Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([NH2:27])=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.B>O1CCCC1>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC(N)=O)c2c1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCCN)c2c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 21.8 %

Procedure:
To a solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionamide (30 mg, 0.073 mmol) in tetrahydrofuran (2 mL) was added a solution of borane in tetrahydrofuran (1 mL, 2 M) in an ice bath. The mixture was stirred at 65° C. for 3 hours and then cooled naturally to room temperature. The reaction was quenched with methanol and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 6.3 mg of the desired product. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=1.2, 8.0 Hz, 1 H), 7.88 (d, J=7.2 Hz, 1 H), 7.64-7.56 (m, 3 H), 7.45 (dd, J=6.8, 7.6 Hz, 1 H), 7.37 (dd, J=1.6, 8.4 Hz, 1 H), 7.06 (s, 1 H), 5.22 (s, 2 H), 4.57 (brs, 2 H), 3.61 (t, J=4.8 Hz, 2 H), 3.07 (t, J=8.0 Hz, 2 H), 2.94 (t, J=7.6 Hz, 2 H), 2.45 (s, 3 H), 2.04-1.96 (m, 2 H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccc(Cl)cc1
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2ccc(Cl)cc2)c2ccc(O)cc21
Reaction time: 7 h
Yield: 57 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(4-chlorophenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate and being stirred for 7 h to obtain the title compound (57%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:12][CH2:13][C:14](Cl)=[O:15])(=[O:11])[CH3:10].C(N(CC)CC)C.O>C(Cl)Cl>[C:9]([O:12][CH2:13][C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)=[O:15])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(Br)cn1

Procedure:
In 29 ml of methylene chloride was dissolved 1 g of 2-amino-5-bromopyridine which was then reacted with 0.93 ml of acetoxyacetyl chloride in the presence of 1.61 ml of triethyl amine at room temperature for 1 hour with stirring. Water was added to the reaction mixture before extraction with methylene chloride. The organic layer thus obtained was washed with brine, dehydrated, filtered and concentrated in vacuo. Recrystallization of the concentrate in ethyl ether gave the title compound. 615 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=O)[CH3:2].[CH:18]1([NH:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=[N+:24]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[O-:25])[CH3:2]
Reactant: ONC1CCCCC1
Reactant: CCOc1cc(OCC)c(C=O)c(OCC)c1
Product: CCOc1cc(OCC)c(C=[N+]([O-])C2CCCCC2)c(OCC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2,4,6-triethoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 87.4% yield as a solid, m.p. 145.7° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:24]>>[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1)[CH3:24]
Reactant: CCN(CC)[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CCN(CC)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-N,N-diethylpyrrolidin-3-amine (1.2 equiv) to give 202 (M+1 438.0)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1>>[CH3:22][O:21][C:15]1[N:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([CH:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[N:14]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C1Cc2cc(F)ccc2N1
Product: COc1nc(OC)nc(C2C(=O)Nc3ccc(F)cc32)n1

Procedure:
5-Fluoro-1,3-dihydro-2H-indol-2-one (10 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (15.5 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 92% area (19 g, 91% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O.C([O-])(=[S:19])C.[NH4+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][S:19][C:12]1=[O:13]
Reactant: CC([O-])=S
Reactant: CCc1cccc(C)c1NC1CCOC1=O
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCc1cccc(C)c1NC1CCSC1=O
Temperature: 0 °C
Yield: 48.4 %

Procedure:
11 g (0.05 mol) of N-(2-methyl-6-ethylphenyl)amino-tetrahydrofuran-2-one and 4.7 g (0.05 mol) of ammonium thioacetate are stirred in 80 ml of dimethylsulfoxide at 90° to 100° C. After cooling, the solution is poured into ice-water and extracted with methylene chloride. The combined extracts are repeatedly washed with water, dried over sodium sulfate and filtered and the filtrate is concentrated. Distillation of the residue under a high vacuum yields 5.7 g (48.5% of theory) of colourless N-(2-methyl-6-ethylphenyl)-amino-tetrahydrothiophen-2-one. Boiling point 167°-173° C. under 0.5 mm Hg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:18]=[C:17]3[N:28](C4CCCCO4)[N:29]=[C:30]([CH:31]4[CH2:33][CH2:32]4)[C:16]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl>O1CCOCC1>[CH:31]1([C:30]2[C:16]3[C:17](=[N:18][C:19]([C:21]4[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:28][N:29]=2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1ccc(-c2cc(CN3CCNCC3)c3c(C4CC4)n[nH]c3n2)cc1
Reaction time: 16 h
Yield: 80.2 %

Procedure:
600 mg of 4-[3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 6 ml of 1,4-dioxane and 2 ml of dichloromethane and treated with 4.8 ml of hydrochloric acid (4M in dry dioxane). After standing at rt for 16 h the volatiles were removed in vacuo. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) and 315 mg (73%) of the title compound were obtained as hydrochloride.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:19])=[C:12]([CH:20]([CH3:22])[CH3:21])[CH:11]=2)[C:5]1=[O:23])(=O)C.[OH-].[Na+].Cl>CO.C1COCC1>[CH:16]([C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=1[OH:19])[CH:9]=[C:6]1[CH2:7][CH2:8][NH:4][C:5]1=[O:23])([CH3:18])[CH3:17]
Reactant: CC(=O)N1CCC(=Cc2cc(C(C)C)c(O)c(C(C)C)c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(C=C2CCNC2=O)cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 810 mg (2.57 mmol) of the thus obtained 1-acetyl-3-(3,5-di-isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one in 5 ml of methanol and 10 ml of THF was added 2 ml of 1N aq. sodium hydroxide at room temperature and the mixture was stirred for 3 hours. The reaction mixture was poured into ice-water containing ethyl acecate and 3 ml of 1N hydrochloric acid. The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated under reduced pressure to give a residue, which was crystallized from a ether/n-hexane mixture to give 800 mg of the objective compound as yellowish white crystal in 100% yield.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])[CH:22]=1
Reactant: Nc1cccnc1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccnc3)ccc12
Yield: 34.2 %

Procedure:
This compound was prepared according to the method of Example 15, using 58 mg (0.210 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 22 mg (0.231 mmol, 1.1 equiv) 3-aminopyridine as starting materials, to give 24 mg (34%) of white crystals: mp 133-135° C.; HRMS calcd for C20H22N4O+H: 335:1872. Found: 335.1900.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].Cl>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:20](=[O:19])[C:15]3=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:23][CH:22]=[C:16]3[C:17]2=[O:18])[CH2:3]1)[CH3:9]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCN1CCCC(N)C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCN1CCCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C1
Temperature: 25 °C

Procedure:
6.40 Grams of 3-amino-1-ethylpiperidine in 150 milliliters of chloroform were added to a suspension of 9.65 grams of 4-nitrophthalic anhydride in 100 milliliters of chloroform. The solution formed was stirred at room temperature for twenty minutes and evaporated to dryness. The gummy residue was dissolved in 50 milliliters of acetic anhydride and the mixture was heated to 100° C. for thirty-five minutes. The excess acetic anhydride was distilled and the residue extracted into 100 milliliters of chloroform and the solution was washed with 50 milliliters of saturated sodium bicarbonate solution, 50 milliliters of water, dried over magnesium sulphate and evaporated to give a brown oil. The oil was dissolved in 20 milliliters of isopropanol and ethereal hydrogen chloride was added to give 9.33 grams of the title compound as the hydrochloride, quarterhydrate.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][N:17]([CH:23]1[C:32]2[N:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][N:17]([CH:23]1[C:32]2[N:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]
Reactant: C[Si](C)(C)CCOCn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Yield: 66.2 %

Procedure:
To a solution of N1-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (73 mg, 0.16 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (4 mL) and the resultant solution was stirred at room temperature overnight then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and water (5 mL) and treated with NaOH (10 M, ˜2 mL) until the aqueous phase was basic (pH 14). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 15:1:1 CH2Cl2—CH3OH—NH4OH) provided 37 mg of N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine as a white foam.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:10][C:11]1[N:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([NH2:20])=[C:13]([CH:21]([CH3:23])[CH3:22])[CH:12]=1>CO>[Cl:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:10][C:11]1[N:16]=[C:15]([CH:17]([CH3:18])[CH3:19])[C:14]([N:20]=[CH:4][N:2]([CH3:1])[CH3:3])=[C:13]([CH:21]([CH3:22])[CH3:23])[CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(Oc2ccc(Cl)c(Cl)c2)nc(C(C)C)c1N
Solvent: CO
Product: CC(C)c1cc(Oc2ccc(Cl)c(Cl)c2)nc(C(C)C)c1N=CN(C)C

Procedure:
A 25 ml single-necked round-bottomed flask, fitted with a reflux condenser is charged with dimethylformamidedimethylacetale (1.6 g), DMF (10 ml) and 6-(3,4-dichloro-phenoxy)-2,4-diisopropyl-pyridin-3-ylamine (1.70 g). The reaction mixture is heated under reflux and methanol is destilled off for 2.5 hours. The mixture is then concentrated in vacuo at 50° C. The crude material is crystallised from hexane/toluene acetate 4:1 (v:v): to obtain 1.41 g of the compound as a white solid (MP: 102-103° C.).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=O)=[C:26]([F:33])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28]#[N:30])=[C:26]([F:33])[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(N)=O)c(F)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine and trifluoroacetic anhydride were added to a dioxane solution of 4-tert-butyl-2-fluorobenzamide and stirred at room temperature for 3 hours. By post-treating the reaction liquid, 4-tert-butyl-2-fluorobenzonitrile was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:15])[CH:4]=1)#[N:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[Cl-].[Li+]>CCOC(C)=O>[C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[CH:18][N:19]([CH3:21])[CH3:20])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:15])[CH:4]=1)#[N:2]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN(C)C)c1cc(F)c(C#N)cc1C
Yield: 96.4 %

Procedure:
Combined methyl 2-(4-cyano-5-fluoro-2-methylphenyl)acetate (5.00 g, 24.13 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (32.2 mL, 241 mmol), and lithium chloride (0.102 g, 2.413 mmol) and heated to 105° C. After 2 hours the reaction mixture was concentrated in vacuo and repeatedly diluted with EtOAc (30 mL) and concentrated to give an oil. The oil was dissolved in EtOAc (50 mL) and washed with water, 10% aqueous sodium chloride, and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford a thick red oil, which was crystallized to give the title compound as a yellow solid (6.1 g, 23.26 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3 H) 2.34 (s, 1 H) 2.54-2.81 (m, 6 H) 3.50 (s, 3 H) 7.20 (d, J=10.11 Hz, 1 H) 7.58 (s, 1 H) 7.72 (d, J=7.07 Hz, 1 H). ESI-MS m/z [M+H]+ 263.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[OH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS me/(%) 308 (M+H+, 100)
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH3:18])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(OC(C1CCN(C2C=CC=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][N:21]([C:2]2[CH:20]=[CH:19][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][N:15]4[CH3:18])=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:26])[CH3:29]
Reactant: Cn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Reactant: CCOC(=O)C1CCNCC1
Agent: CCOC(=O)C1CCN(c2ccccn2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(C)c4c3)cn2)CC1

Procedure:
5′-(1-Methyl-1H-indol-6-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 6-chloro-N-(1-methyl-1H-indol-6-yl)-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5′43-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C23H26N4O3 [M+H]+: 407.2078. Found: 407.2076.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:32]=1)[C:26](N(OC)C)=[O:27].CC(O)C>CCOCC>[Br:20][C:21]1[CH:32]=[C:25]([C:26]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[O:27])[CH:24]=[N:23][CH:22]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
n-BuLi (15.3 mL, 2.5 M in Hexane, 38.2 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 36.4 mmol) in Et2O (300 mL) at −78° C. and stirred for 1 h. 5-Bromo-N-methoxy-N-methyl-nicotinamide (8.9 g, 36.4 mmol) was added to the reaction mixture slowly and stirred for 3 h, warmed to room temperature, and stirred for an additional I h. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and stirred for 20 min. The aqueous layer was extracted with EtOAc (3×300 mL) and the combined organic layers were washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude brown solid. Trituration with 2-propanol provided the title compound as a pure off-white solid (7.0 g, 51%). MS: 380.7 (MH+); HPLC Rf: 5.5 min. (HPLC method 4).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:12]1([NH:18][C:19](=[O:32])[CH:20]([O:23][C:24]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=2[Cl:31])[CH2:21][CH3:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>O>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([N:30]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:29][C:24]=1[O:23][CH:20]([C:19](=[O:32])[NH:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][CH3:22]
Reactant: CCC(Oc1cc(N)ccc1Cl)C(=O)Nc1ccccc1
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Solvent: O
Product: CCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.52 g. of cyclohexane-1,2-dicarboxylic anhydride, 3.05 g. of N-phenyl-α-(5-amino-2-chlorophenoxy)butyramide (melting point of 78° to 80° C.) and 10 ml. of acetic acid was refluxed with stirring for 2 hours and the reaction mixture was cooled to room temperature and water was added to obtain a crude crystal. The product was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 3.86 g. of Compound No. 294 shown in Table 1.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([OH:15])=O)[C:6]([S:9][C:10](=[O:12])[CH3:11])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:16]([NH:19][CH:20]([C:26]([OH:28])=[O:27])[CH2:21]SC(=O)C)(=O)[CH3:17]>>[C:6]([O:28][C:26](=[O:27])[C@@H:20]1[CH2:21][CH2:17][CH2:16][N:19]1[C:13](=[O:15])[C@H:5]([C:6]([S:9][C:10](=[O:12])[CH3:11])([CH3:7])[CH3:8])[NH:4][C:1](=[O:3])[CH3:2])([CH3:8])([CH3:7])[CH3:5]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Reactant: CC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)=O
Product: CC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)(C)SC(C)=O

Procedure:
By substituting N,S-diacetyl-penicillamine for the N,S-diacetyl-D,L-cysteine in the procedure of Example 53, N-acetyl-3-acetylthiovalyl-L-proline t-butyl ester is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N[C:22]1C=CC=C(C)C=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cccc(N)c1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: Cc1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 100 %

Procedure:
(RK1-1-27B) I This compound was prepared according to the procedure described for compound 11a except using m-toluidine to obtain required product as a light tan solid, (264 mg, 100%). Mp=121-124° C. (lit 138-139° C. Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.90 (br s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.56 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([P:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O-:12][Mn](=O)(=O)=O.[K+].P(O)O.Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:1]1([P:7](=[O:12])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OP(O)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: OPO
Solvent: O
Solvent: CC(C)=O
Product: O=P(O)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of phenylphosphonous acid (1 g, 0.007 mole) in acetone (10 ml) and water (10 ml) was added a solution of sodium hydroxide (0.281 gm, 0.007 mole) in water (10 ml) until a pH of about 7 was reached. A solution of KMnO4 (0.663 g, 0.007 mole) in water (10 ml) was added slowly to the vigorously stirred solution of phosphonous acid at 20°-25° C. After the addition (5 minutes), the reaction mixture was stirred for 5 minutes at ambient temperature and acidified with concentrated HCl acid until a pH of 1 was reached. Saturated sodium bisulfite solution was added to the reaction mixture thereby resulting in formation of a precipitate.