Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:14]CC)=[C:11]([CH3:13])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([CH:20]1[O:26][CH2:25][CH:24]=[CH:23][CH2:22][O:21]1)([CH3:19])[CH3:18]>>[CH:17]([CH:20]1[O:26][CH2:25][C:24]2[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:12][C:11]([CH3:13])=[C:10]([OH:14])[C:23]=2[CH2:22][O:21]1)([CH3:19])[CH3:18]
Reactant: CCOc1oc(Cc2ccccc2)nc1C
Reactant: CC(C)C1OCC=CCO1
Product: Cc1nc(Cc2ccccc2)c2c(c1O)COC(C(C)C)OC2
Temperature: 180 °C

Procedure:
A mixture of 12.6 g (60 millimoles) of 2-benzyl-4-methyl-5-ethoxy-oxazole and 42.6 g (300 millimoles) of 2-isopropyl-4,7-dihydro-1,3-dioxepine is heated for 5 hours at 180° C. On cooling the mixture in an ice bath, 4.2 g of 3-isopropyl-6-benzyl-8-methyl-1,5-dihydro-[1,3]dioxepino[5,6-c]pyridin-9-ol crystallize out. A further 2.0 are obtained by evaporating the mother liquor, partitioning the residue between methylene chloride and dilute sodium hydroxide solution and neutralizing the alkaline phase. Recrystallization from ethyl acetate gives a pure product, of melting point 193°-194° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN(Cc2ccc(F)cc2)C(=O)c2c(OCc3ccccc3)c3n(c21)CCN(C)C3=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 80 °C

Procedure:
A mixture of methyl 10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,3,4,6,7,8,9-octahydropyrido[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.4 g, 0.81 mmol) and manganese(IV) oxide (0.21 g, 2.44 mmol) in toluene (10 mL) was heated in a sealed tube in an oil bath 80° C. overnight. The reaction mixture was cooled to rt, diluted with chloroform (100 mL) and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The filtrate was subjected to column chromatography on silica gel eluting with ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].C(S([C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]2=[N:15][CH:16]=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)(=O)=O)C>ClCCl>[CH3:1][O:2][C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]2=[N:15][CH:16]=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1
Reactant: CCS(=O)(=O)c1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
420 mg (2.2 mmol) of 28% methanol solution of sodium methoxide was added to 10 ml of a methanol solution of 0.44 g (0.96 mmol) of 2-ethylsulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]- 3H-imidazo[4.5-b]-pyridine was dispersed in 150 ml of dichloromethane. The mixture was refluxed for 40 minutes. The solvent was distilled out at a reduced pressure. The residue was mixed with water and neutralized with 2N HCl. An extract with dichloromethane was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure. The residue was treated with ethanol and ether for recrystallization to obtain 300 mg of the above named compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[C:46]([NH2:47])=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:47][C:46]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[N:42][C:41]=1[O:40][CH3:39]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Yield: 42.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.34 mmol) was treated with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (202 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (31 mg, 0.04 mmol) in 1,2-dimethoxyethane (3.6 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 93 mg (40% yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])C.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH:23]1([CH2:22][O:21][C:19]2[CH:20]=[C:15]([CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=2)[CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:28])=[C:8]([CH3:27])[CH:9]=2)[CH2:24][CH2:25]1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC3CC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)ccc1OCC(=O)O

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161 mg; 1.3 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:40])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(C(=O)c4ccccc4)CC3)n[nH]c12
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A mixture of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.051 g, 0.17 mmols), triethylamine (0.1 mL, 0.71 mmols), DMAP (0.0021 g, 0.017 mmols), and benzoylchloride (0.020 mL, 0.17 mmols) in DMF (3 mL) was kept at ambient temperature overnight. The mixture was concentrated in vacuo and the resulting residue purified via preparative HPLC, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give 0.036 g of a white solid. LC/MS-M+H 425
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:22])([CH3:21])[CH2:18][CH:19]=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:22])([CH3:21])[CH2:18][C:19]([OH:25])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CC=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)(CC(=O)O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a stirred solution of the above 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanal in acetone (3 mL) was added Jones' reagent (1 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min before being concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate solution and 10% aqueous citric acid solution, and then extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried (Na2SO4), concentrated and purified by reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanoic acid (100 mg, 0.32 mmol, 43% yield for 2 steps) as a yellow oil.
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32].[OH-].[Na+]>C1COCC1.CO>[NH2:33][C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:36]=[CH:35][CH:34]=1)=[O:32]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 9 from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-aminobenzoic acid amide in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][NH2:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])(=O)C.[Cs+].CS(C)=O>C(OCC)(=O)C.[Cu]>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:9][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:22]([NH2:23])=[N:13]2)[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](NN)C1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2nc(N)c3cccnc32)C1
Temperature: 100 °C

Procedure:
Tert-butyl(trans-3-hydrazinylcyclobutyl)carbamate (4 g, 19.87 mmol), 2-chloro-3-cyanopyridine (3 g, 21.65 mmol), cesium acetate (14 g, 72.9 mmol), and copper powder (0.126 g, 1.987 mmol) were placed under nitrogen. Dry dimethylsulfoxide (20 mL) was added and the mixture stirred at 100° C. After 1 hour the mixture was cooled and diluted with ethyl acetate (300 mL). The mixture was filtered through a pad of celite and the filtrate washed with 10% saturated sodium bicarbonate (500 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (10% (2 N ammonia in methanol) in dichloromethane) gave the desired tert-butyl(trans-3-(3-amino-1H-pyrazolo[3,4-b]pyridin-1-yl)cyclobutyl)carbamate (2.72 g, 8.97 mmol, 45.1% yield).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1([CH2:8][C:15]([NH2:2])=[NH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCc1ccccc1
Reactant: [NH4+]
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)Cc1ccccc1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
Ammonium chloride (2.9 g, 54 mmol) was suspended in 20 mL of anhydrous toluene, stirred under argon, and cooled to 0° C. To this suspension was added 25 ml (50 mmol) of a 2M solution of trimethylaluminum in toluene. The reaction was allowed to warm to room temperature and stirring continued until the evolution of methane ceased (˜1 hour). Then, 3.46 mL (30 mmol) of benzyl cyanide in 10 mL of anhydrous toluene was added and the reaction was heated to 80° C. for 18 hours. The reaction was then cooled to room temperature and slowly poured into a slurry of 15 g of silica gel in 50 mL of chloroform and stirred for 5 minutes. The silica was filtered and washed with methanol. The filtrate and washings were combined and reduced to a volume of ˜15 mL and refiltered. Then, 18 mL (54 mmol) of a 3N solution of methanolic HCl was added to the filtrate followed by 400 mL of diethyl ether. After 16 hours of stirring at room temperature, a white precipitate formed and was subsequently filtered. This crude solid was then added to 150 mL of a 4:1 mixture of isopropanol-acetone and stirred for an additional 16 hours at room temperature. Undissolved ammonium chloride was then removed by filtration and the filtrate reduced to ˜15 mL, and 300 mL of diethyl ether was added and the mixture stirred for ˜1 hour. The white precipitate was then filtered and dried to yield 3.7 g (72%) of the objective compound as the hydrochloride salt. MS: (ESI, Pos) m/z 157.9 (M+23) 1H NMR (500 MHz, DMSO-d6): δ (ppm) 9.06 (br.d, 3H), 7.49 (d, 2H), 7.36 (t, 2H), 7.31 (t, 1H), 3.74 (s, 2H).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28].C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCCN=C=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCNC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and propylisocyanate (0.09 mL, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (2×20 mL). The product was extracted with EtOAc (3×50 mL) and CH2Cl2 (3×50 mL). The organic layers were combined, concentrated and the residue was triturated in Et2O (20 mL). The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.20 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 5.84 min (98.91%); mp: 250-252° C.; 1H NMR (DMSO-d6) δ 0.84 (t, J=7.4 Hz, 3H, CH3), 1.22-1.59 (m, 2H, CH2), 1.85-2.10 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.60 (d, J=17.4 Hz, 1H, CHH), 2.78-3.10 (m, 3H, CH2, CHH), 4.21-4.37 (m, 3H, CH2, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.99 (t, J=5.7 Hz, 1H, NH), 6.40 (t, J=5.9 Hz, 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.32, 22.49, 23.19, 31.20, 41.18, 42.92, 47.09, 51.55, 121.73, 122.83, 126.78, 130.11, 142.29, 145.55, 158.02, 167.98, 171.01, 172.86; LCMS: MH=359; Anal Calcd for C18H22N4O4: C, 60.32; H, 6.19; N, 15.63. Found: C, 60.21; H, 6.15; N, 15.51.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)#[N:2].[H-].[Na+].[CH3:36]I>CN(C=O)C>[C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:36])=[CH:7][CH:6]=1)#[N:2]
Reactant: CI
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)Cc2ccc(O)cc2)cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H](C#N)NC(=O)[C@@H]2CCCC[C@@H]2NC(=O)c2cc3ccccc3n2C)cc1
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
To a solution of 1-Methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(S)-1-cyano-2-(4-hydroxy-phenyl)-ethylcarbamoyl]cyclohexyl}-amide (compound 34, 102 mg, 0.229 mmol) in 3 mL of anhydrous DMF, was added sodium hydride powder (15 mg, 0.594 mmol). The reaction mixture was stirred for 5 min. while gas evolution subsided, then methyl iodide (0.2 mL, 3.1 mmol) was added. The reaction mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate, the separated organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered, concentrated and purified by column chromatography (50:50, ethyl acetate/hexanes) to give 74 mg (70%) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(S)-cyano-(4-methoxy-benzyl)-methyl]-carbamoyl}-cyclohexyl)-amide as a white amorphous solid. MS: 459 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1

Procedure:
2-Amino-5-nitropyridine was treated with acetic anhydride in dry pyridine in the presence of 4-dimethylaminopyridine at room temperature for 24 hrs under argon. The solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2, and ether was added to form a solid. The white solid was collected and dried giving 2-acetamido-5-nitropyridine. Hydrogenation of this material using 10% Pd on C in MeOH at room temperature under atmospheric pressure gave 2-acetamido-5-aminopyridine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]=[N+:22]=[N-:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:24]([O:28][CH3:29])(=[O:27])[C:25]#[CH:26]>>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[CH:26]=[C:25]([C:24]([O:28][CH3:29])=[O:27])[N:23]=[N:22]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN=[N+]=[N-])CC1
Product: COC(=O)c1cn(Cc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
1-Boc-4-(2-Azidomethyl-phenyl)-piperazine (0.25 g, 0.79 mmol) was dissolved in deuterated chloroform (3 mL). Methyl propiolate (0.35 mL, 3.9 mmol) was added, and the mixture was heated to reflux for about 4 hours and then cooled to r.t. The mixture was concentrated under reduced pressure and purified using silica chromatography (50% ethyl acetate in hexanes) to give the title compound (0.155 g, 49%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][C:28](Cl)=[O:29]>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH:13][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(Cl)CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCC(=O)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
3,4-dibenzyloxybenzylamine (1.1 g, 3.45 mmol) was dissolved in anhydrous pyridine (8 ml) and cooled to 0° C. with stirring under nitrogen. To this solution, succinyl chloride (0.23 g, 1.42 mmol) was added dropwise over 30 minutes as a solution in dichloromethane (50 ml), while maintaining the reaction mixture at 0° C. The reaction was allowed to warm to room temperature and stirred for an additional 45 minutes. The reaction was poured onto crushed ice (70 g) and the dichloromethane layer was separated. The organic extract was washed with dilute aqueous hydrochloric acid (2×20 ml of 0.1M solution), water (20 ml), and dried (NON. Removal of the solvent at reduced pressure afforded a crude solid, which was triturated with methanol (5 ml) to afford after filtration the protected diamide, yield 300 mg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH3:28])[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH3:28])[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 91.3 %

Procedure:
Pyrrolidine (0.06 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 3 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of the title compound as a solid, mp 174-176° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].S(OCC)(O[CH2:19][CH3:20])(=O)=O>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[CH3:20]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CCC(=O)O)cc1
Temperature: 100 °C

Procedure:
16.62 g (100 mmol) of 3-(4-hydroxyphenyl)-propionic acid is dissolved with stirring and covering with argon in 45 ml (225.0 mmol) of 5 N sodium hydroxide solution, and 15.73 g (100 mmol), (98%) of diethyl sulfate is instilled quickly so that the temperature does not exceed 40° C. (water cooling). After completion of the addition, it is heated for 30 more minutes to 100° C. After the cooling, it is extracted with diethyl ether, then acidified with sulfuric acid to pH 4 and the precipitated compound in ether is taken up. After drying on sodium sulfate, it is evaporated to dryness in a vacuum. The title compound is obtained as solid.