Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:17][CH:18]=[CH:19][C:3]=12.Cl.[Sn].[OH-].[NH4+]>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:17][CH:18]=[CH:19][C:3]=12
Reactant: NC1=c2ccsc2=NCN1c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC1=c2ccsc2=NCN1c1ccc(N)cc1

Procedure:
4-Amino-3-(4-nitrophenyl)thieno[2,3-d]pyrimidine (11.6 g; 272 g/mole; 42.6 mmoles) was treated with 500 mL HCl 6N and 15 g elemental tin at room temperature. After 15 minutes the reaction was complete by TLC (product has Rf=0.50 in 100% ethyl acetate). The system was placed in an ice bath and treated with concentrated ammonium hydroxide to pH 10 (˜300 mL). At this point, extensive precipitation was observed. Precipitate (A) was collected by filtration and reserved, and the clear solution was treated with 1 L methylene chloride. The aqueous layer was then back-extracted with 3×200 mL methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. Precipitate (A), consisting of a mixture of tin salts and product, was extracted with boiling methanol until washings showed no more product by TLC. The resulting solution was combined with the previously reserved organic layers, filtered, concentrated to dryness and dried overnight, generating desired product 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (242 g/mole; nearly quantitative yield), which was recrystallized from methanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5].Cl[C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[C:17]=1[CH3:27].O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:27][C:17]1[C:18](=[O:26])[N:19]([CH2:24][CH3:25])[C:20]([S:22][CH3:23])=[N:21][C:16]=1[S:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=1
Reactant: CCCOc1ccc(CS)cc1
Reactant: CCn1c(SC)nc(Cl)c(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCOc1ccc(CSc2nc(SC)n(CC)c(=O)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Sodium hydride (55% in mineral oil) (0.70 g) was suspended in 20 ml of hexamethyl phosphoric triamide, and then 3.0 g of 4-propyloxybenzyl mercaptan was added thereto. The mixture was stirred for one hour at room temperature and then incorporated with 3.0 g of 6-chloro-5-methyl-2-methylthio-3-ethyl-4(3H)-pyrimidinone. After stirring at room temperature, resulting mixture was heated to 80° C. under stirring for 3 hours. The resulting solution was poured into water and then extracted with benzene. The extract was washed with an aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate and freed of solvent by distillation udner reduced pressure. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with chloroform) to give 2.6 g of the intended product.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:1]
Reactant: [OH-]
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1ccc(Cl)cc1Cl
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (40 ml of 70% w/v solution) was added slowly with stirring to glacial acetic acid (42 g). The temperature rose to reflux and tetrabutylammonium hydrogen sulphate (0.5 g) and 2,4-dichlorobenzyl chloride (100 g) were added and the mixture heated under reflux for eight hours. The mixture was cooled to 70°-75° C. and aqueous sodium hydroxide (35 ml of 70% w/v solution) added. The temperature was maintained in the range 70°-75° C. for 30 minutes. The product was extracted into petroleum ether (boiling range 80°-100° C. 90 ml) at 75° C. and the organic extract was diluted with petroleum ether (150 ml), washed with dilute aqueous hydrochloric acid, and filtered. The filter was washed with petroleum ether (40 ml) and the filtrate and washings combined and allowed to cool to give crystals of 2,4-dichlorobenzyl alcohol having a purity of 99.8% and in a yield of 95%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17]O)[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][Br:1])[CH:11]=1
Reactant: OCc1cc(Br)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1CBr
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4.0 g N-bromosuccinimide are slowly added to a solution of 5.0 g of 4-bromo-1-chloro-2-hydroxymethyl-benzene and 5.9 g triphenylphosphine in 50 mL of tetrahydrofuran chilled to 5° C. After 1 h stirring at ambient temperature the precipitate is filtered off, and the solvent is eliminated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 50:1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]45O[C:13]4([C:22](=[O:23])[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:15]5)[CH2:12][N:11]3[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:9][C:4]=2O[CH2:2]1.[CH2:32](Cl)Cl>Cl.CN(C=O)C>[CH2:25]([N:11]1[CH:12]=[C:13]2[C:14]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]2=[O:23])=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:32][C:4]=2[CH:9]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1c2ccccc2NC23OC12CN(Cc1ccccc1)C3c1ccc2c(c1)OCO2
Reactant: ClCCl
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c2ccccc2[nH]c2c(-c3ccc4c(c3)CCO4)n(Cc3ccccc3)cc12

Procedure:
The title compound was prepared by stirring 3-(1,3-benzodioxol-5-yl)-2,3-dihydro-2-(phenylmethyl)-3a,9a-epoxy-1H-pyrrolo[3,4-b]quinolin-9-(4H)-one, prepared as in Example 1, with HCl (2 drops of 1N aqueous solution) in a mixture of CH2Cl2 and DMF (4:1) for 72 hours at room temperature.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[C:4](Cl)[N:3]=1.C(O)=[O:19]>>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][O:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(Cl)c2ncn(OCC(O)CO)c2n1
Reactant: O=CO
Product: Nc1nc2c(ncn2OCC(O)CO)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
2-Amino-6-chloro-9-(2,3-dihydroxyprop-1-oxy)purine (100 mg, 0.39 mmol) was dissolved in 80% formic acid solution and stirred at 100° C. for 2.5 hours. The reaction was evaporated to dryness under reduced pressure and the residue treated with methanol (5 ml) and 0.88 ammonia solution (3 ml). After stirring the reaction at 60° C. for 2 hours, the solvents were evaporated under reduced pressure and the residue recrystallised from water yielding the title compound (35 mg, 38%), m.p. 252°-3° C. Uv: λmax (H2O) 252 (ε12,600) nm; IR: υmax (KBr) 3330, 1690, 1640, 1605, 1540, 1475 cm-1 ; 1H NMR: δH [(CD3)2SO] 3.39 (2H, m, CH2OH), 3.72 (1H, m, CHOH), 4.10 (1H, dd, J=10.7, 7.6 Hz, 7.6 Hz, CH2ON), 4.33 (1H, dd, J=10.5, 3.3 Hz, CH2ON), 4.70 (1H, t, J= 5.7 Hz, OH), 5.15 (1H, d, J=5.2 Hz, OH), 6.62 (2H, br.s, NH2), 7.90 (1H, s, H-8), 10.58 (1H, br.s, NH); m/z 241 (M+, 3%), 210 (2), 167 (27), 151 (100), 109 (20), 61 (47). Found: C, 38.85; H, 4.66; N, 29.14%, M+ 241.0813. C8H11N5O4 requires C, 39.84; H, 4.60; N, 29.03%, M+ 241.0811.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([N:14]([C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH2:15][CH2:16][CH3:17])[CH3:13])=[CH:7][CH:6]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Fe]>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([N:14]([C@@H:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19])[CH2:15][CH2:16][CH3:17])[CH3:13])=[CH:9][CH:10]=1
Reactant: CCCN([C@H](C)Cc1ccc([N+](=O)[O-])cc1)[C@H](C)c1ccccc1
Agent: [Fe]
Agent: Cl
Agent: O=C[O-]
Solvent: O
Solvent: CCO
Product: CCCN([C@H](C)Cc1ccc(N)cc1)[C@H](C)c1ccccc1
Temperature: 25 °C

Procedure:
(R,R)-N-[2-(4-Nitrophenyl)-1-methylethyl]-N-propyl-(1-phenylethyl)amine hydrochloride was dissolved in ethanol (100 ml) and water (16 ml). To this solution was added iron powder (2.44 g) and ammonium formate (2.25 g). The mixture was heated at reflux for 3 hours, cooled to room temperature and filtered through a glass fiber filter. The filtrate was evaporated in vacuo, and the residue was partitioned between ethyl acetate and dilute sodium hydroxide. The organic layer was dried over sodium sulfate, filtered, and the solvent removed in vacuo to give (R,R)-N-[2-(4-aminophenyl)-1-methylethyl]-N-propyl-(1-phenylethyl)amine as a yellow syrup (2.9 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccccn1

Procedure:
A solution of 2-pyridin-2-yl-ethanol (Aldrich, 0.11 mL, 0.99 mmol), triethylamine (0.42 mL, 3.0 mmol), and methanesulfonyl chloride (0.12 mL, 1.5 mmol) in 5 mL THF were processed as described in Example 1C to give the crude title compound which was used directly in the next reaction.
Reaction SMILES: F[C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([O:12][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1F
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
A mixture of 5-fluoro-4-methyl-2-nitropyridine (0.8 g, 5.12 mmol), 4-hydroxy-2-chloropyridine (0.996 g, 7.69 mmol) and K2CO3 (0.708 g, 5.12 mmol) in DMF (10 mL) was heated at 80° C. for 4 h. The mixture was cooled to RT, poured onto water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (850 mg, 62%) as an off-white solid. MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][O:11][C:10]1=[O:17])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:28]([O:32][C:33](=[O:36])[CH2:34]Br)([CH3:31])([CH3:30])[CH3:29].[NH4+].[Cl-]>C1COCC1>[C:28]([O:32][C:33](=[O:36])[CH2:34][C@@H:2]([C:1]([N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][O:11][C:10]1=[O:17])=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 0 °C

Procedure:
To a solution of 4(37.082 g, 0.154 mol) in THF (300 mL) at −78° C. is added LiHMDS in THF (1.0 M, 0.162 mol, 162 mL) via cannula. The solution is stirred at −78° C. for 1 h. tert-Butylbromoacetate is added and then stirred for 30 more minutes. It is then gradually warmed to 0° C. and stirred at this temperature for 30 min. To this solution is gradually added 100 mL saturated aqueous solution of NH4Cl. The bulk of the THF is removed by rotary evaporation and the remaining mixture was extracted with CH2Cl2 (100 mL×3). The combined CH2Cl2 extracts is washed consecutively with 1N NaOH, 1 N HCl, saturated NaHCO3, and brine. It is then dried over MgSO4 and concentrated in vacuo. The residue is chromatographed in silica gel using hexane/ethyl acetate (5:1) as eluant to afford 5. 1H NMR (400 MHz, CDCl3) δ0.85 (t, J=6.8 Hz, 3 H), 0.91 (d, J=8.15 Hz, 3 H), 0.93 (d, J=8.15 Hz, 3 H), 1.18-1.35 (m, 6 H), 1.40 (s, 9 H), 1.35-1.49 (m, 1 H), 1.56-1.66 (m, 1 H), 2.31-2.39 (m, 1 H), 2.44 (dd, J=16.6, 4.5, 1 H), 2.73 (dd, J=16.6, 10.3, 1 H), 4.11-4.20 (m, 1 H), 4.44 (m, 1 H); 13C NMR (75.45 MHz, CDCl3) δ13.9, 14.4, 17.9, 22.4, 26.4, 27.9, 28.0, 31.4, 31.6, 31.7, 37.0, 39.2, 58.6, 62.9, 80.3, 153.5, 171.2, 175.8. HRMS calcd for C19H34NO5 (MH+): 356.2436. Found (DCI): 356.2418 (Δ=5.3 ppm).
Reaction SMILES: CC(O)=O.C1C2C(=CC=CC=2)CCN1.[CH2:15]1C2C(=CC=CC=2)CC[N:16]1[C:25]([O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[C@H:32]1[N:38]([CH3:41])[CH2:39][CH2:40][C@@:31]21[CH3:42])=[O:26].C[C@]12C3C=C(O)C=CC=3N(C)[C@H]1N(C)CC2.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:42][C@:31]12[C:30]3[CH:29]=[C:28]([O:27][C:25]([NH:16][CH3:15])=[O:26])[CH:36]=[CH:35][C:34]=3[N:33]([CH3:37])[C@H:32]1[N:38]([CH3:41])[CH2:39][CH2:40]2
Reactant: CN1CC[C@@]2(C)c3cc(OC(=O)N4CCc5ccccc5C4)ccc3N(C)[C@@H]12
Agent: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Temperature: 20 °C
Yield: 89 %

Procedure:
To a solution of physostigmine (290 g) in dry THF (2.3 L) at 15° C. under a nitrogen atmosphere was treated with KOtBu (126.4 g), added over 0.05 hour. The mixture was kept at 15° C. for 0.5 hour, then treated with glacial HOAc (64.1 mL, 1 equiv., pH=10) to give a mixture containing physostigmine (II) and eseroline (III) in a 1/99 HPLC ratio. Addition of 1,1'-carbonyldiimidazole (195.8 g, 1.15 equiv) in 10 (0.1 equiv.) and 3 (0.05 equiv.) portions at -30° C. over 2 hours gave the following HPLC ratios of imidazolecarbonyl intermediate (V) and eseroline after 1.0, 1.1 and 1.15 equiv.: 92/8, 98/2 and 99/1. Addition of glacial HOAc (482 mL, 8 equiv., pH-5) followed by 1,2,3,4-tetrahydroisoquinoline (175 g, 1.25 equiv., added over 1.5 hours at - 10° C.) and warming to 20° C. for 15 hours gave a mixture containing (3aS-cis)- 1,2,3,3a,8,8a-hexahydro- 1,3a,8-trimethylpyrrolo-[2,3-b]indol-5-yl 3,4-dihydro-2(1H)-isoquinolinecarboxylate and eseroline in a 99/1 HPLC ratio. Addition of water (500 mL), cooling to -10° C., partial neutralization to pH=8 with 50% NaOH (471 g, 0.7 equiv based in HOAc), concentration of the THF under 30° C., toluene extraction (1×1L and 2×0.5L) of the residue, washing with water (500 mL), 5% NaCl (500 mL) and concentration under reduced pressure at 50° C. gave 370 g of crude product. This material was further purified by silica gel chromatography using ethyl acetate/methanol to give 346 g of 99% pure product in 89% yield from physostigmine. Recrystallization from methanol/water gave 321 g of crystalline product in 99% PHLC purity and 84 % yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13]([NH:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+]>Br.O>[CH3:18][C:15]1[N:14]=[C:13]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:12]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Yield: 89.8 %

Procedure:
[3-(4-Methoxybenzenesulfonyl)-6-methyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine from Example 9 (3.0 g, 7.57 mmol) was heated in 48% HBr (40 mL) at 110° C. for 48 h. After cooling it was diluted with water (100 mL) and neutralized with Na2CO3. Then it was extracted with EtOAc (3×100 mL each) and the combined organic extracts were dried and stripped in vacuo. The residue was washed with ether to give 4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenol as a solid (2.6 g), mp 226–228° C. mass spec. (AP+): m/z 383 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10](=[N:13][C:14]#[N:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10]([NH:19][CH3:18])=[N:13][C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccc(Cl)nc1)C(=NC#N)SC
Reactant: CN
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)nc1)C(=NC#N)NC
Yield: 81.4 %

Procedure:
To a mixture of 0.42 g of 1-(6-chloro-3-pyridylmethyl)-3-cyano-1-ethyl -2-methylisothiourea and 5 ml acetonitrile was added each 0.5 g of 40% methylamine aqueous solution at an hour interval in total six time (3.0 g), while refluxing and stirring. The reaction mixture was stirred for 6 hours in total. Then, the mixture was concentrated to afford 0.32 g of 1-(6-chloro-3-pyridylmethyl)-2-cyano-1-ethyl-3-methylguanidine (Compound No. 3).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([BH3-])#[N:7].[Na+].[N+:10]([C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19]C2=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl>CO>[N+:10]([C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][CH:6]2[NH2:7])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: [BH3-]C#N
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: NC1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Yield: 60.4 %

Procedure:
24 g (314 mmol) of ammonium acetate and 13.8 g (220 mmol) of sodium cyanoborohydride were added to a solution of 6.0 g (31 mmol) of 7-nitro-3,4-dihydro-2H-naphthalen-1-one in 150 ml of methanol, and the reaction mixture was heated at 60° C. for 3 h. After acidifying to pH<2 with dil. hydrochloric acid, the reaction mixture was concentrated in vacuo and the residue was stirred with water and EA. A precipitate which appeared here was filtered off with suction, washed with EA and then combined with the acidic aqueous phase. After rendering the mixture alkaline, it was extracted with EA and the organic phase was dried with magnesium sulfate and concentrated in vacuo. 3.6 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthylamine were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18]3)[N:10]([C:31]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)=[O:32])[CH2:9][CH2:8][C:7]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Product: CCOC(=O)C1(C2c3[nH]c4ccc(OC)cc4c3CCN2C(=O)c2ccco2)CCC1

Procedure:
The procedure is as in Example 55, using as substrate the compound of Example 7 and as reagent 2-furoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[CH:11]=[C:10]([I:12])[CH:9]=[N:8][C:6]=2[N:7]=1.[CH3:14][CH2:15][O:16]CC>CN(C)C1C=CN=CC=1.C(OC(=O)C)(=O)C>[C:15]([NH:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[CH:11]=[C:10]([I:12])[CH:9]=[N:8][C:6]=2[N:7]=1)(=[O:16])[CH3:14]
Reactant: CCOCC
Reactant: Nc1nc(O)c2cc(I)cnc2n1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(O)c2cc(I)cnc2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
Analogously, a mixture of 0.52 g of 2-amino-4-hydroxy-6-iodopyrido[2,3-d]pyrimidine and 0.03 g of 4-dimethylaminopyridine in 10 ml of acetic anhydride is heated under reflux under nitrogen for 3 hours. After cooling the reaction mixture to room temperature, anhydrous ether is added, and the reaction mixture filtered to give 0.52 g (87%) of 2-acetamido-4-hydroxy-6-iodopyrido[2,3-d]pyrimidine as a tan colored solid: m.p.>280° C.; NMR (DMSO-d6, 80 MHz) delta 2.18 (s, 3H), 8.67 (d, 1H, J=2.5 Hz), 9.02 (d, 1H, J=2.5 Hz); M/S 330 (M+), 315 and 288.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[Na].I[CH3:18]>C(O)C>[CH3:18][S:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]c(S)n2)cc1
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: CSc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
2-Mercapto-4-(4-nitro-phenyl)-1H-imidazole (21.1 g) was added in portions to a solution of sodium (2.3 g) in ethanol (190 ml). After 15 minutes of stirring, a solution of iodomethane (14.2 g) in ethanol (50 ml) was added dropwise. After an additional 2 hours of stirring at room temperature, the solution was evaporated to dryness. The residual solid was treated with water, filtered off and dried to give 18.1 g of the title compound.
Reaction SMILES: [ClH:1].NC(C1N=C(NC(=O)C)C=CC=1Br)CC1C=C(F)C=C(F)C=1.[Br:24][C:25]1[C:26]([C@H:33]([NH:43][S@](C(C)(C)C)=O)[CH2:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1>>[ClH:1].[Br:24][C:25]1[C:26]([C@H:33]([NH2:43])[CH2:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=2)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1
Reactant: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)N[S@@](=O)C(C)(C)C)n1
Agent: CC(=O)Nc1ccc(Br)c(C(N)Cc2cc(F)cc(F)c2)n1
Agent: Cl
Product: CSc1ncc(Br)c([C@H](N)Cc2cc(F)cc(F)c2)n1

Procedure:
The title compound (11F) was prepared according to the method presented for the synthesis of compound 1F of Example 1 utilizing 11E. MS (m/z) 361.66 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[NH:23][C:22]2=[O:30])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[O:33].O>C1C=CC=CC=1>[OH:33][CH:32]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]1=[O:30])[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)C=O
Reactant: CC#CCSC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
3-(Triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (1.03g) and t-butyl glyoxalate (3.3g) were refluxed in dry benzene (50ml) with provision for the removal of water. After one hour the benzene solution was washed 5 times with water, dried and evaporated. Chromatography of the residue on silica --H gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous white solid (0.978 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH2:22][C:23]([F:31])([F:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:13])=[N:8][CH:7]=1.O[Li].O>C1COCC1.O>[F:31][C:23]([F:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][N:14]([C@H:15]1[CH2:16][CH2:17][C@H:18]([CH3:21])[CH2:19][CH2:20]1)[C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([S:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:7][N:8]=1
Reactant: COC(=O)CSc1cnc(NC(=O)N(CC(F)(F)c2ccccc2)C2CCC(C)CC2)s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](N(CC(F)(F)c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {2-[3-(2,2-difluoro-2-phenyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (350 mg, 0.725 mmol) in THF (50 mL) was added LiOH.H2O (183 mg, 4.35 mmol) in water (3 mL) at RT. The mixture was stirred at RT for 16 h. Water was added and the mixture was extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate. The solvent was removed at reduced pressure and the residue was purified by preparative HPLC to give {2-[3-(2,2-difluoro-2-phenyl-ethyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid