Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:53])[CH2:37][N:38](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:32][C:31]=1[NH:54][S:55]([CH3:58])(=[O:57])=[O:56])C1C=CC=CC=1>>[OH:53][CH:36]([C:33]1[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:32]=1)[CH2:37][NH:38][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.2 Hz, 3H), 1.20-1.40 (m, 2H), 1.50-1.70 (m, 4H), 1.95-2.10 (m, 2H), 2.40-2.60 (m, 2H), 2.94 (s, 3H), 2.90-3.20 (m, 5H), 3.62-3.75 (m, 2H), 4.70-4.80 (m, 1H), 5.95 (brs, 1H), 6.85-6.95 (m, 3H), 7.00-7.10 (m, 3H), 7.24 (d, J=2.0 Hz, 1H), 8.70 (brs, 1H), 9.33 (brs, 1H); MS (ES) m/z: 541.0 (MH+); HRMS Calcd. for C24H37N4O6S2 (MH+): 541.2155. Found: 541.2161.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.C([Li])CCC.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[C:16]([O:26][CH3:27])[C:15]=1[F:28].C(OCC)C>C1COCC1.CCCCCC>[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([C:3]2([C:2]([F:7])([F:6])[F:1])[CH2:4][O:5]2)=[O:19])=[C:16]([O:26][CH3:27])[C:15]=1[F:28]
Reactant: COc1c(C(=O)N(C)OC)ccc(Cl)c1F
Reactant: FC(F)(F)C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(=O)C2(C(F)(F)F)CO2)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.44 ml (5.1 mmol) 1,1,1-trifluoro-2,3-epoxypropane in 7.5 ml THF and 2.2 ml hexane are cooled to −100° C. and 2.03 ml of a 2.5 M n-butyl lithium solution (5.1 mmol) in hexane are added over 15 minutes while the temperature does not exceed −95° C. 10 minutes after complete addition 0.57 g (2.3 mmol) 4-chloro-3-fluoro-2, N-dimethoxy-N-methylbenzamid in 10 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After 3 hours at −100° C. 2.3 ml diethyl ether is added and the reaction mixture is warmed to room temperature over 14 hours. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 570 mg of (4-chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone. 1H-NMR (CDCl3); δ=2.99 (dq, 1H), 3.37 (d, 1H), 4.14 (d, 3H), 7.18 (m, 1H), 7.19 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[CH3:23].[SH:24][C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1.[OH-].[Na+]>C(O)C.O>[CH3:23][C:7]1[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:24][C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(SCCCSc2nc3ccccc3[nH]2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 83 %

Procedure:
2-{[[4-(3-Chloropropylthio)-3-methyl-2-pyridinyl]methyl]thio}-1 H-benzimidazole (1 mmol) is stirred at 60° C. for 20 h with 2-mercapto-1 H-benzimidazole (1.05 mmol) and 1N sodium hydroxide solution (3 ml) in 10 ml of ethanol and subsequently diluted with a further 10 ml of water. The mixture is allowed to cool, and the precipitated solid is filtered off, washed with ethanol/water 1/1 and dried in vacuo at 50° C. The title compound is obtained as a gray powder; m.p. 85°-87° C.; yield: 83% of theory.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@H:13]([CH3:42])[CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[Li+].[OH-]>C1COCC1.O>[ClH:41].[Cl:41][C:32]1[C:33]([C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:15]([CH2:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][C@@H:13]([CH3:42])[CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:43])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(OC[C@H](C)CN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COc1cccc(CC(=O)O)c1)CN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.7 %

Procedure:
To a stirring solution of (R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)acetic acid methyl ester (22 mg, 0.0361 mmol) in THF (0.75 ml) and water (0.25 ml) was treated with LiOH (3.0 mg, 0.072 mmol). The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated and 3 N HCl (aq.) was added until the pH was less than two. The aqueous layer was extracted three times with EtOAc, the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give 18 mg (78% yield) of the title compound as a white solid. MS(ESI) 596.0(M+).
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.[CH3:5][CH:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:7].C(N(CC)CC)C.[OH2:23]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:4][CH2:1][CH2:13][CH2:14][CH2:15][CH:10]1[O:11][C:12](=[O:23])[N:8]([CH:6]([CH3:7])[CH3:5])[CH2:9]1
Reactant: O=C(Cl)Cl
Reactant: O
Reactant: CC(C)NCC1CCCCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)N1CC(CCCCCl)OC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A solution of phosgene (287 mL of a 20% solution, 273 g, 0.55 mol) in toluene and additional toluene (100 mL) was cooled to -10° C. by an ice/methanol bath and a solution of tetrahydro-N-(1-methylethyl)-2H-pyran-2-methanamine (41.13 g, 0.262 mol) and triethylamine (27.9 g, 0.276 mol) in toluene (300 mL) was added dropwise, keeping the temperature below 5° C. The mixture was warmed to room temperature and refluxed under nitrogen for 30 min. Zinc chloride (0.65 g) was added and refluxing was continued for 15 min. An additional portion of zinc chloride (0.32 g) was added, and the mixture was refluxed for 24 hr and allowed to stand at room temperature for several days. Water (750 mL) was added, and the layers were separated. The organic layer was washed twice again with water and once with a saturated sodium chloride solution, dried (magnesium sulfate), treated with charcoal, filtered, and evaporated to an oil. The oil was distilled under reduced pressure, and the fraction distilling from 148°-165° C./0.3 mm was collected to give 46.7 g (81% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[C:8]([O:12][C:13]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[C:8]([O:12][C:13]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1-n1cccn1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 73 %

Procedure:
Sodium hydride (0.54 g) was added to a mixture of pyrazole (1.0 g) and dimethyl sulfoxide (50 ml) under cooling with ice. The reaction mixture was stirred for 1 hour under cooling with ice and then a solution of N-(2-fluoro-5-nitrophenylmethyl)iminodicarboxylic acid di-tert-butyl ester (5.0 g) in dimethyl sulfoxide (50 ml) was added. The reaction mixture was stirred at room temperature for 15 hours and then water was added and extraction with ethyl acetate was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:4) to give the titled compound (yield, 73%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH2:2][NH:1][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:18])=[CH:4][CH:5]=1
Reactant: NCc1ccc(CO)cc1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(CO)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Using General Procedure F: To a stirred solution of 4-aminomethylbenzyl alcohol (203 mg, 1.48 mmol) in DMF (3 mL) was added picolinic acid (198 mg, 1.61 mmol), 1-hydroxybenzotriazole (213 mg, 1.58 mmol), N,N-diisopropylethylamine (0.39 mL, 2.24 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (315 mg, 1.64 mmol) and the mixture stirred overnight at room temperature. Standard work-up afforded the title compound (340 mg, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.67 (d, 2H, J=6.0 Hz), 4.69 (s, 2H), 7.36 (br s, 4H), 7.43-7.44 (m, 1H), 7.85-7.86 (m, 1H), 8.24 (d, 1H, J=9.0 Hz), 8.52 (br s, 1H), 8.52 (d, 1H, J=3.0 Hz). ES-MS m/z 243 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:21][CH:22]([N:24]=[N+:25]=[N-:26])C)(=O)=O.N([CH2:30]CN1C=CC=C(OC)C1=O)=[N+]=[N-]>>[N:24]([CH2:22][CH2:21][CH2:30][C:14]1[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:25]=[N-:26]
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: CC(COS(C)(=O)=O)N=[N+]=[N-]
Reactant: COc1cccn(CCN=[N+]=[N-])c1=O
Product: [N-]=[N+]=NCCCc1cc[nH]c(=O)c1OCc1ccccc1
Yield: 53 %

Procedure:
Reaction of 3-benzyloxypyridine-2-one (0.40 g, 1.99 mmol) and 156b (0.53 g, 2.98 mmol) within 16 h as described for synthesis of 157a gave compound 157b (0.30 g, 53%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 7.28 (m, 5H), 6.84 (dd, J=6.9, 1.6 Hz, 1H), 6.60 (dd, J=7.4, 1.5 Hz, 1H), 5.98 (t, J=7.1 Hz, 1H), 3.97 (t, J=6.8 Hz, 2H), 3.28 (t, J=6.5 Hz, 2H), 1.98 (p, J=6.7 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 157.78, 148.65, 135.93, 128.85, 128.24, 127.69, 127.03, 115.16, 104.53, 70.39, 48.14, 47.06, 27.66. HRMS (EI) calcd for C15H16N4O2 [M]+ 284.1273. found 284.1271.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g, 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[C:4]([CH:16]1[CH2:18][CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl-:1].[CH:16]1([C:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2)=[CH:3][CH2:2][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)Oc1ccc(C(=CCCl)C2CC2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(C(=CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C2CC2)cc1
Product: [Cl-]
Yield: 79.6 %

Procedure:
A stirred solution of 113.5 grams (0.41 mole) of 3-chloro-1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-1-propene and 113.0 grams (0.43 mole) of triphenylphosphine in 400 mL of toluene was heated at reflux for 4 hours. After this time the reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was triturated with 1000 mL of diethyl ether. The ether was decanted from the residue, and the residue was triturated with two more 1000 mL portions of diethyl ether in the manner described above. The solid residue was dried under reduced pressure yielding 176.0 grams of [3-cyclopropyl-3-(4-trifluoromethoxyphenyl)-2-propen-1-yl]triphenylphosphonium chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH2:36])=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH:36][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([C:20]#[N:21])=[CH:4][N:3]=3)=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C#N)CC2CCCN21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (±)-2-chloro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidine-5-carbonitrile (60 mg of 70% pure material from previous step), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzeneamine (65 mg, 0.3 mmol; prepared according to U.S. patent application Ser. No. 13/188,222, filed Jul. 21, 2011, now U.S. patent application publication US2012/0022092) and para-toluenesulfonic acid monohydrate (37 mg, 0.2 mmol) in isopropyl alcohol (3 ml) were combined in a sealed vial, heated to 80° C. and stirred for 4 hours. After cooling, a precipitate emerged which was filtered. The filter cake was suspended in EtOAc (30 ml) and 1N NaOH (50 ml). The aqueous and organic layers were partitioned and the aqueous layer was extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed under vacuum to leave a solid. The solid was freeze-dried from MeCN/H2O to give the product (26 mg) as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[S:5][C:6]([CH2:9][NH:10][C:11]([N:16]([CH3:18])[CH3:17])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1.[N:19]#[C:20]Br.O>CN(C=O)C.CC#N>[Cl:3][C:4]1[S:5][C:6]([CH2:9][N:10]([C:20]#[N:19])[C:11]([N:16]([CH3:18])[CH3:17])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])N(C#N)Cc1cnc(Cl)s1

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) in DMF (3 ml) was added a solution of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (0.49 g) in DMF (3 ml) dropwise over 5 minutes at room temperature under stirring. After stirring for five minutes, 2.08M solution of cyanogen bromide in CH3CN (1 ml) was added to the mixture over 5 minutes. After stirring for 1 hour, the reaction mixture was poured into 50 ml of water and the reaction vessel was washed with 10 ml of water. The washing was combined with the aqueous layer and precipitated pellets were obtained by filtration and recrystallized from EtOH to afford 0.334 g of 1-(2-chloro-5-thiazolylmethyl)-1-cyano-3,3-dimethyl-2-nitroguanidine (Compound No. 1) as a crystal, m.p. 152°-155° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH-:5].[Li+].Cl[Si:8]([CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19])([CH3:10])[CH3:9]>CCCCC>[CH3:1][O:2][CH2:3][CH2:4][NH:5][Si:8]([CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19])([CH3:9])[CH3:10]
Reactant: COCC[NH-]
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li+]
Solvent: CCCCC
Product: COCCN[Si](C)(C)C1C(C)=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.00 g (24.67 mmol) of lithium methoxyethylamide were added a little at a time at 0° C. to a solution of 5.30 g (24.70 mmol) of (chlorodimethylsilyl)tetramethylcyclopentadiene in 40 ml of dry pentane and the mixture was stirred for 16 hours at room temperature. The pale yellow reaction solution was filtered to remove the precipitated lithium chloride and the pentane was removed under an oil pump vacuum. Subsequent distillation of the remaining oil gave [(methoxyethylamino)dimethylsilyl]tetramethylcyclopentadiene in the form of a hydrolysis-sensitive, greenish yellow oil. Yield: 5.26 g (76%); boiling point: 70-77° C./10-2 torr.
Reaction SMILES: [C:1]1(=O)[NH:10][CH:9]=[CH:8][C:7]2[CH:6]=[N:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.I[C:17]1[CH:18]=[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:22]=1.N1CCC[C@H]1C(O)=[O:38]>O>[C:29]1([C:19]2[CH:18]=[C:17]([N:5]3[C:4]4[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=4[C:2]4[C:7](=[CH:8][CH:9]=[N:10][CH:1]=4)[C:6]3=[O:38])[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Ic1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reactant: O=c1[nH]ccc2cnc3ccccc3c12
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O
Product: O=c1c2ccncc2c2ccccc2n1-c1cc(-c2ccccc2)cc(-c2ccccc2)c1

Procedure:
19.6 g (100 mmol) of benzo[c]-2,6-napthyridinone, 106 g (300 mmol) of 5′-iodo-[1,1′;3′,1″]terphenyl and 2.3 g (20 mmol) of L-proline are stirred at 150° C. in 100 ml for 30 h The solution is diluted with water, extracted twice with ethyl acetate, the combined organic phases are dried over Na2SO4 and evaporated in a rotary evaporator. The residue is purified by chromatography (EtOAc/hexane: 2/3). The yield is 25 g (59 mmol) 60% of theory.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].[OH-].[K+]>CO>[CH3:12][N:13]([CH3:17])[C:14]([O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)=[S:15]
Reactant: CN(C)C(=S)Cl
Reactant: N#CCc1ccc(O)cc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=S)Oc1ccc(CC#N)cc1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Metallic sodium (1.15 g, 50 mg-atom) was dissolved in methanol (100 ml) and 4-hydroxybenzylcyanide (6.7 g, 50 mmol) was added. The obtained solution was concentrated and acetonitrile (2×10 ml) was evaporated from the residue. The obtained salt was dissolved in anhydrous dimethylformamide (200 ml) and about 25 ml of the solvent was removed under reduced pressure. To the obtained solution N,N-dimethylthiocarbamoyl chloride (9.9 g, 80 mmol) was added and the reaction mixture was stirred at 80°-85° C. for 2 hours. Thereafter additional N,N-dimethylthiocarbamoyl chloride (2.5 g, 20 mmol) was added and stirring at 80° C. was continued for further one hour. After cooling the mixture was poured into aqueous 1% KOH (500 ml) and extracted with ether (3×200 ml). The organic extracts were washed with water until neutral, dried over MgSO4 and concentrated. The solid residue was triturated with water and after drying also with isopropyl ether to give the title compound (5.42 g), mp. 120°-124° C., yield: 52.7%.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[O:20][CH3:21]>C(Cl)Cl>[CH3:21][O:20][C:19]([NH:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1)=[O:22]
Reactant: NC1CCc2sccc2C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 3.79 g of 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydrochloride and 4.04 g of triethylamine dissolved in 30 ml of methylene chloride was added dropwise 1.89 g of methyl chlorocarbonate under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, the organic layer was collected by separation and dried, and then the solvent was removed. The resulting crystals were recrystallized from isopropyl ether to obtain 3.80 g of 5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][C:3]=1[F:27].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[F:27]
Reactant: CCOC(=O)CC(c1ccc(Cl)c(F)c1)c1c[nH]c2c(CSC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 1.74 g (4.28 mmol) of the compound from Example 101A in 7 ml of tetrahydrofuran was added dropwise to 15.0 ml (15.05 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 20 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then water and acetonitrile were added, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.36 g (87% of theory) of the title compound were obtained.