Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19](/[C:22](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone (320 mg, 1 mmol) in methanol (30 mL) was added semicarbazide hydrochloride (334 mg, 3.0 mmol). Triethyl amine was added dropwise to the reaction mixture to adjust the pH to 5˜6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 250 mg (yield: 66%) title compound as a white solid. 1H-NMR 400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.85 (dd, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.77 (d, 1H), 7.66 (s, 1H), 7.47 (q, 1H), 6.73 (b, 2H), 4.56 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+=378, tR=4.64 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([C:19]([F:18])([F:27])[F:28])=[CH:21][CH:22]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C(F)(F)F)cc3)c2cc1OC
Yield: 71.7 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.322 g of 4-(trifluoromethyl)aniline, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.268 g of 6,7-dimethoxy-4-(4-trifluoromethyl-phenylamino)-quinoline-3-carbonitrile as a solid, mp 116-118° C.; mass spectrum (EI, m/e): M 373.1031.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([C:34](O)=[O:35])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:70]1([CH2:75][CH2:76][NH2:77])[CH2:74][CH2:73][CH2:72][CH2:71]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([C:34]([NH:77][CH2:76][CH2:75][N:70]2[CH2:74][CH2:73][CH2:72][CH2:71]2)=[O:35])=[CH:4]1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 44f) (7 g, 14.30 mmol) in N,N-Dimethylformamide (DMF) (50 mL) was added HATU (8.16 g, 21.45 mmol) and DIPEA (7.49 mL, 42.9 mmol), the resulting mixture was stirred at r.t. for 30 min. 2-(Pyrrolidin-1-yl)ethanamine (2.70 mL, 21.45 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with MeOH/DCM (0-30%) to afford 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (6.6 g, 11.27 mmol, 79% yield) as a pale yellow solid. LCMS: (M+H)+: 586.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:29]([Cl:30])=[CH:28][C:18]3[C:19]([CH3:27])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:21][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[CH2:25]([O:24][C:22]([C:20]1[O:21][C:17]2[CH:16]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:29]([Cl:30])=[CH:28][C:18]=2[C:19]=1[CH3:27])=[O:23])[CH3:26].[ClH:31]
Reactant: CCOC(=O)c1oc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2c1C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1oc2cc(OC3CCNCC3)c(Cl)cc2c1C
Reaction time: 2 h

Procedure:
The above prepared 4-(5-chloro-2-ethoxycarbonyl-3-methyl-benzofuran-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.457 g, 3.327 mmol) was dissolved in 8 mL of dioxane and treated with HCl (16.5 mL of 4N [dioxane], 20 eq.) and the mixture kept at ambient temperature for 2 h. Careful evaporation of all solvents and drying yielded 1.36 of the title product as hydrochloride as white crystals, which was further processed without additional purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([CH2:12][O:13][CH2:14][O:15][CH3:16])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:23][CH:24]=O>CO.O.C(Cl)Cl>[CH3:16][O:15][CH2:14][O:13][CH2:12][C:4]1[N:3]2[CH:23]=[CH:24][N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COCOCc1ccc(C(=O)OC)c(N)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COCOCc1ccc(C(=O)OC)c2nccn12
Reaction time: 16 h
Yield: 70.4 %

Procedure:
To a stirred suspension of methyl 2-amino-6-({[(methyloxy)methyl]oxy}methyl)-3-pyridinecarboxylate (496 mg, 2.192 mmol) and sodium bicarbonate (193 mg, 2.302 mmol) in a mixture of methanol (15 mL) and water (7.5 mL) was added chloroacetaldehyde (50% wt. solution in water, 0.311 mL, 2.412 mmol). The mixture was heated to reflux for 2 hours when LCMS indicated that no reaction has occurred. More chloroacetaldehyde (0.311 mL, 2.412 mmol) was added and heating continued for 16 hours when LCMS indicated the reaction to be complete. The mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic phase was separated and the aqueous phase back extracted with ethyl acetate (50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give crude product (450 mg). This material was dissolved in DCM and purified on silica (50 g) using a 0-25% methanol-DCM gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an orange oil (386 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1F

Procedure:
To a solution of 20 g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2 g of 10% Pd—C. The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Br[CH2:12][C:13](Br)=[O:14].O=C1NC2C=C(C#N)C=CC=2OC1>>[F:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][CH2:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Br)CBr
Reactant: Nc1cc(F)cc(F)c1O
Agent: N#Cc1ccc2c(c1)NC(=O)CO2
Product: O=C1COc2c(F)cc(F)cc2N1

Procedure:
Commercially available 2-amino-4,6-difluorophenol (1 g, 6.9 mmol) and bromo acetyl bromide (0.9 mL, 10.3 mmol) were reacted according to the procedure for Intermediate 60 to afford the product as a solid, 208 mg (16%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([N:28]2[CH2:40][CH2:39][C:38]3[N:37]4[C:32]([CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:31][C:30]=3[C:29]2=[O:41])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:25]=[C:19]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][N:18]3[N:17]=2)[C:12](=[O:26])[N:11]([CH3:27])[CH:10]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:4]([N:28]2[CH2:40][CH2:39][C:38]3[N:37]4[C:32]([CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:31][C:30]=3[C:29]2=[O:41])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:25]=[C:19]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][N:18]3[N:17]=2)[C:12](=[O:26])[N:11]([CH3:27])[CH:10]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A mixture of 147b (100 mg, 0.18 mmol), NaBH4 (21 mg, 0.54), and CH3OH (10 mL) was stirred at 25° C. for 1 h. The mixture was extracted with CH2Cl2 (10 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 147 (60 mg, 60%). LCMS: [M+H]+ 555. 1H NMR (500 MHz, DMSO) δ 8.45 (d, J=5.0, 1H), 8.19 (s, 1H), 8.06 (d, J=5.0, 1H), 7.41 (d, J=2.0, 1H), 7.29 (d, J=5.0, 1H), 6.04 (s, 1H), 5.88 (s, 1H), 4.92 (s, 1H), 4.33-4.42 (m, 2H), 4.11-4.16 (m, 1H), 3.91-3.96 (m, 3H), 3.77-3.82 (m, 2H), 3.57 (s, 3H), 3.45-3.48 (m, 2H), 2.91-3.01 (m, 2H), 2.71-2.79 (m, 4H), 2.35 (s, 3H), 1.90-1.92 (m, 2H), 1.71-1.79 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:35][C:22]3=[CH:23][C:24]4[C:25](=[O:34])[N:26]([CH:31]([CH3:33])[CH3:32])[C:27](=O)[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:20][C:21]3=[CH:29][C:28]4[CH2:27][N:26]([CH:31]([CH3:32])[CH3:33])[C:25](=[O:34])[C:24]=4[CH:23]=[C:22]3[N:35]=2)[CH3:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C(C)C)C3=O

Procedure:
2-(4-((1-(5-Fluoro-2-methylphenyl)propan-2-yl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.138 g) and zinc powder (0.4 g) were suspended in acetic acid (10 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give an off-white solid product, 0.086 g. MS: 473.9 [M+1]. 1H NMR (DMSO-d6, 500 MHz): δ 13.06 (s, 1H), 11.15 (s, 1H), 11.01-11.00 (d, 1H), 7.95 (s, 0.5H), 7.84-7.82 (d, 0.5H), 7.70 (s, 0.5H), 7.30-7.10 (m, 3H), 6.91-6.84 (m, 1H), 6.15-6.11 (dd, 1H), 4.51-4.42 (m, 3H), 4.18-4.13 (m, 1H), 3.32 (s, 1H), 2.99-2.97 (m, 2H), 2.36 (d, 3H), 1.34 (d, 3H), 1.23 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][N:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc(C)cn2)ccn1
Yield: 42.2 %

Procedure:
2-Bromo-5-methylpyridine (2.93 g, 17.0 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.34 g, 14.2 mmol) were reacted according to Example 31 (step a) to provide the title compound (1.2 g, 42%) as a brown solid: ESI MS m/z 201 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1>C(O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5][CH:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])nc1
Solvent: CCO
Product: CN(C)c1ccc(N)nc1

Procedure:
The N,N-dimethyl-6-nitropyridine-3-amine obtained above is taken up in 25 ml of ethanol. After addition of 4.8 g of stannous chloride, the reaction mixture is heated at reflux for 30 minutes and then concentrated to dryness. The residue is chromatographed on a column of silica (40-63 μm), elution being carried out with a mixture of dichloromethane and ammoniacal methanol (90/10). The fractions comprising the expected product are combined and concentrated to give 750 mg of 5-dimethylaminopyridine-2-amine in the form of a pasty yellow solid.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>CO>[C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CCOC(=O)/C=C/c1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: CCOC(=O)CCc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
(E)-tert-butyl 4-cyano-4-(2-(3-ethoxy-3-oxoprop-1-enyl)phenyl)piperidine-1-carboxylate (21, 278 mg, 0.72 mmol) was dissolved in MeOH (7 mL). The solution was degassed with Ar for 2 min. Pd/C (10%, 30 mg) was added and H2 was bubbled in for a few minutes. The reaction was stirred under a H2 balloon at 23° C. overnight. The solution was filtered through Celite and was concentrated to yield tert-butyl 4-cyano-4-(2-(3-ethoxy-3-oxopropyl)phenyl)piperidine-1-carboxylate. 1H NMR (400 MHz, CDCl3): δ 7.32-7.30 (m, 2H), 7.26-7.24 (m, 2H), 4.28 (bd, 2H), 4.17 (q, 2H), 3.29-3.25 (m, 4H), 2.78-2.74 (m, 2H), 2.34-2.30 (m, 2H), 1.91 (td, 2H), 1.48 (s, 9H), 1.26 (t, 3H). LC/MS RT (5 min method)=2.19 min. Mass observed: 287.22 (M-Boc+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[NH2:24][C@H:25]([C:32]1[CH:37]=[C:36]([C:38]2([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]2)[CH:35]=[C:34]([Cl:44])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:44][C:34]1[CH:33]=[C:32]([C@@H:25]([NH:24][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[C:36]([C:38]2([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]2)[CH:35]=1
Reactant: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C2(C#N)CCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (314.5 mg, 1.02 mmol), ethyl (S)-3-amino-3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)propanoate hydrochloride salt (from step 1 above) (345.15 mg, 1.006 mmol) and 1-hydroxybenzotriazole hydrate (31.2 mg, 0.204 mmol) was dissolved in a mixture of DMF/DCM (1:1) (8 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N′-diisopropylcarbodiimde (225 μL, 1.453 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight (19 h). The solvent was evaporated in vacuo to give a yellow-orange gummy residue. LC-MS analysis of the gummy residue shows the desired product: (3S)-ethyl 3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 597 (35ClM+H), m/z 599 (37ClM+H), m/z 619 (35ClM+Na) and m/z 621 (37ClM+Na); Calcd for C29H33ClN6O6: 597.06. The crude residue is used as such for the saponification with lithium hydroxide monohydrate (Step 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.N1C=CC=CC=1.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of Intermediate 9 (0.028 g) in dichloromethane (2 ml) containing a suspension of polyvinyl pyridine (0.1 g) was treated with valeryl chloride (0.018 ml), and the mixture was shaken at 20° C. for 16 h. Tris (2-aminoethyl)amine polystyrene scavenger resin (Argonaut Technologies, 4.46 mmol/g; 0.067 g) was added, and the mixture was shaken at 20° C. for 2 h. The mixture was filtered and the filtrate applied directly to a silica gel cartridge (1 g Varian Bond Elut). Elution with chloroform, ether, and ethyl acetate gave the title compound (0.0225 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:3]=1.[OH2:18]>C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]2[C:6](=[O:18])[C:16]3[C:11]([S:10][C:4]=2[CH:3]=1)=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3
Reactant: N#Cc1ccc(F)cc1Sc1cccc(F)c1
Reactant: O
Solvent: CCOC(C)=O
Product: O=c1c2ccc(F)cc2sc2cc(F)ccc12
Temperature: 200 °C
Yield: 3 %

Procedure:
Mix 4-fluoro-2-(3-fluoro-phenylsulfanyl)-benzonitrile (15.7 g, 63 mmol) and polyphosphoric acid (60 g), heat to 200° C. for 10 days. Dilute with H2O (300 mL) and ethyl acetate (700 mL), and filter through a pad of celite. Separate layers formed in the filtrate, and extract aqueous with two 150 mL portions of ethyl acetate. Combine organics, dry (MgSO4), filter, and concentrate to a brown solid. Purify on silica gel (0-10% ethyl acetae/hexanes)to afford 430 mg (3%) of the title compound as a yellow solid. MS [EI] 248; HPLC shows 92% purity; 1H-NMR consistent with structure. 1H-NMR (CDCl3) δ 8.67 (dd, 2H, J=9.0, 5.9 Hz), 7.26 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([Cl:15])[N:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:16])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([Cl:15])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(CCO)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)n(CCO)c2nc(N)nc(Cl)c21
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one obtained in step 2 (13 g, 56.7 mmol), K2CO3 (11.5 g, 84 mmol), methyl iodide (12 g, 85.15 mmol) and DMF (130 ml) were stirred at 25-30° C. for 16 hours. The reaction mixture was concentrated and purified by column chromatography using 60-120 silica gel and 4% methanol in DCM as an eluent to obtain 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one (8 g, 58%) as an off white solid.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:37][CH2:38][CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([N:17]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]([CH2:37][CH2:38][CH3:39])=[N:10][C:11]=3[CH:16]=2)(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: CCCc1nc2cc(N(CCCc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(CCCc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Fluoro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.62 (m, 2H), 7.41 (m, 2H), 7.25 (m, 3H), 7.11 (d, 3H), 6.82 (m, 1H), 4.58 (s, 2H), 3.62 (t, 2H), 2.71 (t, 2H), 2.60 (m, 2H), 1.72 (m, 2H), 1.58 (m, 2H), 0.99 (t, 3H). MS calculated for C27H28FN3O4S—H: 508, observed: 508.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:45][CH2:44]1)=[O:20]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 64.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (533 mg, 1.18 mmol, 64%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1(Sc2ccccc2Br)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(Sc2ccccc2Br)CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 1-[(2-bromophenyl)sulfanyl]cyclohexanecarboxylate (89 mg, in MeOH (3 mL) was added 1 M NaOH (1 mL). The mixture was stirred at room temperature for 2 days, then at 65° C. for 6 h. The mixture was then concentrated and the residue was partitioned between ethyl acetate and 1 M HCl. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 1-[(2-bromophenyl)sulfanyl]cyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:14]3[CH2:18][C@H:17]([CH2:19]OS(C)(=O)=O)[O:16][C:15]3=[O:25])[CH:11]=2)[N:6]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])([CH3:4])[CH3:3].[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C=O)C>[N:36]([CH2:19][C@@H:17]1[O:16][C:15](=[O:25])[N:14]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH2:13]3)[CH2:18]1)=[N+:37]=[N-:38]
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](COS(C)(=O)=O)OC3=O)ccc2N1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1Cc2cc(N3C[C@H](CN=[N+]=[N-])OC3=O)ccc2N1C(=O)OCc1ccccc1
Yield: 95.3 %

Procedure:
A mixture of the mesylate from Step 6 (10.56 g, 21.0 mmol) and sodium azide (6.8 g, 104.6 mmol) in DMF (100 ml) is heated at 60° for 7 hours. The DMF is evaporated (45°/0.6 mm) and the residue partitioned between ethyl acetate (250 ml) and water (100 ml). The organic layer is washed with water (100 ml) and brine (50 ml), then dried (MgSO4). Evaporation yielded the product (9.0 g, 95%) as a glassy foam: Anal: Calcd. for C24H27N5O4: C, 64.13; H, 6.05; N, 15.58. Found: C, 63.84; H, 6.15; N, 15.23.