Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1.[CH3:45][O:46][CH2:47][CH2:48][O:49]CCO>C(Cl)Cl.ClCCCl>[CH3:45][O:46][CH2:47][CH2:48][O:49][CH2:35][CH2:30][O:29][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:22]3[CH2:23][CH2:24][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:6][CH:7]=1
Reactant: COCCOCCO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OCCOCCOC)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), DCE (0.4 mL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 h. 2-(2-methoxyethoxy)ethanol (150 μL, 1.25 mmol) is added. This mixture is heated at 80° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-(2-methoxy-ethoxy)-ethyl ester (51 mg, 89%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:4]=1[C:5]([O:7]C)=O)#[N:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:48][C:49]1([F:62])[CH2:54][CH2:53][CH:52]([N:55]2[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1>C(OC)(=O)C(C)(C)C.ClCCl.ClCCl.C(O)C>[F:62][C:49]1([F:48])[CH2:54][CH2:53][CH:52]([N:55]2[CH2:56][CH2:57][CH:58]([N:61]3[C:5](=[O:7])[C:4]4[C:3]([C:1]#[N:2])=[C:12]([F:13])[CH:11]=[CH:10][C:9]=4[CH2:14]3)[CH2:59][CH2:60]2)[CH2:51][CH2:50]1
Reactant: COC(=O)c1c(C)ccc(F)c1C#N
Reactant: NC1CCN(C2CCC(F)(F)CC2)CC1
Agent: COC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c(F)ccc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Temperature: 85 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
To a solution of methyl 2-cyano-3-fluoro-6-methylbenzoate (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 hours. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Triethylamine (0.41 mL, 2.9 mmol) and 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine (280 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90° C. for 3 hours. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (222 mg, 60% yield).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=2)[C:19]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]=2[O:39][CH3:40])=[CH:18]1.[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([Cl:49])=[CH:44][C:43]=1O>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([Cl:49])=[CH:44][C:43]=1[O:35][C:34](=[O:36])[C:33]1[CH:37]=[CH:38][C:30]([CH2:29][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[N:17]([CH3:16])[CH:18]=2)=[C:31]([O:39][CH3:40])[CH:32]=1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Oc2cc(Cl)c(Cl)cc2Cl)ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
1.66 g of dicyclohexylcarbodiimide are added at room temperature, with stirring and in a nitrogen atmosphere, to a mixture of 2.38 g of 4-(1-methyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid [Example 1, Process Step a1)], 1.48 g of 2,4,5-trichlorophenol and 1.0 g of 4-dimethylaminopyridine in 140 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 15 hours and filtered. The filtrate is concentrated by evaporation in vacuo at 50° and the residue is dissolved in 400 ml of chloroform, with heating. The organic phase is washed at room temperature with 50 ml of 2N hydrochloric acid and 50 ml of water and dried over magnesium sulfate, and the solution is concentrated to dryness at 40° under 11 torr. The residue is chromatographed on 350 g of silica gel (eluant: dichloromethane). The 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)-benzoic acid 2,4,5-trichlorophenyl ester obtained in that manner is suspended in 50 ml of ether and isolated by filtration. Yield 67%. Yellow crystals of m.p. 235°-236°.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:30].C(N(CC)CC)C.O>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:30][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]3)[C:15]=2[CH3:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A solution of 4-tert-butylbenzoyl chloride (5.24 g; 26.7 mmol) in dichloromethane (40 mL) was added portionwise to a solution of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4) (6.22 g; 26.7 mmol) and triethylamine (5.6 mL; 40.1 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 16 hr. Water (100 mL) was added and the mixture extracted with dichloromethane (3×70 mL). The combined organic layers were washed with water (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and evaporated under reduced pressure to give 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (5) as a white solid (9.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:25]=[CH:24][C:16]([CH:17]([CH3:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>CO.[Pd]>[CH3:22][O:21][C:19](=[O:20])/[CH:18]=[C:17](\[CH3:23])/[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[NH:2])[NH2:3])=[CH:27][CH:26]=2)=[CH:25][CH:24]=1.[C:19]([O-:21])(=[O:20])[CH3:18]
Reactant: COC(=O)CC(C)c1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)[O-]
Product: COC(=O)/C=C(\C)c1ccc(CCNC(=O)c2ccc(C(=N)N)cc2)cc1

Procedure:
From 190 mg of methyl,(E)-p-[2-(p-amidinobenzamido)ethyl]-β-methylcinnamate there were obtained after hydrogenation in methanol in the presence of 10% Pd/C under atmospheric pressure at room temperature after 24 hours 113 mg of crystalline acetate of methyl rac-p-[2-(p-amidinobenzamido) ethyl]-β-methyl-hydrocinnamate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1I)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.ClCCl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:26]=[C:27]([C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH2:8][CH3:9])[C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)OC(C)(C)C)c1
Temperature: 80 °C

Procedure:
(5-Bromo-2-iodo-benzyl)-ethyl-carbamic acid tert-butyl ester (2.0 g, 4.54 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.67 g, 5.21 mmol), and potassium carbonate (1.57 g, 11.4 mmol) were combined in DME:H2O (2:1) under nitrogen. The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.13 mmol) was added, and the reaction was heated to 80° C. for 36 hours. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and diluted with dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: N#N.[CH3:3]C[O-].[Na+].[CH2:7]([O:9][C:10](=[O:19])[CH:11]([C:16](=[O:18])[CH3:17])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:8].[I-]>C(O)C>[CH2:7]([O:9][C:10](=[O:19])[C:11]([C:16](=[O:18])[CH3:17])([CH3:3])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:8]
Reactant: CC[O-]
Reactant: C=C(C)CC(C(C)=O)C(=O)OCC
Agent: N#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CC(C)(C(C)=O)C(=O)OCC
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A 2000 ml flask, equipped with mechanical stirring, a condenser and N2 atmosphere, is charged with 24.3 g of N2 and 400 ml of ethanol to prepare sodium ethylate. After cooling to 15° C., the ethyl-2-acetyl-4-methyl-4-pentenoate (161.4 g) is added to the solution over 30 min while maintaining the temperature at 15° C.-20° C. To this is then added, all at once, 15 g of iodide. The exothermic reaction is controlled with an ice bath to keep the temperature at 30° C. for about 90 min. Stirring is continued over 2 hrs and 30 min at 20° C., and the mixture is then taken to reflux for 4 hrs. The reaction mixture is left at rest for 56 hrs, and then the NaI precipitate is filtered. Toluene (700 ml) is added and the mixture filtered again. Toluene/ethanol azeotrope (700 ml) (rotavapor. 74° C./6× 104Pa) is distilled and 250 ml of the distillate is added to the residue. After cooling to 5° C., a new filtration is carried out. The filtrate is evaporated (74° C./2.7×104Pa). Raw product is purified on a Vigreux column, and then in a glass bolos column topped by a total reflux head, to yield ethyl-2-acetyl-2,4-dimethyl-4-pentenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:26][CH2:27][S:28](=[O:30])(=[O:29])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccc(Cl)cn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 5-chloro-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}pyridin-2-amine (440 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 265 mg) and 2-chloroethanesulfonyl chloride (648 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (520 mg) as an off-white solid. The solid was crystallized from CH3CN—IPE to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([CH2:4][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1cccc(O)c1Cl
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CN2CCCC2)c1Cl
Yield: 90.7 %

Procedure:
2-Chloro-3-hydroxybenzaldehyde (4.5 g, 0.03 mol) was added in portions for 30 min to a mixture of pyrrolidine (3. mL, 0.036 mol) and NaB(OAc)3H (7.6 g, 0.036 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 3 h and cooled with an ice bath. Water (50 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.76 g, 95%) as white crystals. LCMS-data: (M+H)+ 214.0 and 212.0 (calculated for C11H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.95 (br. s, 1H, ArOH), 7.07 (t, 1H, J1=7.8 Hz, J2=15.7, Ar—H), 6.90 (dd, 1H, J1=1.5 Hz, J2=7.6 Hz, Ar—H); 6.85 (dd, 1H, J1=1.5, J2=9.5, Ar—H), 3.63 (s, 2H, ArCH2), 2.43-2.50 (m, 4H, pyrrolidine (CH2)2N), 1.63-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9]1[C:13]([C:14](C(N)C2C=CC(C(O)=O)=CC=2)=[O:15])=[C:12]([CH3:27])[O:11][N:10]=1.[OH-:28].[Na+].CN([CH:33]=[O:34])C>CO>[Cl:1][C:2]1[C:3]2[C:9]3[C:13](=[C:12]([CH3:27])[O:11][N:10]=3)[C:14](=[O:15])[N:10]([CH2:9][C:3]3[CH:4]=[CH:5][C:6]([C:33]([OH:34])=[O:28])=[CH:7][CH:2]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)C(N)c1ccc(C(=O)O)cc1
Reactant: CN(C)C=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: Cc1onc2c1c(=O)n(Cc1ccc(C(=O)O)cc1)c1cccc(Cl)c21
Temperature: 40 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred suspension at room temperature of 245 (795 mg, 2.05 mmol) in anhydrous DMF (10 ml) was added a solution of NaOH (409 mg, 10.22 mmol) in anhydrous MeOH (5.1 ml). Then, the reaction mixture was warmed up to 40° C. After 3 days, the reaction mixture was concentrated, diluted with water and acidified with 1N HCl until pH 5 in order to get a pale pinky precipitate. After 30 min, the suspension was filtered off and the cake was abundantly washed with water, and dried to afford the title compound 246 (679 mg, 1.84 mmol, 90% yield) as a pale pinky solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): AB system (δA=7.92, δB=7.40, J=8.4 Hz, 4H), 7.56 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 5.59 (bs, 2H), 2.95 (s, 3H).
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](SC)=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[C:13]([CH3:14])=[N:12][CH:11]=[N:10]1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([F:39])[F:38])=[CH:31][CH:30]=1)[C:26](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:56][NH2:57]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:57][N:56]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[C:13]([CH3:14])=[N:12][CH:11]=[N:10]3)=[C:3]([F:2])[CH:4]=2)[N:17]=1)[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH:37]([F:38])[F:39])=[CH:33][CH:34]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)F)cc1
Reactant: CSC(=N)Nc1ccc(-n2ncnc2C)c(F)c1
Reactant: NN
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Product: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)F)cc3)n2)cc1F

Procedure:
Methyl 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (1.22 g, 3.10 mmol, from preparation C) and 6-chloro-2-(4-(2,2-difluoroethoxy)phenyl)hexanoic acid (1.0 g, 3.26 mmol, from preparation AX) were coupled [N-methylmorpholine (1.71 mL, 15.5 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.490 mL, 15.5 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 520.5.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][C:6]=1[Cl:15])[CH:2]=[CH2:3].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:15])[CH:7]=1)[CH3:18]
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(CC(=O)NCC(=O)OCC)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid (4.3 g) was dissolved in dry tetrahydrofuran (20 ml). To the solution was added glycine ethyl ester hydrochloride (2.85 g) in dry chloroform (30 ml) containing dry triethylamine (2.8 ml). DCC (4.1 g) was added and the reaction mixture was stirred overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](=[O:12])(=[O:11])[NH:9][CH3:10])=[CH:6][C:5]([C:13]2[N:14]([C:32](Cl)=[O:33])[CH:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:17]=2)=[C:4]([O:35][CH2:36][CH3:37])[CH:3]=1.O.[OH:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:40]1([O:39][C:32]([N:14]2[C@H:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:17]=[C:13]2[C:5]2[CH:6]=[C:7]([S:8](=[O:12])(=[O:11])[NH:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[O:35][CH2:36][CH3:37])=[O:33])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)On1nnc2ccccc21

Procedure:
In an analogous manner as described in example 29, 5-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide was treated with phosgene and diisopropylethylamine in methylene chloride to give 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The crude carbamoyl chloride was then reacted with 1-hydroxybenzotriazole hydrate and diisopropylethylamine in methylene chloride to give the racemic 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester after purification by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(CC(F)F)[C@@H]1CCCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.58 (m, 1 H) 1.61-1.94 (m, 2 H) 1.97-2.07 (m, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.54-2.87 (m, 3 H) 3.11 (br. s., 3 H) 3.40-3.97 (m, 2 H) 4.20-4.76 (m, 1 H) 6.03-6.58 (m, 1 H) 7.64 (br. s., 1 H) 7.68-7.80 (m, 1 H) 7.94-8.62 (m, 4 H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[NH4+:5].C(O)=O.O1P2[O:15][P:16]3[O:18]P(O2)OP1[O:17]3>>[NH2:5][C:1]([P:16]([OH:15])(=[O:17])[OH:18])([P:16]([OH:18])(=[O:15])[OH:17])[CH3:2]
Reactant: O1P2OP3OP1OP(O2)O3
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Solvent: O=CO
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Yield: 175.6 %

Procedure:
The procedure was as described in Example 1, but a blend of 40.5 g (0.525 mol) ammonium acetate and 23 g (0.5 mol) formic acid was reacted with 55 g (0.25 mol) P4O6. 45 g 1-aminoethane-1,1-diphosphonic acid was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[N:18]1([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:26][CH:27]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(CN2CCCCC2)cc1
Reactant: Nc1cccc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
DIEA (433 μL, 2.49 mmol) was added into a suspension of 3-bromobenzenamine (90.3 μL, 0.829 mmol), 4-(piperidin-1-ylmethyl)benzoic acid (200 mg, 0.912 mmol), BOP (477 mg, 1.08 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was loaded onto a 5 g silica loading cartridge. After solvent in the cartridge was dried out under vacuum, the cartridge was put on the ICSO system for purification (yield: 80%). MS (ESI+) m/z 373.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (4.0 mL, 52 mmol) was added slowly to a 0° C. solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (10.0 g, 43.7 mmol) and diisopropylethylamine (7.3 mL, 52 mmol) in dichloromethane (100 mL) with stirring under a nitrogen atmosphere. After 24 hours at room temperature, the mixture was extracted with water (4×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a clear oil which crystallized upon standing. Mp:60°-63° C. MSCI:252(MH+, base). 1H NMR(300 MHz, CDCl3 /TMS, δ): 4.3(br t,2H), 4.1(br d,2H), 3.0(S,3H), 2.7(br t,2H), 1.7-1.1(m,16H).