethane. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were evaporated and the residue was dissolved in methanol (1 mL) and absorbed onto a TsOH solid phase extraction cartridge. After 1.5 h the cartridge was eluted with 7M ammonia in methanol. The basic eluent was evaporated to dryness. The residue was purified by HPLC to give 5-(5-(3-(hydroxymethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (3.18 mg, 11%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:5]2=[CH:4][C:3]=1I)=[CH:13][C:12]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1>[F:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:5]2=[CH:4][C:3]=1[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[CH:13][C:12]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(I)cc12
Reactant: C1COCCN1
Agent: Cl[Pd+]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(N3CCOCC3)cc12
Reaction time: 8 h
Yield: 23.7 %

Procedure:
A vial charged with (S)-2-fluoro-7-(2-fluoropyridin-3-yl)-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.20 g, 0.41 mmol, prepared as described in Method BB34) and Ruphos palladacycle (0.032 g, 0.041 mmol) was treated with morpholine (0.18 mL, 2.03 mmol) and 4 mL THF. LiHMDS (2.03 mL, 2.03 mmol) was added, the vial was capped under argon, and the reaction mixture was allowed to stir overnight. The reaction mixture was purified directly by column chromatography [0-80% (9:1 DCM/MeOH)/heptane] yielding (S)-2-fluoro-7-(2-fluoropyridin-3-yl)-3-morpholino-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.044 g, 0.097 mmol). [M+H]+=452.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:15][C:16](Br)=[N:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O-:20].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:15][C:16]([O:20][CH3:19])=[N:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2CC1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2

Procedure:
1.00 g (3.00 mmol) bromo-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester, 0.40 g (7.00 mmol) sodium methylate in 15 mL methanol were heated at 100° C. for 4 h under microwave irradiation. The mixture was purified by chromatography.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl.Cl[CH2:18][C:19]1[N:20]=[CH:21][S:22][CH:23]=1>>[S:22]1[CH:23]=[C:19]([CH2:18][N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[N:20]=[CH:21]1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: ClCc1cscn1
Agent: Cl
Product: N#Cc1ccc2c(ccn2Cc2cscn2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole hydrochloride: MS (ES) m/z 308 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15](=[S:17])[NH2:16])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(O)(C)C>C(N(CC)CC)C>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15]3[S:17][CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:16]=3)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCN(CC)c1ccc2cc(C(N)=S)c(=O)oc2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc2cc(-c3nc(-c4ccccc4)cs3)c(=O)oc2c1
Yield: 80.6 %

Procedure:
8.3 parts of 7-diethylamino-3-thiocarbamoylcoumarin and 7 parts of ω-bromo-acetophenone in 30 parts by volume of isopropyl alcohol are boiled with 3 parts of triethylamine for 1 hour. The precipitate is filtered off and washed with isopropyl alcohol and water. 9.1 parts (80.6% of theory) of 7-diethylamino-3-(4-phenylthiazol-2-yl)-coumarin of melting point 127°-130° C. are obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:49][C:50]1[N:55]=[C:54](Cl)[CH:53]=[CH:52][N:51]=1.O>C1COCC1.C(OCC)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C:7]1[C:8]([CH3:40])=[CH:9][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:52]3[CH:53]=[CH:54][N:55]=[C:50]([Cl:49])[N:51]=3)[C:15]2=[O:23])=[CH:11][C:12]=1[CH3:13])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)N(c3ccnc(Cl)n3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
Under an N2 atmosphere, dissolve 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.519 g, 0.862 mmol) in dry THF (2 mL). Cool the reaction to 0° C. Add a solution of potassium t-butoxide (1.0 M) in THF (0.95 mL). Allow the reaction to stir at 0° C. for 10 minutes. Add 2,4-dichloro-pyrmidine (0.141 g, 0.948 mmol), and remove the ice bath. Heat the reaction to 55° C. and stir overnight. Dilute the reaction with water (200 mL) and diethyl ether (200 mL). Separate the layers and wash the aqueous layer with diethyl ether (100 mL). Combine the organic layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Purify the crude oil by flash column chromatography. Elute the column with 20% ethyl acetate in hexanes to give 0.289 g (47%) of the title compound: 1H NMR(DMSO-d6); δ8.60 (d, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.41-7.38 (m, 1H), 7.25-7.22 (m, 1H), 7.17-7.14 (m, 1H), 6.78 (s, 4H), 2.11 (s, 12H), 1.00 (s, 18H), 0.15 (s, 6H), 0.15 (s, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[C:9](OCC)(=[O:15])[C:10](OCC)=[O:11]>COC=COC>[NH:1]1[C@@H:2]2[C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[NH:8][C:10](=[O:11])[C:9]1=[O:15]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CCOC(=O)C(=O)OCC
Agent: COC=COC
Product: O=C1N[C@H]2CCCC[C@H]2NC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of cis-1,2-diaminocyclohexane (4.8 g, 42 mmol) in dimethoxy ethylene (100 mL) was added slowly diethyl oxalate (28.5 mL, 210 mmol). The reaction mixture was stirred at room temperature for 0.5 h and at 100° C. for 2 h. After the suspension was cooled down to room temperature, the resulting white solid precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried to yield (4aR,8aS)-octahydro-2,3-quinoxalinedione (4.6 g, 66%). LCMS: (M+H)+: 169.1.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][O:14][NH2:15])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O=[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14]/[N:15]=[C:19](/[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)\[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxy) benzyloxyamine (5.31 g), ethyl 6-oxo-6-phenylhexanoate (6.76 g), acetic acid (3.54 ml), sodium acetate (3.38 g) and ethanol (150 ml) was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (100 ml), tetrabutylammonium fluoride trihydrate (10.0 g) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (5.64 g, yield 77%) as a colorless oil from an ethyl acetate-hexane (2:7, v/v)-eluted fraction.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=5)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]1>>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[CH:21][C:22]([CH2:23][N:27]6[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]6)=[CH:25][CH:26]=5)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Product: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C1

Procedure:
Reaction of 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (38.9 mg, 0.109 mmol) and azetidine-3-carboxylic acid (55 mg, 0.546 mmol) according to Reference R and the general procedure for reductive amination to give 1-(4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 441.2; Observed: 442.1 (M++1).
Reaction SMILES: COC[N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][N:11]2[CH2:24][CH2:23][C:14]3[N:15]([CH3:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:13]=3[C:12]2=[O:25])[N:6]=[CH:5]1.COCN1C(CN2CCC3N(C)C4C=CC=CC=4C=3C2=O)=C(C)N=C1.C(=O)([O-])[O-].[K+].[K+]>Br>[CH3:22][N:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:13]2[C:12](=[O:25])[N:11]([CH2:10][C:7]3[N:6]=[CH:5][NH:4][C:8]=3[CH3:9])[CH2:24][CH2:23][C:14]1=2
Reactant: COCn1cnc(CN2CCc3c(c4ccccc4n3C)C2=O)c1C
Agent: Br
Agent: COCn1cnc(C)c1CN1CCc2c(c3ccccc3n2C)C1=O
Agent: O=C([O-])[O-]
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O

Procedure:
A solution of 2,3,4,5-tetrahydro-2-[[1-(methoxymethyl)-5-methyl-1H-imidazol-4-yl]methyl]-5-methyl-1H-pyrido[4,3-b]indol-1-one and 2,3,4,5-tetrahydro-2-[[1-(methoxymethyl)-4-methyl-1H-imidazol-5-yl]methyl]-5-methyl-1H-pyrido[4,3-b]indol-1-one (34 mg) in 49% hydrobromic acid (2 ml) was heated on a steam bath for ca. 3 h. After cooling, the reaction mixture was basified by addition of potassium carbonate solution and extracted with ethyl acetate (3×50 ml). The combined, dried organic extracts were concentrated in vacuo to give the title compound (6 mg) as a solid. The 1H-n.m.r. and t.l.c. data obtained for this material were consistent with those obtained for the product of Example 20.
Reaction SMILES: ClC1C=C(C2C=CC=CC=2)C=CC=1C[N:5]1[C:9]2=[N:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:16].ClC1C=C(C2C=CC=CC=2)C=CC=1CN1C2C(=NC(C#N)=CC=2)N=C1C>>[CH3:16][C:6]1[NH:7][C:8]2[C:9]([N:5]=1)=[N:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2
Reactant: Cc1nc2ccc(C#N)nc2n1Cc1ccc(-c2ccccc2)cc1Cl
Agent: Cc1nc2nc(C#N)ccc2n1Cc1ccc(-c2ccccc2)cc1Cl
Product: Cc1nc2nc(C#N)ccc2[nH]1

Procedure:
In the same manner as in the following Preparation Example 14-2, 3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (163 mg and 1-(2-chloro-4-phenylbenzyl)-2-methyl-1H-imidazo-[4,5-b]pyridine-5-carbonitrile (113 mg) were respectively obtained as pale-yellow crystals and pale-yellow amorphous from 2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (200 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([Cl:17])=[C:5]([CH2:7][N:8]2C[C:12]3[CH:13]=[CH:14][S:15][C:11]=3[CH2:10][CH2:9]2)[CH:6]=1.S1C=CC=C1C1[O:25]C1.ClC1C=CC=CC=1CN>>[S:15]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:10]([OH:25])[CH2:9][NH:8][CH2:7][C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[Cl:17]
Reactant: c1csc(C2CO2)c1
Reactant: Clc1ccccc1CN1CCc2sccc2C1
Agent: NCc1ccccc1Cl
Product: OC(CNCc1ccccc1Cl)c1cccs1

Procedure:
Literature precedent for ticlopidine (J. P. Maffrand, R. Boigegrain, Heterocycles, 1979, 12, 1479; FR 2,424,278) shows that (2-thienyl)ethylene oxide 14 reacts with o-chlorobenzylamine to provide the desired N-(2-(2-thienyl)-2-hydroxyethyl)-o-chlorobenzylamine in low yield due to lack of regioselectivity in the epoxide ring opening (Scheme 5).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:18]([CH2:19][CH2:20][C@:3]13[CH3:4])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2.OO.FC1C(=[O:43])CC[C@H]2C=1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@@]31C[C@H]3C[C@H]2O.[OH-].[Na+]>CO.O.ClCCl>[O:43]1[C:12]23[C@H:17]([CH2:16][CH2:15][C:14](=[O:21])[CH:13]12)[C@@H:18]1[C@H:9]([C@:5]24[CH2:8][C@H:6]2[CH2:7][C@H:2]([OH:1])[C@:3]4([CH2:20][CH2:19]1)[CH3:4])[CH2:10][CH2:11]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C(F)C(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@H]2O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@]12CC[C@@H]3[C@H]4CCC(=O)C5OC54CC[C@H]3[C@@]13C[C@H]3C[C@@H]2O
Reaction time: 3 h

Procedure:
17β-Hydroxy-14α,15α-methylene-estr-4-ene-3-one (2 g) was dissolved in 50 ml of methanol and treated at 10° C. with hydrogen peroxide solution (35%). While stirring, 5 ml of a 10 sodium hydroxide solution was added and the stirring was continued for 3 hours. The reaction solution is mixed with 50 ml of dichloromethane and 25 ml of water and the organic phase is removed, washed with semi-concentrated thiosulfate solution, dried and evaporated to dryness. The residue obtained consists of a mixture of 4α,5α- and 4β,5β epoxides and is used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CCN(C(C)C)C(C)C.[CH3:45][C:46]([CH3:53])([C:48]1[S:49][CH:50]=[CH:51][N:52]=1)[NH2:47]>CN(C=O)C>[CH3:45][C:46]([NH:47][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2([CH3:14])[CH2:11][O:12][CH2:13]2)[N:6]=1)=[O:17])([C:48]1[S:49][CH:50]=[CH:51][N:52]=1)[CH3:53]
Reactant: CC(C)(N)c1nccs1
Reactant: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2Br)COC1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) (30 mg, 100 μmol) in dry DMF (1 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (29.1 mg, 105 μmol) and Hunig's base (52.4 uL, 300 umol). The reaction was stirred at r.t for 30 min, followed by addition of α,α-Dimethyl-2-thiazolemethanamine (Example 12c) (14.2 mg, 100 μmol). The reactions was stirred at room temperature overnight and monitored by LC-MS. When the reaction was complete, purification was directly done by preparative HPLC without any work-up procedure to give the title compound (9.8 mg, 23%). MS (EI): m/e=425.9 [M+H]+.