Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cccc(I)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 1 using N-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-iodobenzamide (Stage 9.1) and pyrimidin-5-ylboronic acid to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=2.63 min, m/z=378.0 [M+H]+, m/z=376.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.56-7.64 (m, 1H) 7.66 (dd, J=9.0, 1.2 Hz, 1H) 7.70-7.76 (m, 1H) 7.97-8.11 (m, 3H) 8.36 (s, 1H) 9.25 (s, 1H) 9.26 (s, 2H) 10.67 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH:3]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].Br[CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=2[N:26]=1>CN(C)C=O>[F:31][C:28]1[CH:29]=[CH:30][C:24]2[S:23][C:22]([CH2:21][N:7]3[C:6]4[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=4[S:4][CH:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]3=[O:1])=[N:26][C:25]=2[CH:27]=1
Reactant: CCOC(=O)CC1Sc2ccccc2NC1=O
Reactant: Fc1ccc2sc(CBr)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3cc(F)ccc3s2)C1=O
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Under ice cooling, 1.01 g of ethyl 2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetate was added to a suspension of 176 mg of sodium hydride (60% in mineral oil) in 7 ml of N,N-dimethylformamide. The mixture was stirred for 30 minutes. After a solution of 1.08 g of 2-bromomethyl-5-fluorobenzothiazole in 3 ml of N,N-dimethylformamide was added dropwise to the mixture, the mixture was stirred at room temperature overnight. Thereafter the reaction mixture was poured onto ice water, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily residue was purified by silica gel chromatography to give 1.11 g of the title compound. The structural formula and physical data of this compound are shown in Table 7.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:15][C:16]#[CH:17].C1COCC1>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:17][C:16]#[CH:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Yield: 86.4 %

Procedure:
199 g (1.0 mol) of 4-acetylaminobenzenesulfinic acid were dissolved in 1000 ml of water at pH 6, the solution was added dropwise to a solution of 140 g (1.1 mol) of 3-bromoprop-1-yne and 200 ml of THF at from 40° to 50° C., and the mixture was maintained at that temperature until the reaction had ended (check by TLC). The precipitate formed was filtered off with suction at about 10° C., washed neutral with water and dried, leaving 205 g of 4-acetylamino-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 175°-179° C.). ##STR26##
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:31]C1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)N=C(C2C=CC=CC=2)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([C:19]([CH3:31])=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(-c2ccccc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ncnc(N)c34)ccc12

Procedure:
7-Cyclobutyl-5-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine was prepared using the same procedures described for 7-cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine, except 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline was used in place of 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline and 2 equivalents of cesium carbonate was used in place of 3 equivalents of sodium carbonate; 1H NMR (CDCl3, 400 MHz) δ 2.06 (m, 1H), 2.17 (m, 1H); 2.47-2.52 (m, 2H); 2.67-2.72 (m, 2H); 2.82 (d, J=0.8 Hz, 3H); 4.14-4.25 (m, 1H); 5.78 (brs, 2H); 7.46-7.56 (m, 3H); 7.77 (d, J=0.8 Hz, 1H); 7.92 (s, 1H); 7.98 (dd, J=8.6, 1.8 Hz, 1H); 8.15-8.18 (m, 3H); 8.39 (d, J=1.6 Hz, 1H); MS (ES+): m/z 407.03 (100) [MH+], HPLC: tR=3.54 min (MicromassZQ, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])/[CH:9]=[CH:10]/[C:11]#[N:12])=[CH:4][CH:3]=1>Cl.CO>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]2[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH2:13][CH3:14])/[CH:9]=[CH:10]/[C:11]#[N:12]
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step A (177 mg, 0.406 mmol) and 4 N HCl/MeOH (10 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dried in vacuo to afford the title compound as a white solid. LC/MS m/z=336.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][C:18](=[O:20])[CH3:19])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[S:7][CH:8]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][NH2:35])=[S:33])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[C:18]([O:17][C:5]1[C:4]([C:1](=[N:35][NH:34][C:32](=[S:33])[NH:31][C:29]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([Cl:21])[CH:30]=2)[CH3:2])=[CH:8][S:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(Cl)c(Cl)c1
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Product: CC(=O)Oc1c(C(C)=NNC(=S)Nc2ccc(C(=O)O)c(Cl)c2)csc1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from acetic acid 4-acetyl-2-(3,4-dichlorophenyl)thiophen-3-yl ester (39.5 mg, 0.12 mmol) and 2-chloro-4-(hydrazinecarbothioamido)benzoic acid (40.5 mg, 0.132 mmol) following the procedure described in the synthetic example 185.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:5][CH:1]([CH3:3])[CH3:2])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Solvent: CC(C)O
Product: CC(C)Oc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 2-propanol. White solid. MS (m/e): 222.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.Cl.[OH-].[K+]>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[CH:10][C:11]1[S:12][C:13]2[CH:7]=[CH:8][CH:2]=[CH:1][C:14]=2[N:15]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1nccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Oc1ccccc1C=Cc1nc2ccccc2s1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
Salicylaldehyde (6.1 g) and 2-methylthiazole (7.5 g) were mixed and conc. hydrochloric acid (1.5 ml) was added thereto. The mixture was stirred with heating at 100° C. for 9 hr. The reaction mixture was cooled, and aqueous potassium hydroxide solution was added. The aqueous layer was washed with ether and made acidic with hydrochloric acid and extracted again with ethyl acetate. The organic solvent was dried and concentrated to give the title compound (2.5 g) as pale-yellow crystals, melting point 235-236° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH:36]4[O:40][CH2:39][CH2:38][O:37]4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)(=O)=O)=CC=1>C(O)C>[O:37]1[CH2:38][CH2:39][O:40][CH:36]1[CH2:35][CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][O:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[CH2:23][CH2:24]2)[CH2:29][CH2:30]1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of 0.33 g of potassium hydroxide in 7 ml of 95 percent ethanol is treated with 1.12 g of p-fluorophenol. Thereafter, the mixture is treated with a solution of 2.26 g of [trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)-ethyl)cyclohexyl]cyclohexyl]methyl p-toluenesulfonate in 23 ml of ethanol and stirred at 80° C. (bath temperature) for 24 hours. Subsequently, the reaction mixture is partitioned in 1 N hydrochloric acid and methylene chloride. The organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether gives 1-[[trans-4-(trans-4-(2-(1,3-dioxolan-2-yl)-ethyl)cyclohexyl]cyclohexyl]methoxy]-4-fluorobenzene.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH3:15].Cl>O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:15])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: N
Agent: Cl
Solvent: O
Product: NC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
A mixture of methyl 4-hydroxy-3-nitrobenzoate (1.00 g, 5.07 mmol) and concentrated aq ammonia (10.0 mL, 162 mmol) was heated to 100° C. for 90 mins (3×30 mins) in a microwave reactor. The mixture was poured into water (70 mL), acidified with 6N HCl and extracted with EtOAc (4×25 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was triturated with DCM (20 mL) filtered and washed with DCM before drying under vacuum to afford the crude title compound as a yellow solid 0.49 g, 53.0%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:13]I)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[Cl:49])[N:45]=[C:44](Br)[C:43]([CH2:51][P:52]([O:56][CH3:57])([O:54][CH3:55])=[O:53])=[CH:42]2.O>C1C=CC=CC=1.CC(N(C)C)=O.[Cu].[Zn].[Pd](Cl)Cl>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:13][C:44]1[C:43]([CH2:51][P:52]([O:54][CH3:55])([O:56][CH3:57])=[O:53])=[CH:42][C:41]2[C:46](=[CH:47][C:48]([Cl:49])=[C:39]([Cl:38])[CH:40]=2)[N:45]=1)[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COP(=O)(Cc1cc2cc(Cl)c(Cl)cc2nc1Br)OC
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H](Cc1nc2cc(Cl)c(Cl)cc2cc1CP(=O)(OC)OC)NC(=O)OC(C)(C)C
Reaction time: 2.75 h
Yield: 63.3 %

Procedure:
A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.66 g, 2 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml) was added to a zinc-copper couple (0.31 g). The resulted mixture was sonicated at 40°-45° C. under nitrogen for 2.5-3 h until no starting material remained (as judged by TLC). Tri-o-tolylphosphine (0.06 g, 0.2 mmol) and palladium chloride (0.02 g, 0.1 mmol) were added followed by a solution of 6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline (0.4 g, 1 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml). The resulted mixture was stirred under nitrogen at 50°-60° C. for 2.5-3 h and then allowed to cool. Water was added and the mixture was filtered through Celite, the latter was washed with ethyl acetate. The combined organic phases were separated, dried, (MgSO4) and concentrated in vacuo. The residue was coevaporated several times with toluene to remove most of the dimethylacetamide and then purified on a silica gel column using 0-2% methanol in chloroform as eluent to give 0.33 g of methyl (R)-α-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:63]/[O:64]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][CH:30]2[C:61](=[O:62])[N:32]3[C:33]([C:45]([O:47]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:46])=[C:34](/[CH:37]=[CH:38]\[C:39]4[N:40]=[N:41][S:42][C:43]=4[CH3:44])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O.Cl.C(=O)(O)[O-].[Na+:92]>>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:63]/[OH:64])/[C:27]([NH:29][CH:30]2[C:61](=[O:62])[N:32]3[C:33]([C:45]([O-:47])=[O:46])=[C:34](/[CH:37]=[CH:38]\[C:39]4[N:40]=[N:41][S:42][C:43]=4[CH3:44])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1.[Na+:92]
Reactant: Cc1snnc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cc1snnc1/C=C\C1=C(C(=O)[O-])N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(5-methyl-1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.5 g, 0.4 mmol) was stirred at room temperature for 2 hours by addition of formic acid (5 ml). Concentrated hydrochloric acid (40 μl) was added to the reaction solution and it was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then the residue was cleansed with ether thereby a powdered product was obtained. This one was dissolved in aqueous sodium bicarbonate solution and purified by HP-20 column chromatography thereby sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(5-methyl-1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.13 g) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([F:13])[CH:5]=2)[CH2:3][CH2:2]1>[Pd]>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1F
Agent: [Pd]
Product: Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A slurry of palladium on carbon (200 mg, 10% wt.) in IMS was added to a degassed solution of 4-cyclopropyl-2-fluoro-1-nitro-benzene (1.45 g, 8 mmol) in IMS (50 mL), the atmosphere was evacuated and back-filled with nitrogen then re-evacuated and back-filled with hydrogen. The reaction mixture was stirred under 1 atmosphere pressure of hydrogen at room temperature for 24 hours before filtering through a pad of Celite® then washing with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound as a pale purple residue (1.19 g, 98%). 1H NMR (CDCl3, 400 MHz) 6.72-6.63 (3 H, m), 3.56 (2 H, s), 1.83-1.75 (1 H, m), 0.93-0.82 (2 H, m), 0.59-0.54 (2 H, m).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.Cl.[F:23][C:24]1([F:32])[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[C@H:25]1[NH2:31].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:31][C@H:25]1[C:24]([F:32])([F:23])[CH2:29][CH2:28][CH2:27][C@H:26]1[NH:30][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a screw-cap vial was added methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (200 mg, 0.663 mmol), cis-3,3-difluorocyclohexane-1,2-diamine hydrochloride (148 mg, 0.795 mmol), and DIPEA (347 μL, 1.989 mmol) in DMF (3.9 mL). The resulting brownish-yellow mixture was stirred at RT for 2 h and then at 60° C. for 12 h. The reaction mixture was cooled to RT, diluted with EtOAc (30 mL) and washed with water (2×10 mL) and brine (20 mL). The organic layer was collected, dried over Na2SO4, and concentrated to give a thick brown oil, which included the title compound and isomers (328 mg, 119%). The crude product was used without further purification. [M+H] calc'd for C21H23F2O2, 416. found, 416.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[NH:10]1[C:15]2[CH:16]=[CH:17][S:18][C:14]=2[C:13](=[O:19])[NH:12][C:11]1=[O:20]>>[N+:6]([C:17]1[S:18][C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[NH:10][C:15]=2[CH:16]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c(=O)c2sc([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
A stirred mixture of concentrated sulphuric acid (98%, 270 ml) and fuming nitric acid (270 ml) at 0° C. was treated portionwise with Example 1 (90 g, 530 mmol). Upon complete dissolution, stirring was continued at room temperature for a further 20 min. The solution was added slowly to vigorously stirred ice/water (2000 ml). After 30 min stirring at room temperature, a yellow solid was filtered, washed with water and dried in vacuo at 40° C. to give the title compound in 61% yield, >95% purity. LC-MS m/z=251.0 [M+H]+; RT=2.92; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 7.66 (1H, s), 11.71 (1H, b), 11.79 (1H, b).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]1[CH:32]([C:33]([F:36])([F:35])[F:34])[N:31]([CH3:37])[C:30]([C:38](=[NH:40])[NH2:39])=[N:29]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:40]=[C:38]([C:30]4[N:31]([CH3:37])[C:32]([C:33]([F:36])([F:35])[F:34])=[N:28][N:29]=4)[N:39]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: CN1C(C(=N)N)=NN(O)C1C(F)(F)F
Product: CCc1ccc(C2CC(c3nc(-c4nnc(C(F)(F)F)n4C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 70 mg (0.33 mmol) of 1-hydroxy-4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazole-3-carboximidamide were reacted according to the General Method 2. Yield: 37 mg (30% of theory)
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[NH:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N(C1CCCCC1)C1CCCCC1.Cl>CCCCCC>[N:5]([P:1]([Cl:4])[Cl:2])([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClP(Cl)Cl
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CCCCCC
Product: ClP(Cl)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A mixture of 34.4 g (0.25 moles) of PCl3 in 400 mL of hexane was treated with Cy2NH (90.7 g, 0.50 moles) dropwise at ° C. for 30 min. The resulting white slurry was warmed to room temperature and stirred for 1 h, refluxed overnight before removal of Cy2NH—HCl by filtration. The white solids were washed with hexane (2×100 mL). The combined filtrates were concentrated to give the crude Cy2N—PCl2 (54.0 g, 77% yield). 31P NMR (121 MHz, CD2Cl2): δ171.3 (s) ppm.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:35])([F:34])[F:36])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH2:15](OC=O)[CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([NH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)OCCC2CN
Solvent: CC(=O)OC(C)=O
Product: CCNCC1CCOc2cc(OC)ccc21

Procedure:
The product from Example 2 was reacted as described in Example 3 replacing ethylformate with acetic anhydride, giving the desired product, (M+H)+ 222. 1H NMR(CDCl3): 1.15 (t,3H); 2.05 (m,2H); 2.6-2.0 (m,4H); 3 75 (s,3H); 4 2 (m,1H), 6.3-7.1 (m,3H).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17](/[CH:18]=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of (R)-2-methylpropane-2-sulfinamide (2.4326 g, 20.07 mmol) and Cs2CO3 (9.81 g, 30.1 mmol) in DCM (50 mL) was added dropwise a solution of 3-bromobenzaldehyde (4.08 g, 22.08 mmol) in DCM (50 mL) over 10 min and the mixture stirred at ambient temperature for overnight. The reaction mixture was filtered through celite and the filter pad washed with DCM then with EtOAc. Filtrate was dried over MgSO4 and concentrated to give an oil which was purified by silica gel chromatography to give 161A (4.7626 g, 16.53 mmol, 82% yield) as an faint yellow colored oil. 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 8.05 (t, J=1.8 Hz, 1H), 7.76 (dt, J=7.7, 1.2 Hz, 1H), 7.68-7.65 (m, 1H), 7.41-7.36 (m, 1H), 1.31-1.29 (m, 9H).
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH3:37])[C:34](Cl)=[O:35])[CH3:32]>C(O)CO>[I-:1].[CH2:31]([N:33]([CH3:37])[C:34]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:35])[CH3:32]
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Reactant: CCN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OCCO
Solvent: CC#N
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1

Procedure:
Mix 7.9 g (0.02 mol) (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 180 ml of acetonitrile, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, let it react at 20° C. for 16 hours. Filter it and reduce the pressure to recover 9.8 g of red-brown liquid to be directly used in the next reaction.