Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]1([CH3:34])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:31]2[CH2:32][CH2:33][CH:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:34])[CH2:29][CH2:30]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: Cc1ccccc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Yield: 84.1 %

Procedure:
The title compound was prepared from 21 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 16 mg of 4-(2-tolyl)-piperidine-hydrochloride, 0.013 mL of DIEA and 23 mg of sodium triacetoxy-borohydride using a procedure analogous to that described in Example 9, Step B to provide 27 mg of the title compound. HPLC (YMC "Octyl" 4.6×250 mm column, 60:40 v/v H2O/CH3CN+0.5% TFA, 1.5 mL/min, 200 nm): Retention Time: 6.69 min. 1H NMR (300 MHz, CDCl3): δ1.58-1.74 (m, 6H), 1.91-1.99 (m, 2H), 2.28 (s, 3H), 2.47-2.82 (m, 6H), 2.98-3.00 (m, 3H), 3.70 (ABq, J=13 Hz, 2H), 7.04-7.40 (m, 14H). Mass Spectrum (ESI): 425.2 (M+H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:37])=[C:34]([CH3:49])[NH:33][C:32]=1[CH:50]=O>N1CCCCC1.C(O)C>[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:37])=[C:34]([CH3:49])[NH:33][C:32]=1/[CH:50]=[C:23]1\[C:24](=[O:29])[NH:25][C:26]2[C:22]\1=[CH:21][C:20]([S:17]([CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])=[CH:28][CH:27]=2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Yield: 51.3 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (41 mg, 0.1 mmol) was condensed with 3,5-dimethyl-4-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (35 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solid was collected by vacuum filtration and purified on a silica gel column to give 36 mg (35%) of the titled compound.
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:8][CH:7]([NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][CH:17]=4)=[C:14]([NH2:29])[N:13]=[CH:12][N:11]=3)[CH2:6]2)[CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[C:39](O)(=[O:42])[C:40]#[CH:41].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl>[NH2:29][C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][CH:7]2[CH2:8][C:5]3([CH2:4][N:3]([C:39](=[O:42])[C:40]#[CH:41])[CH2:2]3)[CH2:6]2)[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1
Reactant: C#CC(=O)O
Reactant: Nc1ncnc(NC2CC3(CNC3)C2)c1-c1ccc(Oc2ccccc2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CC(=O)N1CC2(CC(Nc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
In a microwave vial containing N-(2-Aza-spiro[3.3]hept-6-yl)-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (80.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml) was added DIPEA (0.16 ml; 0.98 mmol; 5.00 eq.) and propiolic acid (24.20 μl; 0.39 mmol; 2.00 eq.) followed by 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.12 ml; 0.29 mmol; 1.50 eq.). The reaction was stirred at rt for 1 h before it was concentrated and purified by preparative HPLC (0.1% TFA-H2O/ACN). Fractions containing the desired product were combined and lyophilized overnight to afford 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one as a white solid (27.8 mg, 26.1%). HPLC purity: 99%. MS: m/z=426 [M+H]+. 1H NMR (CD3OD) δ 8.25 (s, 1H), 7.18-7.49 (m, 9H), 4.32 (d, 1H), 4.09 (d, 2H), 3.89 (d, 1H), 2.60 (m, 2H), 2.29 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:24])[NH2:25]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC(N)=O)c([N+](=O)[O-])c1

Procedure:
is obtained analogously to Example 55) starting from 3.66 g of 4-methoxycarbonyl-2-nitrophenol, 6.91 g of potassium carbonate and 4.62 g of iodoacetamide: mp 185°-7° C.; Rf (O)=0.56.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].CN(C=O)C>O>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:19][CH3:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a 500 ml three-neck flask equipped with a mechanical stirrer and an inert gas tube were added 30.5 g of isovanillin, 55.2 g of potassium carbonate, 49.9 g of iodoethane and 140 ml of DMF. The mixture was stirred overnight at the room temperature. The mixture was poured into 1400 ml of water, and then the resultant mixture was extracted with ethyl acetate (600 ml×2). The ethyl acetate layers were combined. The organic phase was washed with saturated Na2CO3 (200 ml×3), 200 ml of water and 200 ml saturated NaCl, dried over anhydrous MgSO4, and filtered. The solvent was evaporated to give a straw yellow solid. The solid was recrystallized with a mixed solvent of ethyl acetate and petroleum ether (1:4) to give a white needle crystal (32.9 g). MS (m/z): 181 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:17]=1)=[O:15])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C)C=O>[CH2:34]([N:10]([C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:14][C:13]2[CH:31]=[CH:32][CH:33]=[CH:11][CH:12]=2)=[O:29])[CH:17]=1)=[O:15])[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(C(=O)c2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
60% Sodium hydride in mineral oil (0.13 g) was added to a solution of 4-[3-(3-tert-butoxycarbonylaminobenzoyl)-indol-1-yl]butyric acid (0.47 g) in N,N-dimethylformamide (7 ml). The mixture was stirred at 0° C. for 1 hour. Benzyl bromide (0.95 g) was added to the mixture and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and 0.5N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of n-hexane and ethyl acetate (5:1) to give benzyl 4-[3-[3-(N-benzyl-N-tert-butoxycarbonylamino)benzoyl]indol-1-yl]butyrate (325 mg) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].O>CN(C)C=O>[CH3:31][S:32]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: CS(=O)[O-]
Reactant: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2cccs2)cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2-c2cccs2)cc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 23.4 %

Procedure:
A mixture of the benzil from Step 3 (2 g, 6.8 mmol) and sodium methylsulfinate (775 mg, 7.1 mmol) in dimethylformamide (10 ml) was stirred at 90° C. for 16 hours. The reaction was cooled, poured into water (120 ml) and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The residue was recrystallized from ethyl acetate and hexane to give 760 mg (45%) of the desired sulfone: mp 130-132° C. Anal. Calc'd. for C16H13FO4S2 (MW 352.41): C, 54.53; H, 3.72; S, 18.20. Found: C, 54.20; H, 3.51; S, 18.40.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:16]>>[C:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:16])=[CH:40][CH:41]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 52 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:11]
Reactant: BrCCBr
Reactant: N#Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A suspension of 3,5-difluoro-4-hydroxybenzonitrile (10 g, 0.0649 mol; see Preparation B(iv) above), anhydrous K2CO3 (17.94 g, 0.1298 mol) and 1,2-dibromoethane (73.2 g, 0.389 mol) in dry DMF (100 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 1.5% ethyl acetate in petroleum ether as eluent, to yield 12 g of the sub-title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]([Cl:23])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18]3)[C:13]([Cl:23])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1CCC1
Reactant: CCOC(=O)c1oc2cc(OC3CCNCC3)c(Cl)cc2c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1oc2cc(OC3CCN(C4CCC4)CC3)c(Cl)cc2c1C
Reaction time: 5 h

Procedure:
The above prepared 5-chloro-3-methyl-6-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (1.35 g, 3.32 mmol) was dissolved in 45 mL of CH2Cl2 and treated successively with cyclobutanone (0.506 g, 2 eq.), acetic acid (0.413 mL, 2 eq.) and sodium triacetoxyborohydride (1.529 g, 2 eq.), and the mixture then kept at ambient temperature for 5 h. Pouring onto crashed ice/NaHCO3, five fold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) generated 1.190 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]Cl)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([CH3:31])[C:19]=1[CH3:32]>>[Cl:1][C:2]1[C:6]([CH2:7][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH3:31])[C:19]=2[CH3:32])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1ccc(-c2snc(Cl)c2CCl)cc1
Product: COc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 127 following Step 6 and 7 by coupling of 3-chloro-4-(chloromethyl)-5-(4-methoxyphenyl)-1,2-thiazole and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR: (300 MHz, CDCl3) δ: 7.502 (d, J=6.6 Hz, 2H), 7.00 (t, J=6.0 Hz, 3H), 6.784 (d, J=6.0 Hz, 1H), 4.925 (s, 2H), 3.87 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H22ClNO4S, 430.1 (M−H). found 430.1.
Reaction SMILES: CO.CS(O)(=O)=O.C(OC([NH:18][CH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:39])[NH2:38])[CH:33]=3)[CH:28]=2)=[O:25])=[CH:22][CH:21]=1)=O)C1C=CC=CC=1.CS(O)(=O)=O.[H][H]>[Pd].CN(C=O)C>[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:38])[NH2:39])[CH:33]=3)[CH:28]=2)=[O:25])=[CH:40][CH:41]=1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)OCc4ccccc4)cc3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)cc3)ccc2c1
Reaction time: 3 h
Yield: 103.3 %

Procedure:
To a solvent mixture comprising100 ml of methanol and 20 ml of DMF, were added 5.0 g 6-amidino-2-naphthyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, 1.0 g of 10% Pd-C and 1.1 g of methanesulfonic acid. Hydrogen was introduced into the mixture with vigorous stirring for 3 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to about half the volume. Ethyl ether was added to the concentrate and the precipitated crystals were collected by filtration to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl 4-aminomethylbenzoate dimethanesulfonate.
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH2:50]>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH:50][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14]1)=[O:17]
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: CC1(C)CCC(C)(C)C1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
To a stirred solution of N-Cbz-1-aminocyclopropanecarboxylic acid in dry CH2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethyl-1-cyclopentyl amine dissolved in CH2Cl2. After stirring for 48 hours, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (2×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl amide.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7].[CH3:16]I>>[I:1][C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][N:11]([CH3:16])[C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1
Product: Cc1nc(I)c(C)n1-c1ccn(C)c(=O)c1

Procedure:
The title compound, white solid, MS: m/e=330.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1H-pyridin-2-one and methyl iodide.
Reaction SMILES: [Mg].II.[CH2:4](Cl)[CH:5]=[CH2:6].[CH2:8](Cl)/[CH:9]=[C:10](/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])\[CH3:11]>C(O)(=O)C.CCOCC>[CH3:11][C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9][CH2:8][CH2:6][CH:5]=[CH2:4]
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: C=CCCl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=CCCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (51 g., 2.1 mole) were suspended in 1700 ml. of ether and activated with a crystal of iodine. Allyl chloride (153 g., 2.0 mole) in 200 ml. of ether was added dropwise so as to maintain the mixture at reflux temperature throughout the addition. The mixture was refluxed for an additional 2 hours, then a solution of technical 82% pure geranyl chloride (210 g., 1.05 mole) in 200 ml. of ether was added dropwise at reflux temperature. The mixture was stirred for 2 hours at room temperature, then it was cooled down to 10° and slightly acidified with 20% aqueous acetic acid. The mixture was extracted with ether. The extracts were neutralised with 10% NaOH, washed with water, dried as usual and concentrated. The residue gave 217 g. of crude triene as a light yellow liquid the purity of which was 80% according to vapour phase chromatography; it was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH2:17])=[O:16])=O.[OH-:18].[Na+]>>[OH:18][CH2:2][C:3]1[N:17]=[C:15]([OH:16])[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]=2[N:5]=1
Reactant: [OH-]
Reactant: NC(=O)c1c(NC(=O)CCl)sc2c1CCCC2
Agent: [Na+]
Product: OCc1nc(O)c2c3c(sc2n1)CCCC3
Yield: 25 %

Procedure:
The 2-(2-chloro-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide (20 g, 0.073 mol) in 150 ml of 1.5M-NaOH solution was refluxed for 4 h. The reaction mixture was cooled and filtered. The filtrate was acidified (pH=5) with dilute hydrochloric acid to give solid material. The solid was filtered, washed with water, and dried to provide 2-hydroxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ol (4.5 g, 25%) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.70-1.80 (m, 4H), 2.68-2.75 (m, 2H), 2.80-2.88 (m, 2H), 4.35 (d, 2H), 5.61 (t, 1H), 11.95 (s, 1H); LC-MS: [M+H]=237.2 m/z.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[CH:19]([N:22](C(C)C)[CH2:23][CH3:24])(C)[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>CN(C=O)C>[CH2:19]([N:22]([CH2:23][CH3:24])[C:8]([C:6]1[N:7]=[C:2]([NH2:1])[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1)=[O:10])[CH3:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nc(C(=O)O)cn2nc(-c3ccco3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cn2nc(-c3ccco3)nc2c(N)n1

Procedure:
A solution of 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid (20 mg, 0.082 mmol; see Example 8 above), diisopropylethylamine (14 μL, 0.082 mmol), HATU (47 mg, 0.123 mmol), and diethylamine (0.163 mmol) in DMF (300 μL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by HPLC (C18, H2O:MeCN gradient). 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=6.9 Hz, 6H), 3.41 (m, 4H), 6:76 (dd, J3.4, 1.7 Hz, 1H), 7.18 (dd, J=3.4, 0.7 Hz, 1H), 7.69 (br. s, 2H), 7.96 (dd, J=1.7, 0.7 Hz), 8.34 (s, 1H). MS: m/z 301 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: N#CCc1ccc(Br)cn1
Reactant: BrCCCCBr
Product: N#CC1(c2ccc(Br)cn2)CCCC1
Yield: 78 %

Procedure:
The title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,4-dibromobutane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 78% of theory; Mass spectrum (ESI+): m/z=251/253 (Br) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][C:5]([Br:9])=[C:6]([Br:8])[CH:7]=1.N([O-])=O.[Na+].N1C=CC=CC=1.[FH:21]>>[Br:9][C:5]1[C:6]([Br:8])=[CH:7][C:2]([Br:1])=[C:3]([F:21])[N:4]=1
Reactant: F
Reactant: Nc1nc(Br)c(Br)cc1Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1nc(Br)c(Br)cc1Br
Yield: 84 %

Procedure:
The reaction and post-treatment were carried out according to Example (8a) using 3,5,6-tribromopyridin-2-amine produced in Example (15a) (2.34 g, 7.07 mmol), sodium nitrite (0.73 g, 10.6 mmol) and hydrogen fluoride-pyridine (5 mL) to obtain the title compound (1.98 g, 84%) as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].[OH-].[K+]>>[CH2:10]([S:14][CH2:7][CH:6]([CH3:8])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCS
Reactant: C=C(C)C(=O)OCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCSCC(C)C(=O)OCCO

Procedure:
To the reactor described in Example I was charged 55 grams of 2-hydroxyethylmethacrylate, 37 grams of n-butanethiol, 1.5 grams of Triton™ B and 3 pellets of KOH. The flask contents were reacted at 40° to 50° C. until the reaction was complete by gas chromatography analysis. The yield was theoretical.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C([O:14][C:15](=[O:33])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1/[CH:25]=[C:26]1/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/1)C>>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]([OH:33])=[O:14])=[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)=[O:4])[C:27]2=[O:32])[CH:20]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(CC(=O)c2ccc(Cl)cc2)C1=O

Procedure:
Prepared from 2-bromo-1-(4-chlorophenyl)ethanone and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16 (yield: 8.2 mg, 34%): LC/MS (an10p8): Rt 2.8 min, m/z 510 [M−H]−. 1H NMR (DMSO-d6): δ 3.01-3.09 (m, 1H), 3.57-3.63 (m, 1H), 4.79 (s, 2H), 5.17 (s, 2H), 5.21-5.24 (m, 1H), 6.91-6.95 (m, 1H), 7.44 (m, 2H), 7.66-7.69 (m, 2H), 8.07-8.09 (m, 2H).