Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]([F:62])([F:61])[C:53]1[CH:60]=[CH:59][C:56](CO)=[CH:55][CH:54]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][C:56]2[CH:59]=[CH:60][C:53]([C:52]([F:62])([F:61])[F:51])=[CH:54][CH:55]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccc(C(F)(F)F)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 64 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (105 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-trifluoromethylbenzyl alcohol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 48%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.FC1C(O)=C(F)C(F)=C(F)C=1F.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.Cl.[NH2:62][CH2:63][CH2:64][C:65]1[N:69]=[CH:68][NH:67][CH:66]=1>C(OCC)(=O)C.CN(C)C=O>[NH:67]1[CH:66]=[C:65]([CH2:64][CH2:63][NH:62][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])[N:69]=[CH:68]1
Reactant: NCCc1c[nH]cn1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1c[nH]cn1
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.401 g, 1.01 mmol) in dry ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added pentafluorophenol (0.189 g, 1.03 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.200 g, 1.04 mmol). This mixture was stirred 2 hours, then triethylamine (0.36 mL, 2.6 mmol) and histamine dihydrochloride (0.240 g, 1.30 mmol) were added. After stirring an additional 40 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with water. The organic phase was dried over MgSO4, concentrated, purified by flash chromatography (SiO2, 4×20 cm, 230-400 mesh, 10% methanol/dichloromethane eluant), and dried for 48 hours under vacuum at 70° C. to provide 0.234 g (47%) of product; 1H NMR (CDCl3) δ1.40-1.60 (2H, m), 1.57 (3H, s), 1.65-2.00 (13H, m), 2.65-2.75 (2H, m), 3.25-3.45 (4H, m), 4.82 (1H, br s), 5.42 ([H, br s), 6.67 (1H, s), 6.81 (1H, br s), 6.91 (1H, br s),7.00-7.20 (2H, m), 7.34 (1H, d, J 7 Hz), 7.46 (1H, s), 7.55 (1H, d, J 7 Hz), 8.67 (1H, br s).
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:43]=[CH:42][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]4[CH2:40][N:39]([CH3:41])[CH2:38]4)[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[C:19]([F:44])[CH:18]=1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[F:44][C:19]1[CH:18]=[C:17]([NH:16][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)=[S:57])[CH:43]=[CH:42][C:20]=1[O:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]2[CH2:32][CH2:33][N:34]([CH:37]3[CH2:40][N:39]([CH3:41])[CH2:38]3)[CH2:35][CH2:36]2)=[O:30])[CH:23]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (29.4 mg) to a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (31.8 mg) in ethanol (1.5 ml), the mixture was stirred for 10 minutes at room temperature. A solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 0.634 ml) was added thereto, and stirring was carried out at room temperature for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated, and the residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and saturated aqueous sodium hydrogencarbonate was added to the residue. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was concentrated to provide the title compound (8.0 mg, 16.9%) as white powder.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.[CH2:20]([O:27][CH:28]1[CH2:31][CH:30]([NH2:32])[CH2:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.CCOC(C)=O>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[NH:32][C@H:30]1[CH2:31][C@@H:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:29]1
Reactant: Clc1nc2ccccc2s1
Reactant: NC1CC(OCc2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: c1ccc(CO[C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)cc1
Temperature: 130 °C

Procedure:
A mixture of N-ethyl-N-isopropylpropan-2-amine (3 g, 24 mmol), 2-chlorobenzo[d]thiazole (2.0 g, 12 mmol), and 3-benzyloxy-cyclobutylamine (2.08 g, 12 mmol) in DMA (20 mL) was heated to 130° C. for 20 h. Then it was cooled to RT and diluted with EtOAc (50 mL). The mixture was washed with water (2×25 mL), brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography (0 to 30% EtOAc/hexane gradient) to give two products as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:3]=2[C:2]([F:1])([F:17])[F:18])=[CH:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1cc(Cl)ccc1Oc1ccccc1
Solvent: S=C=S
Product: CC(=O)c1ccc(Oc2ccc(Cl)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In this preparation 23.18 g (0.085 mol) of 4-(2-trifluoromethyl-4-chlorophenoxy)-benzene and 6.66 g (0.085 mol) of acetyl chloride are admixed with 200 ml of carbon disulfide and then 27.52 g (0.17 mol) of ferric chloride is added and the resulting mixture stirred at room temperature for about 23 hours. The mixture is then washed three times with ice-water, dried over magnesium sulfite and filtered. The filtrate is evaporated to dryness and the residue chromatographed on a silica gel column eluting with hexane; 5 vol.% tetrahydrofuran-hexane; and then 10 vol.% tetrahydrofuran-hexane, affording 1-acetyl-4-(2-trifluoromethyl-4-chlorophenoxy)-benzene.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH:15](OC)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.C[C:27](C)=[O:28]>>[CH3:27][O:28][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COC(Br)C(=O)c1ccccc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccccc3OC)cs2)c(C)s1
Yield: 95 %

Procedure:
Methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)-5-methylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2-methoxy acetophenone (0.467 mmol; 110 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the solution concentrated. The crude product was dissolved in 100 mL of CH2Cl2 and washed one time with 50 mL of 1N NaOH. The organic layer was obtained, dried over sodium sulfate, concentrated and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 160 mg (95% yield) of methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11]C1CCCC1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O.[Si](OCCN)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:19][C:18]([CH3:22])([CH3:21])[CH3:17])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Agent: CC(C)(C)[Si](C)(C)OCCN
Product: CC(C)(C)CNCCO[Si](C)(C)C(C)(C)C

Procedure:
This compound was prepared following the same method as described for [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) from 2,2-dimethyl-propionaldehyde (1 g, 11.61 mmol) and 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (2.0 g, 11.6 mmol) as colorless oil (1.1 g, 38.6%).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9]1.[CH3:21][NH:22][CH3:23]>C(=O)(O)[O-].[Na+]>[CH3:21][N:22]([CH3:23])[S:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][C:3]2[NH:2][CH2:6][CH2:5][N:4]=2)[CH:9]=1)(=[O:19])=[O:18]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1cn(CC2=NCCN2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1cn(CC2=NCCN2)c2ccccc12
Reaction time: 0.25 h

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonyl chloride hydrochloride (0.297 g, 1 mmol) was dissolved in 1-methylpyrrlolidinone (14 mL) and stirred. Excess dimethylamine in 1-methylpyrrlolidinone was added to the stirring solution, after which the mixture was allowed to stand at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate (30 mL) was then added, and the mixture was evaporated to dryness. The residue was purified by preparative HPLC to provide 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonic acid dimethylamide as a crystalline solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([OH:3])=[O:2].CO.[C:29](OCC)(=O)C>C(Cl)Cl>[CH3:29][O:2][C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:3]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Carboxyphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.57 mmol) obtained in Example 52 is dissolved in methylene chloride (10 ml), and thereto are added 1-ethyl-3-(3′-dimethyl aminopropyl)-carbodiimide.hydrochloride (0.13 g, 0.68 mmol) and methanol (0.10 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added ethyl acetate (100 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give the title compound (0.17 g) as colorless oil.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:19][N:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC[K]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CNC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)N(C)C1CCCCC1
Yield: 50.2 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and N-methylcyclohexylamine (1.15 g) to give 0.64 g of ethyl N-methyl-N-cyclohexyl-2,3-epoxysuccinamate (Compound No. 31) as colorless needles melting at 52°-55° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:14].O1CCCC1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:30])[OH:26])=[C:3]([CH3:14])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(CC)c1ccc(B(O)O)c(C)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol (19.4 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 23.3 cm3 (58 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the mixture for approximately 2 h with stirring at −70° C. and then add dropwise 13.5 cm3 of triisopropyl borate (58 mmol), over 20 minutes. Leave the mixture with stirring for 3 h, allowing the temperature to increase to −10° C. Hydrolyse the mixture with saturated NH4Cl solution and extract two times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and dry them over sodium sulfate. Evaporate the solvents under vacuum. This gives 5 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=9/1) to give 4-(1-ethyl-1-hydroxypropyl)-2-methylphenylboronic acid in the form of a highly viscous oil. (Yield=71%)
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:20].C([Cl:24])(=O)C>C(#N)C>[ClH:24].[CH3:1][N:2]([CH2:4][CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[CH:19][C:10]=2[O:9][CH3:8])[C:15]1=[O:20])[CH3:3]
Reactant: COc1cccc2c1CCCC2=O
Reactant: CC(=O)Cl
Reactant: CN(C)CN(C)C
Solvent: CC#N
Product: COc1cccc2c1CCC(CN(C)C)C2=O
Product: Cl
Reaction time: 3 h

Procedure:
3.9 ml of bis-(dimethylamino)-methane were added to a solution of 5 g of 5-methoxy-1-tetralone in 12 ml of acetonitrile; 2.0 ml of acetic acid chloride were added dropwise at from 0 to 10° C., a further 10 ml of acetonitrile were added, and stirring was carried out for 3 hours at 50° C. and then for 18 hours at room temperature. The resulting solid was filtered off with suction, washed twice with diethyl ether and dried in vacuo (yield 6.4 g).
Reaction SMILES: [CH3:1][N:2]1[CH:10]2[CH:6]([CH2:7][C:8]([P:15]([OH:18])(=[O:17])[OH:16])([P:11]([OH:14])(=[O:13])[OH:12])[CH2:9]2)[CH2:5][CH2:4][CH2:3]1.[C:19]([S:22][CH2:23][CH2:24][Br:25])(=[O:21])[CH3:20].C>O.CS(C)=O>[Br-:25].[P:11]([C:8]1([P:15]([OH:16])([OH:18])=[O:17])[CH2:9][CH:10]2[CH:6]([CH2:5][CH2:4][CH2:3][N+:2]2([CH2:24][CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH3:1])[CH2:7]1)([OH:12])([OH:14])=[O:13]
Reactant: CN1CCCC2CC(P(=O)(O)O)(P(=O)(O)O)CC21
Reactant: CC(=O)SCCBr
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)SCC[N+]1(C)CCCC2CC(P(=O)(O)O)(P(=O)(O)O)CC21
Product: [Br-]

Procedure:
Octahydro-1-methyl-1-pyrindine-6,6-diphosphonic acid (0.12 mmol) is dissolved in a mixture of water (25 ml) and DMSO (5 ml). To this is added 2-acetylthioethyl bromide (0.60 mmol) and the reaction mixture is heated at 60° for 24 hours. The reaction mixture is cooled, treated with charcoal, filtered and concentrated under reduced pressure. The crude residue is triturated with diethylether and the product can be obtained by recrystallizing the solid residue in water and isopropanol.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=O)C.[OH-].[Li+]>O1CCCC1.CO.O>[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(OC)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(S(=O)(=O)c2ccc3[nH]ccc3c2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of the product of step D (25 mg, 0.04 mmol), lithium hydroxide (14 mg, 0.32 mmol) in tetrahydrofuran (1.25 mL), methanol (0.62 mL) and water (0.31 mL) was stirred at ambient temperature for 8 h. The reaction was quenched with aqueous ammonium chloride (15 mL) and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) to give tert-butyl 8-((1H-indol-5-yl)sulfonyl)-6-methoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (18 mg, 83%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.62 (s, 1H), 8.33 (s, 1H), 7.77-7.62 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.35-7.30 (m, 1H), 6.70-6.64 (m, 1H), 4.53 (s, 2H), 4.02 (s, 3H), 3.80 (t, J=5.4 Hz, 2H), 2.92-2.76 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]3[CH:18]=[CH:19][N:20]([CH3:21])[C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:24]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:24][C:18]1[C:15]2[CH:16]=[N:17][C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:22]=[CH:23][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[CH:13][C:14]=2[N:20]([CH3:21])[CH:19]=1
Reactant: Cn1ccc2cnc(NC(=O)c3ccc(C(C)(C)O)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc(C(C)(C)O)cc3)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
In a 125 ml round bottom flask, 4-(2-hydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (2.8 g, 9.05 mmol) was dissolved in DMF (25 ml). To this was added N-chlorosuccinimide (1.5 g, 11 mmol) and the mixture was stirred at 50° C. for 3 hours. The mixture was then poured into 50 ml water and then extracted with ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by preparatory HPLC (RFA-mode: eluting with 25-55% ACN in water). Fractions containing the desired mono chlorinated product were combined and concentrated. To the residue was added saturated NaHCO3 and the aqueous mixture was extracted with ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated to obtain the title compound (840 mg, 27% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.26 (m, 1 H) 1.46 (s, 139 H) 3.66-3.86 (m, 3 H) 5.17 (s, 1 H) 7.40-7.69 (m, 3 H) 8.01 (d, J=8.59 Hz, 2 H) 8.34 (s, 1 H) 8.59 (s, 1 H) 10.68 (s, 1 H)
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35].[C:36](OCC)(=O)C>>[ClH:35].[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:36]3)=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Reaction time: 0.01 h
Yield: 89 %

Procedure:
To a solution of the product of Example 7 (8.7 g, 18.5 mmol) stirring in ethyl acetate (100 mL) was added a saturated solution of hydrochloric acid gas in ethyl acetate (250 mL). After 0.5 min, the resulting solution was concentrated to give 8.0 g (89%) of the desired product as a white foam which was used without further purification: 1 -NMR (300 MHz, DMSO) δ 7.70-7.85 (m, 4H), 7.30-7.50 (m, 7H), 7.10 (s, 1H), 6.80-7.00 (m, 2H), 4.25-4.40 (m, 4H), 4.00-4.20 (br s, 3H), 3.35-3.55 (m, 4H), 2.85-3.55 (m, 2H) , 1.70-1.90 (m, 4H) , 1.30-1.45 (m, 2H); Anal. Calc'd for: C, 76.29; H, 7.02; N, 2.87. Found: C, 76.56; H, 7.18; N, 2.91; MS (FD) m/e 452 (M+-hydrochloric acid).
Reaction SMILES: C(O)(=O)C.C[O:6][C:7](=[O:35])[C@@H:8]([NH:15][C:16](=[O:34])[CH:17]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:36]>O.C(O)(=O)C>[ClH:36].[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:17]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]([NH:15][C@@H:8]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:7]([OH:35])=[O:6])=[O:34])=[CH:24][CH:23]=1)(=[NH:26])[NH2:27]
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)O)C2CCCCC2)C2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
[3-(4-Carbamimidoyl-phenyl)-2-(R,S)-cyclohexyl-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester acetic acid salt was dissolved in a mixture of hydrochloric acid (100 ml), water (100 ml) and acetic acid (50 ml) within 1 hour. After 15 hours stirring at room temperature and 8 hours at 50° C., the mixture was evaporated and after addition of water lyophilized to yield a diastereomeric mixture (2.7 g, 72% step g and h) of the desired product. MS m/z: 414.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:21])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(N=C=NC2CCCCC2)CCCCC1.[O:37]1[CH2:39][CH:38]1[CH2:40]O>C(Cl)Cl>[O:37]1[CH2:39][CH:38]1[CH2:40][O:19][C:18]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[C:10]([F:21])[CH:11]=2)[CH2:17][CH2:16]1)=[O:20]
Reactant: OCC1CO1
Reactant: O=C(O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OCC1CO1)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
1-(3′,4′-Dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (2.00 g, 6.15 mmol), dicyclohexylcarbodiimide (DCC, 2.54 g, 12.30 mmol), 4-dimethyl-aminopyridine (DMAP, 0.075 g, 0.614 mmol), and oxiran-2-ylmethanol (0.490 ml, 7.38 mmol) were dissolved in dry DCM (40 mL). The reaction mixture was stirred at room temperature (r.t.) overnight, then it was filtered and the filtrate was evaporated to dryness to afford 4.4 g of crude. The crude was purified by gradient flash chromatography eluting with petroleum ether/EtOAc (from 97/3 to 90/10 v/v) to afford 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid oxiranylmethyl ester (1.0 g, 42.6% yield).