Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O.Cl>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
420 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C. under a nitrogen atmosphere, 350 ml of THF are added, then, dropwise, a solution of 57.6 g of 4-chlorophenylacetic acid in 70 ml of THF is added and the mixture is left stirring at −60° C. for one hour. 66 g of methyl 2,4-dichlorobenzoate are subsequently added dropwise at −60° C., the mixture is left stirring at −60° C. for 40 minutes and then the temperature is allowed to rise to 0° C. The reaction mixture is poured onto an ice/1 liter of 2N HCl mixture and extracted with ether, the organic phase is dried over Na2SO4, the solvent is concentrated under vacuum to a volume of 150 ml, 200 ml of pentane are added and the crystalline product formed is filtered off. 60 g of the expected compound are obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])=[CH:23][CH:24]=2)=[O:14])[NH:10][CH:11]=1)=O>C(Cl)Cl.CO>[CH3:2][N:3]([CH2:5][C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])=[CH:23][CH:24]=2)=[O:14])[NH:10][CH:11]=1)[CH3:4]
Reactant: CNC
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 180 but using dimethylamine hydrochloride (1.5 equiv) instead of N,N,N′-trimethylethylenediamine and 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (Example 7). Title compound: ES-MS: 469 [M+H]+; tR=3.14 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][NH2:12].C(O)(=O)C.[BH4-].[Na+]>CO>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][NH:12][CH3:11]
Reactant: COc1ccccc1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
To a solution of 2-anisaldehyde (5.56 g, 40 mmol) in methanol (40 mL) was added methylamine (40 wt % solution in water, 6.9 mL, 80 mol) and acetic acid (240 mg, 4 mmol). The reaction mixture was stirred at room temperature for 16 hours and then cooled in an ice bath. To this ice-cooled mixture was added sodium borohydride (1.51 g, 40 mmol) in portions. The reaction mixture was stirred at room temperature for 3 hours. Most of the solvent was removed under the reduced pressure. The residue was diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to provide the desired 2-methoxybenzyl methylamine (4.7 g, 79%): 1H NMR (CDCl3, 500 MHz) δ 7.23 (d, J=7.4 Hz, 2H), 6.91 (t, J=7.4 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 2H), 2.42 (s, 3H); ESI MS m/z=152 [M+H]+. This crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:31][CH2:30][C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH2:23][C:24]3([CH2:25][CH2:26][N:27]([C:35](=[O:36])[CH2:34][C:32]#[N:33])[CH2:28][CH2:29]3)[CH2:30][CH2:31]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CCNCC5)CC4)n3)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CC4)CCN(C(=O)CC#N)CC5)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
To a solution of 5-chloro-N2-(2,3-dimethyl-2H-indazol-6-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (485.3 mg, 1.10 mmol) and 2-cyanoacetic acid (137.0 mg, 1.61 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (520.8 mg, 1.37 mmol) and Et3N (0.36 g, 3.55 mmol). After addition, the reaction mixture was stirred at rt for 6 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (171.0 mg, 30.6%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)N)[CH2:23][CH2:22]2)[N:12]=1.CS(OCCC1C=CC=C([I:49])C=1)(=O)=O>CN(C)C=O>[I:49][C:31]1[CH:30]=[C:29]([CH2:28][CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:18]=3[CH:19]=[CH:20][C:11]([CH3:10])=[N:12]4)[CH2:26][CH2:25]2)[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Temperature: 90 °C
Yield: 86.7 %

Procedure:
N,N-Diisopropylethylamine (1.7 mL; 1.5 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (1.31 g; 0.9 eq) and 2-(3-iodophenyl)ethyl methanesulfonate (2.1 g) in dimethylformamide (20 mL). The reaction mixture was heated to 90° C. for 5 hours. The dark solution was concentrated under reduced pressure, and purified by ion-exchange chromatography (SCX-2), eluting with methanol-ammonia/methanol (1M), (1:0) to (0:1). The combined basic fractions were concentrated under vacuum and purified by column chromatography (SPE cartridge, SiO2) using dichloromethane-methanol (95:5) to afford the title compound (1.5 g, 60% yield).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C1O[C:40]2[CH:39]=[CH:38][C:12]([CH2:13][N:14]([C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=4)[CH:26]=3)[CH2:15][CH2:16][CH2:17][N:18]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:11][C:10]=2O1.C1O[C:61]2[CH:60]=CC(CNCCCN3C=CC=CC=C3)=[CH:45][C:44]=2O1>>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:12]1([CH2:13][N:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)[CH:26]=2)[CH2:15][CH2:16][CH2:17][N:18]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=[CH:19]2)[C:11]2[C:10](=[CH:45][CH:44]=[CH:61][CH:60]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Fc1cc(F)cc(-c2cc(N(CCCN3C=CC=CC=C3)Cc3ccc4c(c3)OCO4)on2)c1
Reactant: C1=CC=CN(CCCNCc2ccc3c(c2)OCO3)C=C1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(-c2cc(N(CCCN3C=CC=CC=C3)Cc3cccc4ccccc34)on2)c1

Procedure:
The title compound is prepared using a similar procedure as described for the preparation of 3,4-methylenedioxybenzyl-[3-(3,5-difluorophenyl)-isoxazol-5-yl]-(3-azepin-1-yl-propyl)-amine TFA salt (example 4) while substituting 1-Naphthylmethyl-(3-azepin-1-yl-propyl)-amine for 3,4-methylenedioxybenzyl-(3-azepin-1-yl-propyl)-amine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[CH:10]([NH2:13])([CH3:12])[CH3:11].C[O-].[Na+]>>[CH3:7][N:6]([CH3:8])[CH2:5][CH2:4][C:3]([NH:13][CH:10]([CH3:12])[CH3:11])=[O:2]
Reactant: CC(C)N
Reactant: COC(=O)CCN(C)C
Agent: C[O-]
Agent: [Na+]
Product: CC(C)NC(=O)CCN(C)C
Reaction time: 72 h
Yield: 98.1 %

Procedure:
Methyl-3-dimethylaminopropionate (131 g) is stirred as isopropylamine (71 g) as added followed by 30% methanolic sodium methoxide solution (18 g). After 3 days at ambient temperature, GC analysis indicated 98% conversion. Excess isopropylamine is evaporated off under reduced pressure leaving 3-dimethylamino-N-isopropylpropanamide (155 g) as a pale yellow oil.
Reaction SMILES: [SH2]=N.C(O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([NH:16][C:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH3:15].C1(O)C=CC=CC=1.[OH-].[Na+]>O>[CH2:12]([NH:16][C:17](=[O:18])[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CCCCNC(=O)O
Agent: N=[SH2]
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Product: CCCCNC(=O)Oc1ccccc1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
5 g N-butyl-carbamic acid benzoic acid sulfimide are suspended in the mixture of 1.67 g of phenol and 50 ml of water, then while stirring (5 hours), a solution of 0.71 g of sodium hydroxide in 50 ml water is added. After stirring another 3 hours, the mixture is extracted with 2×30 ml of ether. The ethereal extracts are dried with sodium sulfate, then the solvent is evaporated in a vacuum at a temperature not above 30° C. 2.15 g of phenyl N-butyl-carbamate are obtained, which can be distilled at 146°-148° C. at 2 mmHg.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1CCCCC1.[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16].I[CH2:24][CH2:25][CH2:26][Si:27]([O:32][CH3:33])([O:30][CH3:31])[O:28][CH3:29]>C1COCC1>[CH3:29][O:28][Si:27]([O:32][CH3:33])([O:30][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CO[Si](CCCI)(OC)OC
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CO[Si](CCCCC(=O)OC(C)(C)C)(OC)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To an 1.5 M solution of LDA.THF in cyclohexane (53.33 mL, 80.00 mmol) and THF (160 mL), cooled to −78° C. in a dry ice/acetone bath, t-butyl acetate (9.29 g, 80.00 mmol) was added dropwise over 15 min. After 1 h at −78° C., 3-iodopropyltrimethoxysilane (23.21 g, 80.00 mmol) was added dropwise over 15 min. The reaction mixture was allowed to stir at −78° C. for 1 h, sealed with a teflon stopper, and kept in a freezer at −15° C. for 3 days. The cold reaction mixture was vacuum filtered through silica gel (300 mL), eluted with 1:1 hexanes/THF (600 mL), and concentrated to provide 21.48 g of a pale yellow oil. A quick distillation produced the volatile components, and 17.76 g of a colorless oil was recovered: bp 55-85° C. (0.2 mm). This material was purified by fractional distillation to provide 6.26 g (28%) of a colorless oil: bp 62-3° C. (0.03 mm); 1 HNMR (CDCl3) δ 3.56 (s, OMe), 2.21 (t, CH2CO), 1.62 (quintet, CH2), 1.45 (m, CH2), 1.44 (s, tBu), 0.66 (m, CH2Si).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:4].[OH-].[Na+]>CO>[C:19]([CH2:18][CH2:17][CH:16]([CH3:23])[C:15]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][CH:5]1[C:3]([OH:4])=[O:2])=[O:24])([OH:21])=[O:20]
Reactant: COC(=O)CCC(C)C(=O)N1c2ccccc2CCC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CCC(=O)O)C(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 1.5 g of 1-(4-carbomethoxy-2-methylbutanoyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester in 13.5 ml of methanol is added 13.5 ml of N aqueous sodium hydroxide and the mixture is stirred at room temperature for 3 hours. It is concentrated at room temperature and reduced pressure, the aqueous solution filtered, cooled and acidified with concentrated hydrochloric acid. The mixture is extracted with methylene chloride, the extract dried, evaporated, the residue recrystallized from petroleum ether and triturated with diethyl ether, to yield the 1-(4-carboxy-2-methylbutanoyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid melting at 117°-119°.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[S:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22](=O)[CH3:23])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]([C:21]1[S:13][C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[N:14][C:22]=1[CH3:23])=[O:26])[CH3:18]
Reactant: NC(=S)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1C
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of 4-phenoxy-thiobenzamide (1.02 g, 4.43 mmole) and 2-chloro-3-oxo-butyric acid ethyl ester (625 μl, 4.52 mmole) in ethanol (15 ml) was refluxed for 18 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (1.41 g). MS: (+) m/z 340.07 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+].O>C(O)C>[CH2:8]([S:7][CH2:6][CH:5]([CH2:15][O:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[C:4]([OH:23])=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(COC1CCOCC1)CSCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(COC1CCOCC1)CSCc1ccccc1

Procedure:
A solution of 3-benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid ethyl ester (1.27 g) in ethanol (30 ml) was treated with 2N NaOH (9.4 ml) overnight. Usual water work up gave the title compound as white solid; MS: 333 (M+Na), 311 (M+1); LCMS retention time 3.7 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][CH:16]([OH:18])[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CC(C)=O.CS(C)=O>C(OCC)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:15][C:16](=[O:18])[CH2:17]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc3nc(N4CC(O)C4)sc3c2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: Cn1cc(-c2ccc3nc(N4CC(=O)C4)sc3c2)cn1
Temperature: 25 °C

Procedure:
A suspension of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-ol (Reference Example 2, 0.143 g, 0.50 mmol) and Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, CAS #87413-09-0, 0.636 g, 1.50 mmol) was stirred in 15:1 acetone/dimethyl sulfoxide (15 mL/1 mL). The reaction mixture was heated to near reflux for 4 hours, then additional Dess-Martin periodinane (0.212 g, 0.50 mmol) was added. The reaction was cooled to room temperature after an additional 3 hours of heating at near reflux. The reaction mixture was diluted with diethyl ether (15 mL) and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to remove all but the dimethyl sulfoxide. This residue was partitioned between 9:1 CH2Cl2/hexane (20 mL) and water (10 mL). The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (90:10 to 40:60 CH2Cl2/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to give a gummy solid, which after trituration with diethyl ether, provided 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-one as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 3.95 (s, 3H), 5.00 (s, 4H), 7.46 (dd, J=2, 8 Hz, 1H), 7.59 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.75 (s, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].C(N(CC)CC)C.O.[NH2:11][C:12]1[C:17]([CH:18]=[O:19])=[N:16][C:15]([Cl:20])=[C:14](Cl)[N:13]=1>CN(C)C=O>[NH2:11][C:12]1[C:17]([CH:18]=[O:19])=[N:16][C:15]([Cl:20])=[C:14]([S:2][CH3:1])[N:13]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: CS
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C=O)nc1Cl
Temperature: 0 °C

Procedure:
In 3 ml of dimethylformamide there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine prepared as described in Example 1, Steps A and B. The solution was cooled in an ice bath, and there was then bubbled therethrough methane thiol, for 2 minutes followed by addition of triethylamine (223 mg; 2.2 mMol), followed by methane thiol addition for another 3 minutes. The reaction mixture was stirred for 30 minutes at the ice bath temperature and for 30 minutes at room temperature. The methane thiol and dimethylformamide were then blown off, the residue was treated with water, and the product precipitated, was filtered and washed (333 mg). Elemental Analysis for C6H6N3OSCl:
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=4[N:14]4[CH:24]=[N:25][N:26]([CH3:27])[C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:37][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]4[CH:24]=[N:25][N:26]([CH3:27])[C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(N)(=O)=O
Reactant: CN1N=CN2C1=Cn1c(cc3c(C4CCCCC4)cccc31)-c1cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CN1N=CN2C1=Cn1c(cc3c(C4CCCCC4)cccc31)-c1cc(C(=O)NS(=O)(=O)N(C)C)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 10-cyclohexyl-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (54 mg, 0.13 mmol) and N,N-dimethylsulfamide (81 mg, 0.65 mmol) in DMA (2 mL), was added DMAP (80 mg, 0.65 mmol), and EDCI-HCl (100 mg, 0.52 mmol). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxamide (29 mg, 0.056 mmol, 43%) as a bright yellow solid. 1H NMR (500 MHz, CD3OD) δ 1.22-1.34 (m, 1H), 1.41-1.62 (m, 3H), 1.77-1.85 (m, 2H), 1.95-2.18 (m, 4H), 2.71 (s, 3H), 2.90-3.00 (m, 1H), 3.05 (s, 6H), 5.09 (d, J=15.9 Hz, 1H), 6.03 (d, =15.9 Hz, 1H), 7.67 (dd, J=8.2, 1.5 Hz, 1H), 7.79-7.87 (m, 4H), 8.00 (d, J=8.6 Hz, 1H), 8.33 (s, 1H). LCMS: m/e 519 (M+H)+, ret time 1.96 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].CN(C)C=O.[NH2:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>O>[NH2:10][C:11]1[CH:16]=[C:15]([S:4][CH3:3])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: CS
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2 g. sodium hydroxide, 2.4 g. methylmercaptan and 20 ml. dimethylformamide is stirred at room temperature for two hours. 3.0 g. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for 1 1/2 hours. Water is added and the crude product filtered off. Recrystallization from methanol yields pure 2-amino-4-methylthio-1-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:18]([CH3:17])[C:14]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[CH:12][N:11]=1)=[O:16])([CH3:22])([CH3:21])[CH3:20]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)ccn1
Product: CN(C(=O)c1cc(-c2cccc(Cl)c2)ccn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(3-chlorophenyl)picolinic acid (CAN 1207725-34-5) and N,2-dimethylpropan-2-amine (CAN 14610-37-8) as starting materials and isolated (10 mg, 77%) as colorless oil; MS (ESI, m/z): 303.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[CH3:10]
Reactant: Cn1cc(C=O)cn1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cnn(C)c1

Procedure:
prepared by reaction of the commercially available 1-methyl-1H-pyrazole-4-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid 5.0 g, 0.0166 mole) 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1 hour with nitrogen bubbling through it. The reaction mixture was then heated at reflux for 1 hour under nitrogen during which a solution formed. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was heated at 50° C. overnight under nitrogen. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate (100 ml of each). The two layer mixture was filtered to remove an insoluble solid and the layers were separated. The aqueous layer was re-extracted once with ethyl acetate and the combined organic layers were washed once with a 5% potassium hydroxide solution (100 ml), dried over sodium sulfate, filtered, and evaporated to a residue weighing 8.9 g. The residue was dissolved in hot isopropyl alcohol, filtered, cooled to room temperature, and water was added. Solid formed which was collected by filtration to give 4.84 g (76%) of a white solid, after drying under vacuum overnight, mp 104°-105.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]COCC.CN(CCN(C)C)C.[Li]CCCC.IC>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: COc1ncccc1NC(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Product: COc1nccc(C)c1NC(=O)OC(C)(C)C
Temperature: -10 °C

Procedure:
To a stirred solution of 1.12 g (5 mmol) of 3-(tert-butoxycarbonylamino)-2-methoxypyridine in 25 mL of dry ether containing 1.8 mL, (12 mmol) of TMEDA at -78° C. under an argon atmosphere was added 4.8 mL (12 mmol) of a 2.5M solution of nBuLi in hexanes. The mixture was then warmed to -10° C. for 2 h. Recooling to -78° C. and treatment with iodomethane (0.99 g, 7 mmol) followed by warming to room temperature for 1 h produced the desired product which was purified by quenching with water, washing the ether layer with 0.1N HCl, drying (MgSO4), concentration and flash chromatography (9:1 hexanes:EtOAc). Yield: 1.00 g (84%). Recrystallization from heptane provided further purification. m.p.: 93°-95° C.