Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[S:12][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[I:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:7]([O:6][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][C:16]([I:27])=[CH:17][C:18]=2[P:19]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:20])[S:12][CH:13]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)c1csc(-c2sccc2P(=O)(OCC)OCC)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)c1csc(-c2sc(I)cc2P(=O)(OCC)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In a mixed solvent of chloroform and acetic acid at 1:1, 0.0877 g (0.2 mmols) of 4,3′-bis(diethoxyphosphoryl)-[2,2′]-bithiophene was dissolved, to which 0.2250 g (1.0 mmol) of commercially available N-iodosuccinimide was added at room temperature. Thereafter, the reaction mixture was stirred at room temperature for 8 hours. After the reaction, a sodium thiosulfate aqueous solution was added, followed by extraction with chloroform. The organic phase was washed with a 0.2 N sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=2:1) to obtain the specified substance in the form of a yellow solid at a yield of 0.0880 g (yield: 78%). The thus obtained product was used as it is for reaction in Example 12(12).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:26]([OH:28])=O)[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34]>>[NH2:29][CH:30]([C:26](=[O:28])[C@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:23])([CH3:24])[CH2:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: NCCCCN
Product: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)C(N)CCCN

Procedure:
S-benzyl-N-(3-benzylthio-2,2-dimethylpropionyl)-L-cysteine and 1,4-diaminobutane were used as starting materials.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]([CH2:4][C:5](O)=O)=[CH2:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:5][CH2:4][CH:2]([CH2:1][OH:9])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: OCC1CCN(Cc2ccccc2)C1

Procedure:
This was prepared from itaconic acid and benzylamine by the procedure described by Feldkamp et al. J. Am. Chem. Soc.. (1961). 1519.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:19][CH:20]1[C:25]([CH3:37])([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]3[N:33]=[N:34][NH:35][CH:36]=3)[CH:27]=2)[CH2:24][CH2:23][NH:22][CH2:21]1.[I-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[N:5]1([CH2:4][CH2:3][N:22]2[CH2:23][CH2:24][C:25]([CH3:37])([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][NH:35][CH:36]=4)[CH:27]=3)[CH:20]([CH3:19])[CH2:21]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Reactant: ClCCN1CCCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(CCN2CCCCCC2)CCC1(C)c1cccc(-c2c[nH]nn2)c1

Procedure:
A solution of 1-(2-chloroethyl)perhydroazepine hydrochloride (42 mg, 0.21 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (30 μL, 0.22 mmol) then transferred to a flask containing 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 45 mg, 0.176 mmol) in N,N-dimethylformamide (2 mL). Sodium iodide (32 mg, 0.21 mmol) and sodium hydrogencarbonate (18 mg, 0.21 mmol) were added and the resultant mixture was heated at 60° C. overnight. The solvent was then removed in vacuo and the residue was partitioned between saturated aqueous sodium hydrogencarbonate solution (5 mL) and dichloromethane (5 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×5 mL). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase preparative HPLC (condition 2) to give the acetate salt of the title compound. The free base was obtained by treating with dilute aqueous ammonia solution (2 mL) and extracting with ether (4×3 mL). Drying over Na2SO4, filtering and evaporation to dryness gave the title compound as a white solid (16 mg, 24%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].[CH:13]1([S:16](Cl)(=[O:18])=[O:17])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.Cl.O>[CH:13]1([S:16]([NH:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CNS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Nitrobenzylamine HCl (1.48 g), cyclopropanesulfonyl chloride (1 g) and triethylamine (2.98 mL) were dissolved in dichloromethane (20 mL). The reaction solution was stirred at rt overnight. The reaction mixture was diluted with 1N HCl aq. solution (50 mL) and water (100 mL). The solution was extracted with ethyl acetate (2×100 mL). The organic solution was evaporated to give N-cyclopropylsulfonyl-3-nitrobenzylamine.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:17]2[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:24])[CH3:8])(=O)=O.[CH3:25][S-:26].[Na+]>CN(C=O)C.O>[CH3:24][C:10]1[N:9]([CH:7]([CH3:8])[CH2:6][S:26][CH3:25])[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:21])([F:23])[F:22])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)COS(C)(=O)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a solution of 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propyl methanesulfonate (0.145 g, 0.402 mmol) in DMF (3 mL) was added sodium thiomethoxide (0.056 g, 0.805 mmol) in one portion. After 90 min, additional sodium thiomethoxide (2 eq) was added, and the mixture stirred for another 1 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (30 mL). The organic phase was washed with 0.1N HCl (1×20 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 0-30% EtOAc-hexane gradient to give 2-methyl-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.094 g, 71% yield) as a colorless oil: MS (ESI): m/z 313 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[NH:14][CH2:13][CH2:12][CH2:11]3.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH2:24][CH3:25]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:14]([CH2:23][CH2:24][CH3:25])[CH2:13][CH2:12][CH2:11]3
Reactant: CCCI
Reactant: COc1cccc2c1C[C@H]1CCCN[C@@H]1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCC[C@@H]2Cc3c(cccc3OC)C[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 g of trans-1,2,3,4,4a,5,10,10a-octahydro-6-methoxybenzo[g]quinoline are dissolved in 100 ml of dimethylformamide. 3.8 g potassium carbonate and 1.8 ml of n-propyl iodide are subsequently added and the obtained suspension is stirred for 2 days at room temperature.
Reaction SMILES: Cl[Si:2]([CH3:20])([CH3:19])[CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:18].[CH3:21][C:22]1[CH-:26][C:25]([CH3:27])=[C:24]([CH3:28])[C:23]=1[CH3:29].[Na+]>O1CCCC1>[CH3:19][Si:2]([CH3:20])([CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:18])[C:26]1[CH:25]([CH3:27])[C:24]([CH3:28])=[C:23]([CH3:29])[C:22]=1[CH3:21]
Reactant: Cc1[cH-]c(C)c(C)c1C
Reactant: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1=C(C)C(C)=C(C)C1C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a light yellow solution of chlorodimethyl(2-methyl-4-phenyl-1H-indenyl)silane (9.40 g, 31.4 mmol, 1.00 eq.) in tetrahydrofuran (40 mL) at −30° C. was added sodium (tetramethylcyclopentadienide) (4.76 g, 33.0 mmol, 1.05 equiv.) in portions to give a cloudy orange solution. The reaction was allowed to warm to room temperature and stirred for 23 hours. The mixture was evaporated under vacuum leaving an orange residue. The residue was extracted with pentane (50 mL) and the extract was filtered to give a bright yellow solution and yellow solid. The solution was evaporated under vacuum to yield thick, orange oil. Yield 10.16 g (84%). 1H NMR (C6D6): δ 7.61 (d, 2H), 7.41 (m, IH), 7.31 (m, 4H), 7.19 (m, IH), 6.85 (s, IH), 3.60, (s, IH), 3.16 (br s, IH), 2.00 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H), 1.82 (s, 6H), −0.23 (s, 3H), −0.24 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([N:18]4[CH2:23][CH2:22][C:21]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][C:19]4=[O:34])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:35][N:4]1[CH:5]=[CH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([N:18]4[CH2:23][CH2:22][C:21]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][C:19]4=[O:34])[CH2:16][CH2:17]3)=[CH:11][CH:10]=2)=[CH:8][C:3]1=[O:2]
Reactant: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccnc(OC)c4)cc3)CC2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccn(C)c(=O)c4)cc3)CC2)C(=O)O1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of 3-(1-(4-(2-methoxypyridin-4-yl)phenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (26.5 mg, 0.058 mmol), K2CO3 (16 mg, 2 equiv), iodomethane (250 μL, excess) and acetonitrile (3 mL) was heated at 90° C. for 1.5 h in the microwave oven. LC-MS found the reaction was complete. The mixture was filtered, concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford the title compound (22 mg, 83%). LC-MS Method 1 tR=1.68 min, m/z=455.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][C:14]3=[O:27])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 200 mg of 6-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (bs, 1H), 8.64 (d, 1H, J 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, 1H, J 9.0 Hz), 7.23 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 12.3, 2.9 Hz), 3.30 (dd, 1H, −16.3, 12.3 Hz), 2.87 (dd, 1H, −16.3, 2.9 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[N:22]1([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(I)c1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-n2ccnc2)c1
Temperature: 90 °C
Reaction time: 70 h

Procedure:
3-Iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 204 mg, 0.5 mmol), 1H-imidazole (68.1 mg, 1 mmol), CuI (9.52 mg, 0.050 mmol), L-proline (11.51 mg, 0.100 mmol), K2CO3 (138 mg, 1.000 mmol) and DMSO (500 μL) were added to a vial, which was sealed, evacuated/purged with argon and the RM stirred at 90° C. for 70 h. The RM was diluted with DCM/EtOAc, filtered and stirred with of Chelex® 100 (950 mg). The mixture was washed with sat. aq. Na2CO3, brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH+1% NH4OH from 2% B to 10% MeOH+1% NH4OH) to afford the title compound as an off white powder. UPLC-MS (Condition 1) tR=1.55 min, m/z=348 [M+H]+, m/z=346.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.16 (s, 1H) 7.40 (d, J=8.8 Hz, 2H) 7.69 (t, J=7.9 Hz, 1H) 7.85-7.93 (m, 2H) 7.90 (d, J=9.0 Hz, 3H) 8.18 (s, 1H) 8.37 (s, 1H) 10.52 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](=[O:8])[CH3:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:16](Cl)([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:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[Cl-].[Na+].O>[C:17]1([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:1]2[CH:5]=[C:4]([C:6](=[O:8])[CH3:7])[N:3]=[CH:2]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(1H-imidazol-4-yl)ethanone (200 mg, 1.82 mmol) in DMF (4 mL) was introduced triethylamine (0.38 mL, 2.72 mmol) and trityl chloride (506.34 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 2 h. Aqueous brine solution (5 mL) was added to the reaction mixture and the product extracted with EtOAc (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute, 1-10% methanol gradient in DCM) to give the title intermediate as a clear oil: 1H NMR (500 MHz, CDCl3) delta 2.55 (3H, s), 7.18-7.06 (6H, m), 7.40-7.29 (9H, m), 7.44 (1 H, d, J=1.3 Hz), 7.58 (1H, d, J=1.4 Hz); LC-MS: m/z=+375.10 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]1([S:16][CH2:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: CN1CCCC1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCSc1ccccc1
Yield: 10012.5 %

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (1.30 g, 0.08 mmole), thiophenol (1.00 g, 9.08 mmole), potassium carbonate (12.56 g, 90.8 mmole) and DMF (18 mL) were combined, yielding 1.77 g (8.01 mmole, 89%) of the desired compound.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[S:18]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:20])(=[O:19])[NH2:21]
Reactant: NS(N)(=O)=O
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CO
Product: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Yield: 64.6 %

Procedure:
In 30 ml of methanol was dissolved 4.09 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and then 15 ml of a methanol solution of 2.88 g of sulfamide was added to the solution under refluxing. After refluxing for about 3 hours, the solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) as the developing solvent to provide 3,26 g of N-sulfamoyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physical chemical properties:
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8](=[O:10])[C:7]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.C[O-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]#[N:40])=[CH:29][CH:28]=1>C(O)(C)C.O.CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]#[N:40])=[CH:31][CH:32]=2)[C:8](=[O:10])[C:7]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h

Procedure:
A RB flask was charged with 2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one (7.0 g), toluene (70 ml), DMF (30 ml) and sodium methoxide (2.2 g) at room temperature and stirred for 15 min, followed by the addition of 4-(bromomethyl)-2′-cyanobiphenyl (10 g). The reaction mixture was stirred for 1 hour and then quenched by the addition of water (100 ml). The layers were separated and organic layer was evaporated to get oily residue. The obtained residue was taken in isopropyl alcohol (10 ml) and water (10 ml) and stirred at room temperature to get solid material. The solid material was filtered and washed with IPA and water mixture and then dried under vacuum.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[C:8](=[O:14])[NH:9][C:10](=[O:13])[C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.[OH-].[K+].S(O[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>C(O)C.CS(C)=O.O>[O:14]=[C:8]1[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:12][C:11]=2[C:10](=[O:13])[N:9]1[CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:34][CH2:35]1
Reactant: O=C1NC(=O)c2cc3c(cc21)OCO3
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C2=O)OCO4)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a 1 L reaction vessel, 52 g (0.27 mol) of [1,3]dioxolo[4,5-f]isoindole-5,7-dione (compound V-1, synthesized according to the method in the references: J. Am. Chem. Soc., 1951, 73, 1371 and J. Am. Chem. Soc., 1963, 85, 473) and 320 ml dimethyl sulfoxide was added, and the mixture was stirred and heated to 60° C., 110 ml solution of 23.4 g (0.42 mol) of potassium hydroxide in ethanol was added after the solid was completely dissolved, the resulting mixture was stirred for 15 min, and then 160 ml solution of 117 g (0.31 mol) of tert-butyl 4-[2-(tosyloxy)ethyl]piperidine-1-carboxylate (compound VI-1, synthesized according to the method disclosed in the PCT application WO2007082731) in dimethyl sulfoxide was added, after addition, the reaction was kept at 60° C. for 5 h until the reaction was completed, 500 ml ethyl acetate and 300 ml water were added, extraction was carried out and the organic layer was collected, dried over sodium sulfate, filtered, the filtrate was concentrated to dry, and 102.2 g crude product was obtained, it was separated by column chromatography, and 72 g compound XI was obtained, with yield of 65.8%. 1H NMR (DMSO-d6): δ 0.90-1.00 (m, 2H), 1.36 (s, 10H), 1.46 (q, 2H, J=7.0 Hz), 1.66 (d, 2H, J=11.9 Hz), 2.62 (br s, 2H), 3.51 (t, 2H, J=7.0 Hz), 3.88 (d, 2H, J=11.5 Hz), 6.24 (s, 2H), 7.32 (s, 2H); MS (ESI): m/z 425 [M+Na]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:22][C@@H:23]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 155 g) and (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (CAN 2743-40-0) as starting materials. MS (EI): m/e=413.2 [M+H]+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C@@H:43](O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C@@H:43]([CH3:42])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC[C@@H](C)O
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(OC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To an argon-flushed flask containing 2.32 g (8 mmol) of 4'-hydroxy-4-biphenylyl benzoate and 1.25 eq of triphenylphosphine in 200 ml of dry THF was added a solution of 1.052 g (8.08 mmol) of (R)-2-octanol dissolved in 15 ml of dry THF via syringe. Then 1.2 eq of diethyl azodicarboxylate in 30 ml of dry THF was added dropwise over 30 min. The reaction mixture was stirred at room temperature for 20 h and then 5 drops of water was added and stirring was continued for an additional 1 h. The solvent was evaporated and the crude product was triturated for 1 h in a mixture of hexanes/ethyl acetate [70/30]. The solution was filtered through a short silica gel pad and the solvent evaporated. Flash chromatography on silica gel using hexanes/ethyl acetate [98/2] as eluent afforded 2.42 g (75%) of (S)-4'-(1-methylheptyloxy)-4-biphenylyl benzoate (Compound 39, Scheme VIII, R2 =(S)-OCH(CH3)C6H13) as a white solid (mp. 84° C.); Rf [hexanes/ethyl acetate 95/5]: 0.34; 1H NMR (300 MHz, CDCl3): δ 0.89(t, 3H, J=6.8 Hz), 1.14-1.68(m, 9H), 1.32(d, 3H, J=6.1 Hz), 1.75(m, 1H), 4.39(m, 1H), 6.95(d, 2H, J=9 Hz), 7.25(d,2H, J=8.4 Hz), 7.46-7.68(m, 7H), 8.22(dd, 2H, J=1.2 Hz J=6.9 Hz); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.73, 22.55, 25.50, 29.24, 31.75, 36.48, 73.96, 116.10, 121.88, 127.72, 128.58, 129.61, 130.21, 132.64, 133.59, 138.79, 149.87, 157.94, 165.30; IR (CHCl3): 3020, 2930, 2850, 1745, 1600, 1500, 1260, 1240, 1170, 1190, 1070, 1000, 840, 820 cm-1 ; Mass spectrum, m/z(rel.intensity): 402(M+ 16), 290(14), 105(100), 77(16), 43(6).