Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:17]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[CH2:16][N:15]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[C:12]2=[CH:13][CH:14]=1)(=O)C.[OH-].[Na+].IC.O>CO.O1CCCC1>[CH3:1][S:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:17]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)[CH2:16][N:15]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[C:12]2=[CH:13][CH:14]=1
Reactant: CC(=O)SCCCCc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CSCCCCc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-(acetylthio)butyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (89.2 mg, 0.163 mmol) was dissolved in methanol (1.5 mL) and tetrahydrofuran (1.5 mL). Thereafter, a 4 N aqueous solution of sodium hydroxide (0.4 mL, 1.6 mmol) and iodomethane (51 μL, 0.815 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo, to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-(methylthio)butyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (85 mg, quant.) in the form of a brown oily product.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[C:21]2[N:20]=[CH:19][CH:18]=[N:17][C:16]=2[C:15]([C:22]([OH:24])=O)=[CH:14][CH:13]=1.Cl.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:22]([C:15]3[C:16]4[N:17]=[CH:18][CH:19]=[N:20][C:21]=4[C:12]([C:3]4[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:13][CH:14]=3)=[O:24])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Agent: Cl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4F)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 94.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Step 26.1) and stirring the reaction mixture for 6 days at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 531.2 [M+H]+; tR=3.40 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:15][N:16]([CH2:18][C:19](Cl)=[O:20])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:19](=[O:20])[CH2:18][N:16]([CH3:17])[CH3:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCNCC2)cn1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCN(c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(6-chloropyridin-3-yl)piperazine (250 mg, 1265 μmol) and dimethylaminoacetyl chloride hydrochloride, 85% (260 mg, 1644 μmol) were dissolved in DMF (6 mL) and DIEA (661 μl, 3794 μmol).). The reaction was stirred at room temperature for 4 hours and then 20 hours at 60° C. The resulting solution was taken up in ethyl acetate 80 mL) and washed with aqueous K2CO3 (10%, 70 mL), water (70 mL), and brine (70 mL). The organic phase was dried (MgSO4) and evaporated to give a brown oil. Silica gel chromatography (gradient elution dichloromethane/0-10% 2M NH3 in methanol) afforded compound 300 as an orange tar (174 mg, 49%).
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[H-].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>C1(C)C(C)=CC=CC=1>[CH3:45][O:44][C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([O:32][CH3:31])[C:41]=1[O:42][CH3:43])[C:36]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)=[O:37]
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc(C(=O)OC(COc2cccc3c2CCC(=O)N3)CN2CCN(c3ccccc3)CC2)cc(OC)c1OC
Yield: 52.3 %

Procedure:
1.9 grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril and 0.24 g of sodium hydride are dispersed in 40 ml of xylene and heated for 1 hour under refluxing conditions. Then the bath temperature is lowered to 130° C. and 1.40 g of 3,4,5-trimethoxybenzoyl chloride are added gradually and heated for 8 hours under refluxing condition. Xylene is removed from the reaction mixture by distillation, then the residue is poured into 80 ml of water and extracted with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue is recrystallized from ethanol to obtain 1.5 g of 5-[2-(3,4,5-trimethoxybenzoyloxyl)-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 125°-127° C.
Reaction SMILES: [C:1]1([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=[CH:14][CH:13]=1.COC1CCC(OC)O1.O>CN(C)C=O>[N:8]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]([OH:11])=[O:10])[CH:14]=[CH:13][CH:12]=[CH:17]1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC1CCC(OC)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C(c1ccccc1)n1cccc1
Reaction time: 1 h

Procedure:
15.1 g (0.1 mole) of alpha-phenylglycine were resuspended in 450 ml of dimethylformamide, followed by the addition of 15 g of p-toluene sulphonic acid and 13.2 g (0.1 mole) of 2,5-dimethoxytetrahydrofuran. The mixture was heated to boiling, and at about 95° C. all the solid product was dissolved, the boiling temperature being held for about 60 minutes. After this time, the mixture was cooled, 400 ml of cold water were added and the total mixture was cooled to between 0°-5° C. The mixture was extracted twice with 200 ml of ethyl ether each time, the ether phases being discarded. The aqueous phase was extracted with 500 ml chloroform at pH 1.5. The chloroform extract was treated with 600 ml water and the pH was adjusted to 11. After separating the phases, 500 ml of chloroform were added to the aqueous extract, the pH being adjusted to 1.5 with 2N HCl. The chloroform phase was concentrated to obtain an oil which was crystallised from methanol-water. After drying, the alpha-(N-pyrrolyl)-phenylacetic acid obtained weighed 5.8 g.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccc(F)cc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccc(F)cc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([O:18][CH3:19])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH2:16].C(OC)(=O)CCCCCCCC#CCC#CCC=C>C(OCC)(=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:18][CH3:19])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCC=CCC=CCCCCCCCC(=O)OC
Agent: [Pd]
Agent: C=CCC#CCC#CCCCCCCCC(=O)OC
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: C=CC/C=C\C/C=C\CCCCCCCC(=O)OC

Procedure:
For the preparation of methyl hexadeca-9,12,15-trienoate, a solution of methyl hexadeca-15-en-9,12-diynoate (800 mg) in ethyl acetate (15 mL) was hydrogenated in the presence of Lindlar catalyst (300 mg) at ambient pressure using a balloon for 20 h. The catalyst was then removed by filtration, and the solvent was evaporated to yield (9Z,12Z)-methyl hexadeca-9,12,15-trienoate as the major product. A portion of the product was then purified by preparative thin layer chromatography using hexanes:ethyl acetate 98:2 (3 developments) to yield pure (9Z,12Z)-methyl hexadeca-9,12,15-trienoate. The characterization data for (9Z,12Z)-methyl hexadeca-9,12,15-trienoate is provided below.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]#[N:12])[C:5]=1[Cl:13])#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[C:5]([Cl:13])=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: N#CCc1cccc(CC#N)c1Cl
Agent: Cl
Product: N#CCc1cccc(Cc2nc3c(F)c(F)cc(F)c3s2)c1Cl
Yield: 23.2 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-2-chlorobenzene (953 mg, 5 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (1,078 mg, 10 mmol) and the resultant product was crystallized from ethyl acetate-hexane to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-2-chlorophenylacetonitrile (410 mg, 23%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:30]=1)[C:18]1[CH:17]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:25][CH2:26][C:27](=[O:29])[CH3:28])=[CH:9][CH:10]=1.[CH2:31]1COCC1.C[Mg]Cl>CCOCC>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:30]=1)[C:6]1[CH:7]=[C:8]([O:25][CH2:26][C:27]([CH3:31])([OH:29])[CH3:28])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:19]2[CH:24]=[N:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: CC(=O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: C[Mg]Cl
Solvent: CCOCC
Product: CC(C)(O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 2 h

Procedure:
A 15-mL RBF was charged with the product from (S)-1-(2-amino-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)propan-2-one (104 mg, 258 μmol) in THF (2584 μl, 258 μmol). The flask was cooled in an ice-bath for 5 min, and methylmagnesium chloride, (258 μl of a 3.0 M solution in ether, 775 μmol) was added dropwise to it over 20 sec, resulting in a yellowish-white suspension. After 2 h, an additional portion of Grignard reagent (150 uL) was added and the ice-bath was removed. After 2 h, the mixture was quenched with saturated ammonium chloride solution and diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column with 5% MeOH/DCM, then with 8% MeOH/DCM to afford 1-(((4S)-2-amino-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)oxy)-2-methyl-2-propanol as a white solid. MS m/z=419.2 [M+H]+. Calc'd for C23H23N4O4: 419.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]=[O:7]
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
76 g (0.5 mol) of 3-methoxy-4-hydroxybenzaldehyde were placed in a four-necked flask together with 228 g of dimethylformamide and 82.8 g (0.6 mol) of potassium carbonate. 66.4 g (0.525 mol) of benzyl chloride was added dropwise at a temperature of 60° C. for one hour. After the addition, the mixture was stirred at a temperature of 60° C. for five hours. The resulting reaction mixture was washed with 190 g of toluene and 330 g of water. 270 g of the solvent were removed by distillation under reduced pressure of 70 mmHg and then 265 g of n-heptane and 80 g of toluene were added to the distillation residue and the separated crystals were collected by filtration to provide 102.6 g of 3-methoxy-4-benzyloxybenzaldehyde as white crystals in a yield of 84.8%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH2:15])=[O:5])[CH3:2].[N:16]#[C:17][NH2:18].[ClH:19]>O1CCOCC1>[ClH:19].[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[NH:15][C:17]([NH2:18])=[NH:16])=[O:5])[CH3:2]
Reactant: N#CN
Reactant: CCOC(=O)c1c(N)[nH]c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(NC(=N)N)[nH]c2ccccc12
Yield: 38 %

Procedure:
A suspension of 2 aminoindole-3-carboxylic acid ethyl ester (2.04 g, 10.0 mmol), cyanamide (534 mg, 12.7 mmol), and concentrated hydrochloric acid (1 mL) in dioxane (91 mL), are heated under reflux for 48 hr. After the reaction mixture has cooled to 25 C. it is filtered and the solids washed well with dry diethyl ether, and then air dried to give 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride (1.08 g, 38%) 2-guanidinoindole-3-carboxylic acid ethyl ester hydrochloride as an off-white solid, mp >250 C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:23][CH3:24])[CH:31]=1)([CH3:4])[CH3:3]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cccc(-c2ccc(C(=O)OC)cc2C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
A dry round bottom flask containing 8.7 (1.13 g, 3.31 mmol), 3-ethoxyphenylboronic acid (available from Aldrich) (1.10 g, 6.63 mmol), tetrakis(triphenylphosphine)palladium (0.39 g, 0.340 mmol), and potassium carbonate (1.41 g, 10.20 mmol) was evacuated and backfilled three times with argon. Dry DMF (10.000 mL) was then added via syringe under argon. The mixture was then heated at 80° C. and monitored with TLC. After 20 hours, the reaction was cooled to room temperature and diluted with water. The mixture was extracted three times with EtOAc and then concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-25% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 41.1 as a colorless oil (0.87, 84%). MS ESI (pos.) m/e: 313.1 (M+H)+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19])[C:12]3([CH2:14][CH2:13]3)[CH2:11]2)=[N:3][CH:2]=1.[CH3:29][S:30]([CH2:33][CH2:34][CH2:35]O)(=[O:32])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(/N=N\C(=O)OC(C)C)=O)(C)C>C1COCC1.O>[CH3:29][S:30]([CH2:33][CH2:34][CH2:35][N:21]([S:18]([N:15]1[C:12]2([CH2:14][CH2:13]2)[CH2:11][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:17][CH2:16]1)(=[O:19])=[O:20])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: CS(=O)(=O)CCCO
Agent: CC(C)OC(=O)/N=N\C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Tert-butyl N—[[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octan-8-yl]sulfonyl]carbamate (Intermediate 53)(0.12 mmol) was dissolved in dry THF (1 mL) and added 3-methylsulfonylpropan-1-ol (0.13 mmol) and triphenylphosphine (0.15 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.15 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[I:18]CCI.[Cl-].[NH4+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([I:18])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2nccs2)cc1
Reactant: ICCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Clc1ccc(-c2ncc(I)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 2.3 grams (0.012 mole of 2-(4-chlorophenyl)thiazole in 20 ml of diethyl ether was cooled to -78° C. To this solution was added 4.72 ml of a 2.5M solution of n-butyllithium in hexanes. This mixture was stirred for 30 minutes. A solution of 3.3 grams (0.012 mole) of 1,2-diiodoethane in 15 ml of diethyl ether was added, and the resultant mixture was allowed to warm to room temperature and stir for approximately 18 hours. approximately 50 ml of an aqueous, saturated ammonium chloride solution was added, and the resultant mixture was poured into a separatory funnel. The organic phase was washed with water followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1), to yield 2.6 grams of 2-(4-chlorophenyl)-5-iodothiazole as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]C#N.[BH4-].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11]
Reactant: N#CSc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(S)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-nitrophenyl thiocyanate (4.38 g, 20.4 mmole) in dry DMF (70 mL) under inert atmosphere, excess sodium borohydride (1.1 g) was added. The mixture was stirred for half hour and poured over crushed ice. The mixture was acidified with 1 N HCl and left at 0° C. for 1 hr. The precipitate were collected by filtration and redissolved in CH2Cl2. The organic layer was further washed with water and dried with MgSO4. The solvent was removed in vacuo to afford yellow crystals. The product was used in the next step without further purification. 1H NMR (300 MHz, d6-acetone) δ: 8.42 (d, 1H, J=2.7 Hz), 7.98 (dd, 1H, J=8.7, 2.7 Hz), 7.68 (d, 1H, J=8.7 Hz), 5.26 (bs, 1H). 13C NMR (75 MHz, d6-acetone) δ: 147.5, 137.9, 136.4, 131.2, 124.8, 121.7. HR-MS (EI): calcd. for C6H4ClNO2S 189.9646 [M+]. Found 189.9646.
Reaction SMILES: [NH2:1][C:2](=[C:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[NH:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:21]=O>C(Cl)Cl>[CH3:15][N:13]1[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]2[CH:21]=[N:1][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:14]1
Reactant: CCOC(=O)C(N)=C1CN(C)C(=O)c2ccccc2N1
Reactant: C=O
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of ethyl α-amino-1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene-acetate are dissolved in 20 ml of methylene chloride, treated with 0.65 ml of 37 percent aqueous formaldehyde solution and stirred in the presence of air at room temperature for 2 hours. The solution is subsequently washed twice with 10 ml of water each time. The organic phase is separated, dried and decolourised with active carbon. After filtration of the carbon, the filtrate is evaporated in vacuo and the residue is chromatographed on 20 g of silica gel. Elution is carried out firstly with chloroform and subsequently with chloroform/ethanol (985:15). The fractions which contain ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as the main component are combined and evaporated in vacuo. The residue is dissolved in ethanol and crystallised by the addition of diisopropyl ether. There is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 162°-164° C.
Reaction SMILES: C[O:2]C(=O)CCCCC(O)=O.[CH2:12]1[CH2:17][CH2:16][CH:15]([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:14][CH2:13]1.ON1C(=O)CCC1=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:19]([NH:18][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]1)([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)CCCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 1, Compound 4: Adipic acid monomethyl ester is treated with one molar equivalent of DCC, DMAP and N-hydroxysuccinimide in DMF for 30 min. To this a molar equivalent of the compound obtained from Step 3a (Example 1) is added and stirred at ambient temperature for 8 h. Dicylcohexylurea formed during the course of the reaction is filtered off and the product is extracted into ethyl acetate, washed with sodium bicarbonate solution followed by standard workup. The methyl ester thus obtained is treated with LiOH in THF/water to obtain compound 4.