Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[H-].[Li+].COCCO[Al+]OCCOC.[H-].[CH2:22]([S:29][CH:30]([CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:31]([CH2:37][S:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:32]S(C)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:22]([S:29][CH:30]([CH2:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH:31]([CH2:37][S:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH2:32])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)NC(CSCc1ccccc1)C(CCc1ccccc1)SCc1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: NC(CSCc1ccccc1)C(CCc1ccccc1)SCc1ccccc1
Yield: 71.1 %

Procedure:
A 65% bis(2-methoxyethoxy)aluminum lithium hydride toluene solution (3.3 ml) is added to a solution of 2-(benzylthio)-1-[(benzylthio)methyl]-N-mesyl-N-(phenethyl)ethylamine (1.34 g) obtained in 2) in anhydrous toluene (5 ml) under a nitrogen atmosphere, and the mixture is refluxed overnight. A 2 N aqueous sodium hydroxide solution is added to the reaction mixture under ice cooling, and the whole is extracted with ether. The organic layer is washed with a 2 N aqueous sodium hydroxide solution, water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 0.80 g (71%) of the titled compound (Reference compound No. 16-1).
Reaction SMILES: C1C=CN=CC=1.F.[Si:8]([O:15][C@@H:16]([CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>N1C=CC=CC=1.C1COCC1>[Si:8]([O:15][C@H:16]([C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:42][CH2:43][OH:44])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
HF-pyridine in pyridine (40 mL, prepared by slow addition of 12 mL pyridine to 3 mL HF-pyridine complex followed by dilution with 25 mL THF) was added to a solution of TBS ether 12 (4.46 g, 7.07 mmol) in THF (10 mL). The mixture was stirred overnight at room temperature and quenched with sat'd NaHCO3 (100 mL). The aqueous layer was separated and extracted with Et2O (3×50 mL). The combined organic layers were washed with sat'd CUSO4 (3×50 mL), dried over MgSO4, and concentrated. Flash column chromatography (EtOAc/hexane 1:4) afforded 3.26 g (89%) of alcohol 13 as a colorless oil: IR (CHCl3) 3407, 2955, 2928, 2856, 1490, 1471, 1448, 1254, 1058, 1031, 836, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) ε7.57 (m, 6H), 7.37 (m, 9H), 5.78 (dd, J=15.6, 6.5 Hz, 1H), 5.73 (dt, J=15.5, 4.8 Hz, 1H), 3.91 (m, 1H), 3.82 (d, J=5.9 Hz, 2H), 3.69 (d, J=4.4 Hz, 2H), 2.51 (m, 1H), 2.22 (br, 1H), 1.77 (m, 2H), 1.13 (d, J=6.8 Hz, 3H), 1.03 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.2, 134.1, 128.6, 127.7, 127.1, 126.9, 86.8, 74.3, 64.9, 60.4, 42.0, 34.8, 25.9, 18.0, 14.5, −4.4, −4.6; LRMS (ESI) 539.2 [M+Na]+, 243.2; HRMS (ESI) calcd for C33H44O3Si1Na 539.2957 [M+Na]+, found 539.2976; [α]20D−2.8 (c 2.0, CHCl3).
Reaction SMILES: [CH:1]1([C:4]#[C:5][NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]C1.[CH3:13]N(C)C=O>[Cu]I>[CH:4]1([C:5]2[NH:6][C:7]3[C:8]([CH:13]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:1][CH2:3]1
Reactant: C(#CC1CC1)Nc1ccccc1
Reactant: CN(C)C=O
Agent: [Cu]I
Product: c1ccc2[nH]c(C3CC3)cc2c1

Procedure:
0.54 g of copper(I) iodide is added to a solution of 0.42 g of 2-cyclopropylethynylphenylamine in 20 ml of N,N-dimethylformamide under argon. The reaction mixture is refluxed for 2 hours, and is then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 200 ml of water and 100 ml of dichloromethane, filtered through Celite®, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 50 g column of 20-45 μm silica, elution being carried out with a 50/50 v/v cyclohexane/dichloromethane mixture. 0.18 g of 2-cyclopropylindole is thus obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)C.[OH-].[Na+]>CO>[Cl:15][C:11]1[CH:10]=[C:9]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Yield: 92.7 %

Procedure:
(E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid ethyl ester (10.5 g) in methanol (30 mL) was treated with 2N sodium hydroxide solution (20 mL) and the mixture was heated at reflux for 15 minutes. The crude solid, obtained from the usual work up, was crystallized from dichloromethane-hexane to furnish 8.95 g of (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid, mp 167°-68° C. Recrystallization from ether-hexane gave the analytical specimen, mp 167°-168° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9]O)=[CH:2]1.C(N(CC)CC)C.C1(C)C=CC(S([Cl:39])(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:39][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1
Reactant: OCCN(CCCCCCc1ccccc1)Cc1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN(CCCCCCc1ccccc1)Cc1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.533 g (8.470 mmol) of 2-[(3-furylmethyl)-(6-phenylhexyl)amino]ethanol, 1.77 ml (12.7 mmol) of triethylamine and 30 mg of 4-dimethylaminopyridine in 50 ml of dichloromethane, 1.94 g (10.2 mmol) of p-toluenesulfonyl chloride was added at room temperature, followed by overnight stirring at room temperature. The solvent was distilled off under reduced pressure; the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][NH:25]1.C(N(CC)CC)C>O1CCCC1>[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][N:25]1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc3C2)nc1-c1ccc(C)cc1
Yield: 58.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1,2,3,4-tetrahydroisoquinoline (0.108 mL; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.072 g (58%) of the titled compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+].OS([O-])=O.[Na+]>CC(C)=O.CC(C)=O.O.Cl>[CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([C:16]([OH:19])=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)[nH]1
Reaction time: 3 h

Procedure:
Next, to a stirred solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (1.10 g, 4.80 mmol) in acetone (100 mL) is added a solution of potassium permanganate (1.52 g, 9.60 mmol) in 150 mL acetone/water (1:1) dropwise and the mixture is stirred for three hours. The mixture is poured into a solution of 200 mL of 10% NaHSO3 in 1N HCl and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC Retention time 0.88 minutes (condition C): MS 244.3 (M−1).
Reaction SMILES: C1(C[O:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][CH:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16][N:15]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][CH:10]=2)C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(O)cc1
Yield: 62.9 %

Procedure:
A solution of 1-{4-(phenylmethoxy)benzyl}-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.60 g, 1.38 mmol), palladium (5% wt. on activated carbon, 0.06 g), and glacial acetic acid (3 drops) in ethanol (30 mL) was stirred under hydrogen for 15 hours. The reaction was filtered and concentrated to provide the title compound (0.30 g, 63% yield): ES−MS (m/z) 346 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][NH:9][C:8](=O)[C:7]=2[CH:16]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30].C(Cl)Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:30][C:8]1[C:7]2[CH:16]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH3:18])=[CH:5][C:6]=2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CNC2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Temperature: 25 °C

Procedure:
Heat at 125° C. in a sealed tube for 3Y4 hour a solution of 100 mg (0.40 mmol) of 7,8-dimethoxy-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (XVIIaa), 280 μl of dimethylaniline, 800 μl of POCl3, in 10 ml of anhydrous CHCl3. Allow to cool to room temperature. Add 3 g of silica and 5 ml of CH2Cl2. Add at 0° C., 1 ml of triethylamine.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11]=2[N:21]=1.[NH2:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][C@H:23]3[CH2:27][N:26]([C:28]4[CH:29]=[CH:30][C:31]5[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=5[N:37]=4)[C:25](=[O:39])[CH2:24]3)[C:11]=2[N:21]=1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCCN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Reaction time: 0.17 h
Yield: 23 %

Procedure:
Acetic acid (0.06 g, 1 mmol) was added dropwise to a mixture of 3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (synthesized with reference to WO2008/9700; 0.2 g, 0.85 mmol), 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 0.25 g, 1.0 mmol) and N,N-dimethylformamide (4 ml). The mixture was cooled on ice and sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was gradually added thereto. The mixture was stirred for 10 minutes under cooling on ice and subsequently stirred at room temperature for 2 hours. The reaction solution was cooled on ice again and a sodium hydrogen carbonate aqueous solution was added thereto. The obtained mixture was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 90 mg (23%) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:5][C@@H:4]([NH2:27])[CH2:3]1.[O:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1>CN(C=O)C>[CH:18]1[C:12]2[N:11]3[C:7]([C@@H:6]4[C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:27][C:30]5([CH2:32][C:33]#[N:34])[CH2:31][O:28][CH2:29]5)[CH2:5]4)=[CH:8][N:9]=[C:10]3[CH:15]=[N:14][C:13]=2[NH:16][CH:17]=1
Reactant: C[C@@H]1C[C@H](N)C[C@@H]1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: N#CC=C1COC1
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC2(CC#N)COC2)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a solution of (1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.605 g, 1.569 mmol, prepared using FFFFF from Preparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D with NaOH, KK, Y) in DMF (6 mL) was added 2-(oxetan-3-ylidene)acetonitrile (0.298 g, 3.14 mmol, J. Med. Chem. 2010, 53(8), 3227) and the reaction mixture was heated at about 80° C. for about 15 h. 2-(Oxetan-3-ylidene)acetonitrile (0.149 g, 1.569 mmol) was added and the reaction mixture was heated at about 80° C. for about 3.5 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM. A second purification by silica gel chromatography eluting with 50% to 100% EtOAc in heptane followed by 10% MeOH in DCM yielded 2-(3-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acetonitrile (0.262 g, 33%) as a sticky brown solid: LC/MS (Table 1, Method n) Rt=0.75 min; MS m/z 481 (M+H)+.
Reaction SMILES: N[C:2]1[C:3]([Cl:18])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.N([O-])=O.[Na+].[ClH:23]>OS(O)(=O)=O.O.Cl[Cu]>[Cl:18][C:3]1[C:2]([Cl:23])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[C:9]2[C:4]=1[NH:5][C:6](=[O:17])[C:7](=[O:16])[NH:8]2
Reactant: Cl
Reactant: Nc1c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)c(Cl)c2[nH]c1=O
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 25 mg (0.089 mmol) of 6-amino-5-chloro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione in 1 mL of concentrated H2SO4 (97%) was stirred in an ice-bath for 1 h. To the resulting yellow solution was added dropwise solution of 40 mg (0.58 mmol) of NaNO2 in 0.5 mL of H2O and the solution was stirred in an ice-bath for 2 h. To the resulting red solution was added an icy cooled solution of 60 mg of CuCl in 0.8 mL of 6N HCl and the resulting mixture was stirred in ice-bath for 2 h, then at room temperature overnight. The mixture was diluted by 2 mL of H2O and stirred for 1 h, then 2 mL of H2O and stirred for 1 h. It was filtered, washed by water, and dried to leave white solid (20 mg, 74%), mp>250° C. 1H NMR (DMSO-d6), 7.492 (s, 1), 11.849 (mb, 1), 12.229 (s, 1). MS, 298 (M+, 100), 270 (85), 207 (40), 173 (60). HRMS Calcd for C9H335Cl2F3N2O2, 297.9520, found 297.9520.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:12][N:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]([OH:23])=[O:22])=[N:12][N:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCCCSCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nnc(SCCCSCC(=O)O)s2)ccc(C(C)=O)c1O
Yield: 105.9 %

Procedure:
In 2 ml of 90% methanol was suspended 0.14 g of ethyl [[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]propyl]thio]acetate obtained in Example 25. Further 1 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 45 minutes An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and then dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexane-ethyl acetate (1:2) gave 0.14 g of oily [[3-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]propyl]thio]acetic acid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[NH:6]([C:10]1[S:11][C:12]([CH2:15]O)=[CH:13][N:14]=1)[C:7]([NH2:9])=[NH:8].[OH-].[Na+]>Cl>[NH:6]([C:10]1[S:11][C:12]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[CH:13][N:14]=1)[C:7]([NH2:9])=[NH:8]
Reactant: NCCS
Reactant: N=C(N)Nc1ncc(CO)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1ncc(CSCCN)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 697.2 %

Procedure:
Cysteamine hydrochloride (10.6 g; 9.3 mmoles) and 2-guanidino-5-hydroxymethylthiazole (16.0 g; 9.3 mmoles) [prepared in Step B] were dissolved in 80 ml of concentrated hydrochloric acid and the solution stirred at ambient temperature for 1 hour and then heated at reflux temperature for 3 hours. The reaction mixture was cooled, made basic (pH 11) with 40% aqueous NaOH and filtered to give 15 g of product. Recrystallization from acetonitrile yielded the title compound, mp 150°-153°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH:5]([NH:20]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.Cl>O1CCOCC1>[ClH:19].[CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@H](O)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](O)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (113 mg, 0.269 mmol) is treated with 4M HCl in dioxane (2 mL). After being stirred at room temperature for 1 h, the reaction mixture is concentrated. The residue is used for a next step without further purification. HPLC retention time=1.22, 1.29 minutes (condition A): MS (m+1)=320.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)#[N:2].[Cl-].CO[C:23](=[O:33])[C:24]1[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[C:23](=[O:33])[C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 2.50 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine, 2.98 g of isophthalic acid monomethyl ester monochloride and 2.10 ml of triethylamine in 100 ml of CH2Cl2 is stirred at room temperature for 1 hour. Extraction twice with 50 ml of water each time and customary treatment of the organic phase yields a crude product that, after chromatography on silica gel 60 (40-63 μm) using CH2Cl2 as eluant, yields N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-isophthalic acid monoamide that has an Rf value of 0.61 [CH2Cl2 /CH3OH (4:1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][C:15](=N)[CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[OH-].[Na+].ClCCl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC(=N)NC[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNC[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
1 g of the product obtained in Step 1 (containing 47% amidine) is dissolved in 15 mL of methanol; the resulting solution is then cooled to 0° C. and 100 mg (2.61 mmol, 1.2 equivalents) of sodium tetraborohydride are added. Stirring is carried out overnight at ambient temperature, and then 5.3 mL of 20% aqueous sodium hydroxide solution and 20 mL of dichloromethane are added. Vigorous stirring is carried out for 15 minutes. The organic phase is then extracted, washed with water, dried over MgSO4, filtered and then evaporated to dryness. There is obtained 1 g of an oil which is purified by flash chromatography on 100 g of silica (eluant=dichloromethane/ethanol/NH4OH: 90/10/1) to yield 300 mg of expected product in the form of an oil.
Reaction SMILES: BrC1C=CC2OCOC=2C=1.Br[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.[CH2:24]([O:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[C:37](Br)[CH2:38][CH2:39]2)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:41]=[C:40]2[C:35](=[CH:34][CH:33]=1)[CH:36]=[C:37]([C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:38][CH2:39]2)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)OCO2
Agent: Brc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(cc1C1=Cc3ccc(OCc4ccccc4)cc3CC1)OCO2
Yield: 10.9 %

Procedure:
Synthesized from 4-bromo-1,2-(methylenedioxy)benzene according to an analogous synthetic method to Preparation Example 108, 5-bromo-6-nitrobenzo[1,3]dioxole (9.4 g) and 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (6.0 g) were used according to an analogous synthetic method to Preparation Example 107 to provide the title compound (834 mg).