Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:8][CH2:7][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:52][C:53]1([CH3:60])[CH2:57][C:56](=[O:58])[O:55][C:54]1=[O:59]>C(OCC)(=O)C>[CH2:44]([O:43][C:41]([C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([O:33][C:56](=[O:58])[CH2:57][C:53]([CH3:60])([CH3:52])[C:54]([OH:59])=[O:55])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:7][CH2:8]1)=[O:42])[CH3:45]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of ethyl 4-ethyl-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylate (Example 73, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Completion of the reaction was monitored by TLC, the reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753; (100%), [M+1].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=O)=[N:4][CH:3]=1.C([BH3-])#[N:21].[Na+].C([O-])(=O)C.[NH4+].C1COCC1>CCOC(C)=O.CO>[NH2:21][CH:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(N)c2ncc(Br)s2)CC1
Temperature: 80 °C

Procedure:
trans-Ethyl 4-(5-bromothiazole-2-carbonyl)cyclohexanecarboxylate (150 mg, 0.433 mmol), sodium cyanoborohydride (63 mg, 1.00 mmol), ammonium acetate (83 mg, 1.08 mmol), THF (0.6 mL), and methanol (1.8 mL) were combined in a sealed vial and heated to a temperature of 80° C. for 16 hours. The mixture was cooled to 23° C. and subsequently transferred to a separatory funnel containing EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to afford crude trans-ethyl 4-(amino(5-bromothiazol-2-yl)methyl)cyclohexanecarboxylate, which was used directly in the subsequent synthetic transformation without purification. MS ESI calc'd. For C13H20BrN2O2S [M+H]+ 347, 349. found 347, 349.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][CH:15]=[C:14]3[C:18]([OH:20])=O)[CH:8]=2)=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl.Cl.[CH:54]([N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1)([CH3:56])[CH3:55]>C(Cl)Cl.COCCOC>[CH:54]([N:57]1[CH2:62][CH2:61][CH:60]([NH:63][C:18]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:59][CH2:58]1)([CH3:56])[CH3:55]
Reactant: O=C(O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2cccn2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid (62 mg) in DCM (5 mL) was added HOAt (27 mg), EDCI hydrochloride (38 mg) and DIEA (106 μL). The mixture was stirred for 30 min at RT. 1-Isopropyl-piperidin-4-ylamine dihydrochloride (47 mg) and DME (1 mL) were added and stirring was continued for 16 h at RT. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 66 mg of 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its trifluoroacetate salt, MS (ESI+): m/e 433 [M+H]+, chloro pattern.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18].[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=3)[CH:28]=[CH:27][N:26]=2)[CH:22]=[N:21]1>CC#N>[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:2]([N:13]4[CH2:17][CH2:16][NH:15][C:14]4=[O:18])=[O:4])=[N:36][CH:37]=3)[CH:28]=[CH:27][N:26]=2)[CH:22]=[N:21]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1NCCN1
Solvent: CC#N
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCNC4=O)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 134.8 %

Procedure:
A 0° C. solution of triphosgene (0.500 g, 1.685 mmol) in MeCN (10 mL) was treated with a solution of imidazolidin-2-one (0.800 g, 9.29 mmol) in MeCN (10 mL), stirred at RT for 0.5 h, added to a suspension of Example A2 (0.800 g, 2.99 mmol) in MeCN (10 mL) and stirred at RT for 4 h. The solids were collected via filtration to afford N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (862 mg, 76%) as an off-white solid. MS (ESI) m/z: 380.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([OH:21])=[C:4]([C:14]([OH:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:5](OC1C=CC=CC=1)=[O:6].[NH2:22]C1C=CC(C(C2C=CC(OC)=CC=2)C#N)=C(C(F)(F)F)C=1.ClC1C=CC(Cl)=CC=1Cl>>[OH:21][C:3]1[CH:2]=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[C:14]([OH:20])[C:4]=1[C:5]([NH2:22])=[O:6]
Reactant: O=C(Oc1ccccc1)c1c(O)c(Cl)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(C(C#N)c2ccc(N)cc2C(F)(F)F)cc1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: NC(=O)c1c(O)ccc([N+](=O)[O-])c1O
Temperature: 190 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3 parts of phenyl 3-chloro-2,6-dihydroxy-5-nitrobenzoate, 3 parts of 4-amino-α-(4-methoxyphenyl)-2-(trifluoromethyl)benzeneacetonitrile and 30 parts of 1,2,4-trichlorobenzene is stirred for 10 minutes at 190° C. The reaction mixture is cooled and poured onto 140 parts of petroleumether while stirring. The supernatant phase is decanted and the residue is boiled in methylbenzene and stirred with activated charcoal. The latter is filtered off over hyflo. Petroleumether is added to the filtrate till turbid and the product is allowed to crystallize while stirring. It is filtered off, dried and crystallized from acetonitrile, yielding 4.5 parts of 3-chloro-N-{4-[α-cyano-α-(4-methoxyphenyl)methyl]-3-trifluoromethyl)phenyl}-2,6-dihydroxy-5-nitrobenzamide; mp. 206.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]=O)=[CH:5][CH:4]=1.N1CCC[C@@H]1C(O)=O.ClN1C(=O)CCC1=O.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=2)=[CH:32][C:31]=1[F:43]>C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]3[N:40]([C:10]([S:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:11][N:42]=3)[N:41]=2)=[CH:32][C:31]=1[F:43]
Reactant: COc1ccc(SCC=O)cc1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) reaction mixture of [(4-methoxyphenyl)thio]acetaldehyde (36.4 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.2 mL) was added N-chlorosuccinimide. (26.7 mg, 0.2 mmol). The reaction mixture was stirred at 0° C. for 30 min, then gradually warmed to RT for 2 h. To the reaction mixture was added [6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol). The reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated at 100° C. overnight. After cooling, the reaction mixture was filtered and the filtrate was purified by RP-HPLC (pH=10) to afford the desired product. LCMS: (M+H)+=431.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>O1CCOCC1.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>[CH:12]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[CH2:13]
Reactant: Brc1ccc2cnccc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
In a 250 mL round bottom flask, 6-bromoisoquinoline (5 g, 24 mmol) (commercially available from Kalexsyn Product List Order Number 2003-005) was dissolved in dioxane (50 ml). Vinyltributylstannane (9 mL, 29 mmol) was added and the solution was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (3 g, 2 mmol) was added in one portion. The reaction mixture was stirred for 3 hours at 100° C. The reaction mixture was adsorbed onto silica gel, and purified by flash chromatography (5-30%, EtOAc in hexane) to provide the product (3.0 g, 80%). LCMS (API-ES) m/z (%): 156 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[S:16])[NH:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[OH-].[Na+].CO.Cl>O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[C:5]([CH3:6])=[N:1][C:2]([SH:16])=[N:3]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N(NC(N)=S)C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nc(S)nc2C)cc1
Yield: 91 %

Procedure:
A mixture of 14.5 parts of acetic acid 2-(aminothioxomethyl)-1-(4-methoxyphenyl)hydrazide, 5 parts of sodium hydroxide and 80 parts of methanol is stirred and refluxed for 30 minutes. The reaction mixture is cooled and water is added. The whole is adjusted to pH 5 with a hydrochloric acid solution. The precipitated product is filtered off and dried, yielding 12.3 parts (91%) of 1-(4-methoxyphenyl)-5-methyl-1H-1,2,4-triazole-3-thiol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7]2.[CH3:16][N:17]([CH3:23])[C@@H:18]([C:20](O)=[O:21])[CH3:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:16][N:17]([CH3:23])[C@H:18]([CH3:19])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:7][CH2:8]1)=[O:21]
Reactant: C[C@H](C(=O)O)N(C)C
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@@H](C)N(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (2 g, 8.67 mmol) in N,N-dimethylformamide (100 mL) was added N,N-dimethyl-D-alanine (1.524 g, 13.01 mmol), PyBOP (13.54 g, 26.0 mmol), and DIPEA (15.14 mL, 87 mmol). After stirring overnight at rt, the solvent was removed and the residue was suspended in dichloromethane (150 mL), washed with water (100 mL), concentrated on the rotovap, and purified by column chromatography (DCM to 5% MeOH/DCM) to provide 1-[(2R)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 86%). ESIMS (M+H)+=294.
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH2:55])=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH2:38][CH2:37]1.[N:56]1[N:57]([C:61]2[C:62]([C:67](O)=[O:68])=[N:63][CH:64]=[CH:65][CH:66]=2)[N:58]=[CH:59][CH:60]=1>>[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH:55][C:67]([C:62]3[C:61]([N:57]4[N:58]=[CH:59][CH:60]=[N:56]4)=[CH:66][CH:65]=[CH:64][N:63]=3)=[O:68])=[N:41][CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[N:44]=2)[CH2:37][CH2:38]1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 48; 105 mg, 0.33 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 74 mg, 0.39 mmol) except after work-up, the organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM, then methanol and 2M ammonia in methanol and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([C:21]2[CH:22]=[N:23][C:24](S(CCC)(=O)=O)=[N:25][CH:26]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([C:21]2[CH:26]=[N:25][C:24]([N:3]([CH3:4])[CH3:2])=[N:23][CH:22]=2)[CH:7]=1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1ncc(-c2cc(Cl)ccc2OCC(=O)O)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Dimethylamine hydrochloride (0.82 g) was added to a stirred solution of the product from step (iv) (0.2 g) and N,N-diisopropylethylamine (0.9 ml) in No (5 ml). The reaction mixture was heated at 90° C. for 6 h then diluted with EtOAc, washed with water, brine, dried and evaporated under reduced pressure. The residue was dissolved in DCM (10 ml) then trifluoroacetic acid (10 ml) added and stirred for 18 h at RT. The reaction mixture was evaporated to dryness and the residue purified by reverse phase HPLC followed by trituration with methanol to give a white solid. Yield 0.035 g
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])/[C:7](=[N:13]/[C:14](=[O:24])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(Cl)Cl>[CH3:32][S:33]([O:12][CH:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6]/[C:7]/1=[N:13]\[C:14]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])=[O:24])[CH3:11])(=[O:35])=[O:34]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of the product of Example 163 (220 mg, 0.6 mmol) in CH2Cl2 (20 mL) and triethylamine (181 mg, 1.8 mmol) was cooled to 0° C., and treated dropwise with methanesulfonyl chloride (102 mg, 0.9 mmol). The reaction was stirred at 0° C. for 30 min., poured into water, and the mixture was extracted with CH2Cl2 (2×). The organics were combined, dried over MgSO4, filtered and concentrated to afford the title compound (234 mg, 88%). MS (DCI/NH3) m/z 383 (M−Ms+15)+.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=O)[CH2:7][NH:8][C:9](=[O:34])[CH2:10][C:11]1[N:15](C(OC(C)(C)C)=O)[C:14]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[C:26]([CH3:27])[C:13]=2[N:12]=1)C.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:5][C:6]1[CH2:7][NH:8][C:9](=[O:34])[C:10]=1[C:11]1[NH:15][C:14]2[CH:23]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:25]=[C:26]([CH3:27])[C:13]=2[N:12]=1
Reactant: CCOC(=O)CNC(=O)Cc1nc2c(C)cc(N3CCOCC3)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)cc2[nH]c(C3=C(O)CNC3=O)nc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 8.7 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 0.003 g, 0.044 mmol) in toluene (1 mL) was added [2-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-acetylamino]-acetic acid ethyl ester (0.135 g, 0.293 mmol) in tetrahydrofuran (2 mL) over 5 minutes. The mixture was stirred at 90–100° C. for 5 hours, then cooled down to ˜0° C. and ethyl acetate followed by aqueous hydrochloric acid (1N, ˜0.5 mL) were added. The aqueous phase was washed with ethyl acetate (3×) and this was submitted to Prep HPLC (acetonitrile/ammonium acetate/water) to give the title material (0.008 g, 69%) as a white solid. HPLC 100% (220 nm); LCMS (+ESI, M+H+) m/z 315; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.55 (3H, s), 3.18 (4H, br dd), 3.81 (2H, s), 3.88 (4H, br dd), 6.92 (1H, br s), 6.99 (1H, d, J=2.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:6][CH2:5]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 40 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 40% yield: mp 146-147° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.43 (d, J=3.0 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.23-7.17 (m, 1H), 6.55 (t, J=5.7 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 4.06-3.99 (m, 2H), 3.57-3.52 (m, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.44-1.37 (m, 2H), 0.65-0.54 (m, 1H), 0.43-0.35 (m, 2H), 0.06-0.01 (m, 2H): 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.3, 153.5, 149.0, 148.6, 135.7, 134.1, 123.6, 116.7, 44.0, 42.4, 42.0, 41.2, 32.4, 17.2, 8.4, 4.3: MS (ES+) m/z 386.3 (M+1)
Reaction SMILES: [NH2:1][C:2](=[N:14][O:15][C:16](=O)[CH2:17][N:18]([CH:27]1[CH2:30][CH2:29][CH2:28]1)[C:19]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)=[O:20])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(O)(=O)C>CN(C)C=O>[CH:27]1([N:18]([CH2:17][C:16]2[O:15][N:14]=[C:2]([C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[N:1]=2)[C:19]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)=[O:20])[CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cnc(C(=O)N(CC(=O)ON=C(N)c2ccc(OC(F)(F)F)cc2)C2CCC2)c1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2nc(-c3ccc(OC(F)(F)F)cc3)no2)C2CCC2)c1
Temperature: 120 °C
Yield: 9.7 %

Procedure:
A mixture of N-{2-[({amino[4-(trifluoromethoxy)phenyl]methylidene}amino)oxy]-2-oxoethyl}-N-cyclobutyl-1-methyl-1H-imidazole-4-carboxamide (75 mg), acetic acid (0.5 mL) and dimethylformamide (0.5 mL) was stirred while heating at 120° C. for 2 hr. After the solvent was distilled off under reduced pressure, the resulting residue was purified by HPLC to afford the title compound (7 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:19])[C:11]3[C:16]([CH:17]=2)=[C:15]([CH3:18])[CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]#[N:21])=[CH:3][CH:4]=1)[NH:9][C:10]2=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(Br)cc3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C#N)cc3)cc12
Yield: 79 %

Procedure:
3-(4-Bromo-phenyl)-5-methyl-2H-isoquinolin-1-one (200 mg, 0.64 mmol), zinc cyanide (90 mg, 0.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (74 mg, 0.064 mmol) were stirred in DMF (2.1 mL) and degassed with N2. The reaction mixtures were irradiated using a microwave (300 W, 180° C., 30 min). The reaction mixtures were combined and the resulting precipitate was filtered, washed with DMF and water and dried to give 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzonitrile as a yellowish solid (718 mg, 79%) which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([NH:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[I:1])(=[O:20])[CH3:19]
Reactant: NNC(=O)c1ccccc1I
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NNC(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
2-Iodobenzohydrazide (1.38 g, 5.27 mmol) obtained in Step 1 of Example 114 was dissolved in dichloromethane (50 mL), and the mixture was stirred at 0° C. for 1.5 hours after adding pyridine (0.639 mL, 7.90 mmol) and acetyl chloride (0.412 mL, 5.79 mmol). The precipitated solid was filtered off, and the resulting solid was dried under reduced pressure to give N′-acetyl-2-iodobenzohydrazide (1.23 g, 77%).