Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CO.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[Na].[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([CH3:28])[N:22]=1>CS(C)=O>[Cl:20][C:21]1[N:26]=[C:25]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[CH:11][CH:12]=2)[CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc(Oc2ccc(NC(=O)N(C)C)cc2)nc(Cl)n1

Procedure:
4-Hydroxyphenyl-N,n-dimethylurea (14.4 grams; 0.08 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (1.84 grams) in 50 milliliters (ml) of methanol) and the resulting sodium 4-hydroxyphenyl-N,N-dimethylurea solution added gradually over a period of about one hour to a solution of 2,4-dichloro-6-methylpyrimidine (13.04 grams; 0.08 mole) in 70 ml. of dimethylsulfoxide. During the addition, the reaction temperature rose from about 52°C. to a temperature from between about 60° to about 65°C. The resulting reaction mixture was maintained at temperatures from between about 60° to about 70°C. for a period of about 80 minutes. Following the reaction period, the reaction mixture was poured into about 400 ml. of cold water and the resulting tan product precipitate recovered by filtration and washed with additional portions of water. The product precipitate was dissolved in boiling benzene and the resulting solution treated with activated charcoal. Approximately one-half of the solvent was removed by evaporation and the remaining portion was cooled to crystallize the product. As a result of these operations, the desired title product was obtained as a light tan crystalline solid having a melting point of 176°-178°C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:18][C:19]([C:21]1[CH:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1)=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)=[O:20])[C:3]([OH:28])=[O:2])=[CH:11][CH:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Cl)ccn1
Product: COc1ccc(-c2ccnc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 46.4 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (80 mg, 0.20 mmol) was reacted with 4-methoxy phenylboronic acid (61 mg, 0.40 mmol) as described in general procedure D to afford the title compound (42 mg, 46%) as a light yellow solid. LC/MS (m/z): 453 (M+1)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>>[CH:14]([NH:18][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)N
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: CCC(C)NS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid with sec-butyl amine to produce 3-(sec-butylsulfamoyl)benzoic acid which was purified by reverse phase HPLC.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:6]=1[C:7]([NH:9]/[CH:10]=[CH:11]\I)=[O:8].Cl>[Br-].[Zn+2].[Br-].C(OCC)C.C1COCC1.CN(C=O)C>[F:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:6]=1[C:7]([NH:9]/[CH:10]=[CH:11]\[CH3:1])=[O:8]
Reactant: O=C(N/C=C\I)c1c(F)cccc1F
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C/C=C\NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
Zinc bromide (1.68 g, 7.48 mmol) was added in portions to a solution of MeMgBr in diethyl ether (3M, 2.4 ml, 7.23 mmol).After stirring at room temperature there was a thick prepicipitate. Some DMF and THF was added to improve solubility and aid stirring. 2,6-difluoro-N—[(Z)-2-iodovinyl]benzamide (746 mg, 2.41 mmol) was added and then dichloro-bisacetonitrile palladium (12.5 mg, 0.048 mmol) was added, and the mixture stirred overnight at RT and then shaken between diethyl ether and HCl (1 M), dried with MgSO4, evaporated and chromatographed with EtOAc/cyclohexane to yield pure 2,6-difluoro-N—[(Z)-prop-1-enyl]benzamide (406 mg, 86%) m.p. 71-74° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[O:24]1[CH2:3][CH:2]1[CH2:1][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8]
Reactant: C=CCOc1cccc([N+](=O)[O-])c1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1c(OCC2CO2)cccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
22.5 g of 2-allyloxy-6-nitro-benzonitrile are introduced into a solution of 26.8 g of m-chloroperbenzoic acid (85% strength) in 1 liter of chloroform and the mixture is warmed to 50° in the course of 3 hours. The reaction mixture is kept at this temperature for 24 hours and then cooled and the solution is washed with 100 ml of 1 M sodium sulphite solution, then with 100 ml of 2 N sodium hydroxide solution and finally with 100 ml of water. After drying over magnesium sulphate and evaporating the solution, a colourless crystalline residue is obtained and this is ground with 20 ml of isopropanol, the mixture is filtered and the material on the filter is dried in vacuo, after which crude 2-(2,3-epoxypropoxy)-6-nitro-benzonitrile with a melting point of 131°-135° is obtained and this is used further in the form of the crude product.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1)[CH3:4].[C:15]([OH:22])(=[O:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20]>>[OH:1][CH2:2][CH:3]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][C:15]([OH:22])=[O:21])[CH:10]=[CH:11][CH:12]=1)=[O:14])[CH3:4]
Reactant: C#CCCCC(=O)O
Reactant: CC(CO)NC(=O)c1cccc(I)c1
Product: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Yield: 99 %

Procedure:
The iodobenzamide (1) (2.00 g, 6.5 mmol) was coupled with 5-hexynoic acid using method B giving product (4) (1.87 g, 6.42 mmol; 99% yield).
Reaction SMILES: C[C:2]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=1)C(=O)[O-])(C)C.B.C1COCC1>C1COCC1>[Br:17][C:12]1[CH:11]=[C:10]([CH2:9][NH:5][CH3:2])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: CC(C)(C)N(Cc1ccc(F)c(Br)c1)C(=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: CNCc1ccc(F)c(Br)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To the solution of 1,1-dimethylethyl[(3-bromo-4-fluorophenyl)methyl]carbamate (0.755 g, 2.48 mmol) in THF (1 mL) was added BH3.THF (12.5 mL, 1.0 M in THF). The mixture was heated in a microwave machine at about 80° C. for about 30 mins twice. The reaction was then quenched with HCl (10 mL, 1 N) slowly, stirred for 2 h at room temperature, basified with NaHCO3 to pH ˜9, and extracted with EtOAc (50+20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated to afford 0.52 g (96%) of the title compound. LC-MS m/z 218 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17])[C:10](=O)[CH2:9][CH2:8]2.CC1C=CC(N=[CH:27][C:28]2[C:29]([NH2:37])=[CH:30][C:31]3[O:35][CH2:34][O:33][C:32]=3[CH:36]=2)=CC=1>>[CH3:17][O:16][CH2:15][O:14][C:13]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][C:7]2[CH2:8][C:9]3[C:10]([C:11]=2[CH:12]=1)=[N:37][C:29]1[CH:30]=[C:31]2[O:35][CH2:34][O:33][C:32]2=[CH:36][C:28]=1[CH:27]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COCOc1cc2c(cc1OCOC)C(=O)CC2
Product: COCOc1cc2c(cc1OCOC)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 40.2 %

Procedure:
Using the procedure of Example 1, 5,6-dimethoxymethoxyindan-1-one (504 mg, 2 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (508 mg, 2 mmol) to yields 7,8-dimethoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (307 mg, 40% of theory).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:68]1[CH:69]=[C:70]([C:78]([CH:80]2[CH2:85][CH2:84][N:83]([CH3:86])[CH2:82][CH2:81]2)=[O:79])[CH:71]=[C:72]([C:74]([F:77])([F:76])[F:75])[CH:73]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([C:1](=[N:14][C:68]2[CH:69]=[C:70]([C:78]([CH:80]3[CH2:81][CH2:82][N:83]([CH3:86])[CH2:84][CH2:85]3)=[O:79])[CH:71]=[C:72]([C:74]([F:75])([F:76])[F:77])[CH:73]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)c2cc(Br)cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cc(N=C(c3ccccc3)c3ccccc3)cc(C(F)(F)F)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Add benzophenone imine (195 mg, 1.07 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 37 mg, 0.059 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 25 mg, 0.027 mmol] and cesium carbonate (585 mg, 1.79 mmol) to the solution of (3-bromo-5-(trifluoromethyl)phenyl)(1-methylpiperidin-4-yl)methanone (251 mg, 0.717 mmol) in dioxane (5 mL), then stir the reaction mixture overnight at 100° C. Upon reaction completion, filter the mixture and concentrate the filtrate under reduced pressure. Purify the residue with flash chromatography (silica gel, PE:EtOAc=1:1) to afford the product (210 mg, 65%). MS: (M+1): 451.2.
Reaction SMILES: [I:1]I.[OH-].[K+].[N+:5]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[I:1][C:12]1[C:11]2[C:15](=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Iodine (2.14 g, manufactured by Kanto Chemical Co., Inc.) and potassium hydroxide (475 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added to a solution of 6-nitro-1H-indazole (690 mg, manufactured by Wako Pure Chemical Industries, Ltd.) in N,N-dimethylformamide (20 mL, manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred for one hour at room temperature. A saturated aqueous solution of sodium thiosulfate (20 mL) was added to the reaction solution, and the mixture was extracted with chloroform (3×20 mL), washed with brine (40 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.04 g of the title compound. LC-MS: HPLC retention time 0.54 minutes, m/z 290 (M+H), condition C-3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Product: N#Cc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-amino-3-nitrobenzonitrile and was obtained as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 11.58 (s, 1H), 9.18 (d, J=8.7, 1H), 9.04 (d, J=2.4, 1H), 8.65 (d, J=2.1, 1H), 8.26-8.22 (m, 1H), 8.00-7.96 (m, 1H), 7.56 (d, J=9.0, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:35][NH2:36]>C(O)C>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: CCO
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1
Temperature: 100 °C

Procedure:
To 3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e, 100 mg) in a 10 mL microwave vial was added methylamine (2 mL of a 33% solution in ethanol). This was sealed and heated within a CEM Discover microwave for 30 min at 100° C. The volatiles were removed in vacuo and the residue taken up in methanol and purified by preparative HPLC (ACE column, 0.1% TFA:acetonitrile eluent) afforded the title compound. This was dissolved in acetonitrile and filtered through SCX resin eluting with acetonitrile and methanol (discarded) followed by 7N NH3 in methanol. The basic fractions were collected and the volatiles were removed in vacuo. Trituration with diethyl ether afforded the title product as a white solid (46 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][CH2:11][Mg+].[Br-]>C1COCC1.O.Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:9][C:8]1([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: CC[Mg+]
Reactant: N#Cc1ccc(N)cn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C2(N)CC2)nc1
Reaction time: 23 h
Yield: 831.6 %

Procedure:
To a solution of 5-amino-2-cyanopyridine (1.0 g, 8.06 mmol) in dry THF (50 mL) was added titanium(IV) isopropoxide (5.2 mL, 17.7 mmol). EtMgBr (3.0M in Et2O, 10.7 mL, 32.2 mmol) was then added dropwise. The reaction mixture was stirred for 23 h, then diluted with water (100 mL) and 1N HCl (5 mL), and stirred for 5 min. The mixture was filtered and the filtrate was concentrated in vacuo to afford 6-(1-amino-cyclopropyl)-pyridin-3-ylamine as brown oil (10 g) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[S:7][N:6]=[C:5]([Cl:8])[C:4]=1[Cl:9])#[N:2].S1C=CC=N1.S(=O)(=O)(O)[OH:16]>>[Cl:8][C:5]1[C:4]([Cl:9])=[C:3]([C:1]([NH2:2])=[O:16])[S:7][N:6]=1
Reactant: N#Cc1snc(Cl)c1Cl
Reactant: O=S(=O)(O)O
Agent: c1cnsc1
Product: NC(=O)c1snc(Cl)c1Cl
Temperature: 110 °C

Procedure:
Concentrated sulfuric acid (10 ml) was added to 1.0 g of 5-cyano-3,4-dichloroisothiazole. When heated at 110° C. for 20 minutes, the isothiazole compound was dissolved completely. The reaction mixture was cooled under ice cooling, and precipitated crystals were collected by filtration. The crystals were then recrystallized from a 1:1 mixed solvent of ethanol and water.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCCCO)cc2)cc1
Yield: 97.6 %

Procedure:
30 m moles (14.1 g) of the above 4'-(12-acetyloxydodecyloxy)biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 11.7 g of 4'-(12-hydroxydodecyloxy)biphenyl-4-carboxylic acid. (yield: 98%)
Reaction SMILES: CS(O[CH:6]1[CH2:12][C@@H:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:8]([CH2:9][CH2:10]2)[CH:7]1[C:21]([O:23][CH3:24])=[O:22])(=O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C@H:8]12[N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:10][CH2:9]1)[CH2:12][CH:6]=[C:7]2[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1C(OS(C)(=O)=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Yield: 52.1 %

Procedure:
(1S,5R)-8-tert-butyl 2-methyl 3-(methylsulfonyloxy)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (14.22 g, 39.15 mmol) and DBU (58.55 mL, 391.15 mmol) in DMF (73.87 mL) were heated at 100° C. for 10 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic fractions were combined, dried with sodium sulfate and concentrated to give crude product. The crude was purified using flash chromatography (0-100% Ethyl Acetate in Hexane) to give 5.45 g of (1S,5R)-8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate.
Reaction SMILES: [P:1]([O:13][CH2:14][O:15][C@@H:16]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]1[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:65])[NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C@H:41]([CH2:50][CH2:51][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[CH2:42][S:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:36]([S:58]([C:61]([F:64])([F:63])[F:62])(=[O:60])=[O:59])[CH:35]=3)(=[O:33])=[O:32])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)([O:8]C(C)(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C1[C@H](NC(=O)OCC2C=CC=CC=2)CC(=O)O1>CC(C)=O>[P:1]([OH:8])([O:13][CH2:14][O:15][C@@H:16]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]1[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:65])[NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C@H:41]([CH2:50][CH2:51][N:52]4[CH2:53][CH2:54][O:55][CH2:56][CH2:57]4)[CH2:42][S:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[C:36]([S:58]([C:61]([F:63])([F:62])[F:64])(=[O:59])=[O:60])[CH:35]=3)(=[O:32])=[O:33])=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCO[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1)OC(C)(C)C
Agent: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Solvent: CC(C)=O
Product: CC(C)(C)OP(=O)(O)OCO[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 65 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
Nitrolotrimethanol (5.27 mg, 0.05 mmol) was added to a solution of di-tert-butyl ((R)-(4′-chlorobiphenyl-2-yl)(1-(4-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonylcarbamoyl)phenyl)piperidin-4-yl)methoxy)methyl phosphate (EXAMPLE 27, 58.0 mg, 0.05 mmol) in acetone (1.8 ml) and 0.6 ml of pH7.2 buffer (Gibco, Dulbecco's Phosphate Buffered saline 1×). The resulting reaction mixture was stirred at 65° C. for 16 hours. Evaporation of the volatiles under reduced pressure gave a residue which was purified by reverse phase HPLC (Gilson column, eluting with 30→50% H2O with 10 mM NH4OAc/MeCN for 5 minutes) to provide the title product (0.017 g, yield: 19%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](OC)=[O:11].NC1C=C(F)C=CC=1NC1SC2CCCCC=2C=1C(OCC)=O>>[Cl:18][C:16]1[CH:15]=[CH:14][C:3]2[NH:4][C:5]3[CH:9]=[CH:8][S:7][C:6]=3[C:10](=[O:11])[NH:1][C:2]=2[CH:17]=1
Reactant: COC(=O)c1sccc1Nc1ccc(Cl)cc1N
Agent: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2c1CCCC2
Product: O=C1Nc2cc(Cl)ccc2Nc2ccsc21

Procedure:
Methyl 3-(2-amino-4-chloroanilino)-thiophene-2-carboxylate, m.p. 255°-256° C. (EtOAc).
Reaction SMILES: [S-2:1].[Na+].[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][S:1][CH2:7][C:6]1[C:5]([Cl:4])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:13]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: [S-2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1cccc(Cl)c1CSCc1c(Cl)cccc1Cl
Yield: 80.4 %

Procedure:
A mixture of 98.8 g (0.411 mol) of sodium sulfide, 5.0 g of tetrabutylammonium hydrogen sulfate and 110 ml of water are stirred in a reaction vessel equipped with a stirrer, thermometer and heatable dropping funnel, until a solution is obtained. 107.2 g of melted 2,6-dichlorobenzyl chloride are added with vigorous stirring over a period of 25 minutes at such a rate that the inside temperature does not exceed 55° C. The reaction mixture is worked up as in Example 9a) to give 77.6 g (80% of theory) of bis(2,6-dichlorobenzyl) sulfide in the form of white crystals of melting point 128°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1C(=O)N(Br)C(=O)C1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:11][C:9]1[C:10]2=[C:2]([CH2:1][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnn2ccc(C)c12
Reactant: OC1CCNCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (200 mg, 1.12 mmol), NBS (218 mg, 1.23 mmol), and AKIN (spatula tip) in carbon tetrachloride (4 mL) was heated at 80° C. for 1 h. After cooling to rt, the solution was filtered to remove succinimide. To the filtrate was added 4-hydroxypiperidine (126 mg, 1.34 mmol, Aldrich) and DIPEA (214 μL, 1.23 mmol). The reaction was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (229 mg, 74%) as a colorless solid. 1 H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.88 (d, 1H, J=2 Hz), 6.81 (d, 1H, J=2 Hz), 4.54 (br s, 1H), 3.76 (s, 2H), 3.48-3.44 (m, 1H), 2.75-2.71 (m, 2H), 2.62 (s, 3H), 2.10-2.08 (m, 2H), 1.70-1.68 (m, 2H), 1.38-1.36 (m, 2H); MS(ESI+) m/z 279.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11]([OH:23])(=[O:22])[CH2:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[C:16]1([C:14]2[O:23][C:11](=[O:22])[C:12](=[CH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C2N=C(c3ccccc3)OC2=O)cc1
Yield: 83 %

Procedure:
20 ml of anisaldehyde, 50 ml of acetic anhydride, 33.7 g of hippuric acid and 6.7 g of sodium acetate were mixed well and heated on a water bath for 30 minutes. The precipitated crystals were washed with hot water and then filtered. They were then recrystallized from benzene and dried to obtain 40 g of 2-phenyl-4-(4-methoxybenzylidene)-5-oxazolone. Yield: 83%.