Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:23][C@H:22]([NH:24][C:25]([C@:27]34[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:28]3[C@@H:29]3[C@@:42]([CH3:45])([CH2:43][CH2:44]4)[C@@:41]4([CH3:46])[C@@H:32]([C@:33]5([CH3:50])[C@@H:38]([CH2:39][CH2:40]4)[C:37]([CH3:48])([CH3:47])[C@@H:36]([OH:49])[CH2:35][CH2:34]5)[CH2:31][CH2:30]3)=[O:26])[C:21]2([CH3:58])[CH3:57])=[O:19])[CH2:14][CH2:13]1)[CH3:11]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:23][C@H:22]([NH:24][C:25]([C@:27]34[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:28]3[C@@H:29]3[C@@:42]([CH3:45])([CH2:43][CH2:44]4)[C@@:41]4([CH3:46])[C@@H:32]([C@:33]5([CH3:50])[C@@H:38]([CH2:39][CH2:40]4)[C:37]([CH3:47])([CH3:48])[C@@H:36]([O:49][C:6](=[O:8])[CH2:7][C:2]([CH3:9])([CH3:1])[C:3]([OH:5])=[O:4])[CH2:35][CH2:34]5)[CH2:31][CH2:30]3)=[O:26])[C:21]2([CH3:57])[CH3:58])=[O:19])[CH2:14][CH2:13]1)[CH3:11]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)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
Reactant: CC1(C)CC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCN(CC)CC4)C3(C)C)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
Yield: 60.6 %

Procedure:
2,2-Dimethylsuccinic anhydride (238 mg) was added to a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 67, 125 mg) and DMAP (45 mg) in dry pyridine (10 mL) at room temperature. After addition, the reaction mixture was refluxed for 14 hours. After completion of the reaction (monitored by TLC), it was diluted with EtOAc, the organic layer was washed with aqueous 1N HCl, then washed with water and brine, and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford 90 mg of title compound (60.8% yield) as an off white solid with 81.67% HPLC purity. 1H-NMR (300 MHz, CDCl3): δ 5.92 (d, J=7.8 Hz, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.52-4.44 (m, 1H), 4.19-4.09 (m, 1H), 3.90 (m, 2H), 3.7 (m, 2H), 3.15-3.04 (m, 1H), 2.87-2.82 (m, 6H), 2.60 (m, 3H), 2.5-2.3 (m, 3H), 2.00-1.91 (m, 3H), 1.75-1.10 (m, 36H), 0.947, 0.914, 0.900 (s, 18H); Mass: [M+1]+ 806 (100%); IR (KBr, cm−1): 3394, 2957, 2873, 1724, 1623, 1455, 1374, 1367, 1244, 1188, 1146, 980, 883, 765; M.R: 63.8° C.-122.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:42])[CH:10]=[C:11]2[NH:15][C:14]([CH2:23][CH2:24]OS(C)(=O)=O)([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13](=[O:30])[N:12]2[CH2:31][CH:32]2[CH2:37][CH:36]3[CH2:38][CH:34]([C:35]3([CH3:40])[CH3:39])[CH:33]2[CH3:41])=[CH:5][CH:4]=1)#[N:2].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[N:43]1([CH2:24][CH2:23][C:14]2([CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:13](=[O:30])[N:12]([CH2:31][CH:32]3[CH2:37][CH:36]4[CH2:38][CH:34]([C:35]4([CH3:39])[CH3:40])[CH:33]3[CH3:41])[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:42])[NH:15]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: c1c[nH]cn1
Reactant: CC1C(CN2C(=O)C(CCOS(C)(=O)=O)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1C(CN2C(=O)C(CCn3ccnc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: 80 °C
Yield: 66.5 %

Procedure:
Methanesulfonic acid 2-[2-[2-(4-cyano-phenyl)-2-oxo-ethylidene]-5-oxo-4-pyridin-4-ylmethyl-1-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-4-yl]-ethyl ester (300 mg, 0.508 mMol) and imidazole (102 mg, 1.5 mMol) were dissolved in anhydrous dimethylformamide (2 mL) under an atmosphere of dry N2. To this mixture was added K2CO3 (207 mg, 1.5 mMol). The mixture was heated to 80° C. for 24 hours after which time it was cooled to ambient temperature and subsequently concentrated under vacuum. The residue was partitioned between CH2Cl2 and water. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give a foam. The foam was chromatographed on flash silica gel using a gradient of CHCl3—CH3OH (98:2) to CHCl3—CH3OH (96:4) to give 190 mg of the titled compound as a 1:1 mixture of diastereomers: C.I. m/z 563.4 [M+1]; 1H NMR (CDCl3)δ8.42 (m, 4H), 7.86 (m, 4H), 7.74 (m, 4H), 7.38 (s, 1H), 7.31 (s, 1H), 7.06 (m, 4H), 7.04 (s, 1 H), 7.02 (s, 1H), 6.88 (s, 1H), 6.84 (s, 1H), 5.50 (s, 1H), 5.45 (s, 1H), 3.80-4.10 (m, 4H), 2.90-3.35 (m, 8H), 2.60 (m 2H), 2.26 (m, 4H), 1.20-2.00 (m, 14H), 1.15 (s, 3H), 1.14 (s, 3H), 1.04 (m, 6H), 0.90 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]([NH2:35])([CH3:34])[CH3:33].[BH4-].[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH:32]([CH3:34])[CH3:33])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(C)C)c4)cc23)CC1
Yield: 52.9 %

Procedure:
Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), isopropylamine (23 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title compound (11.5 mg, 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[N:11]1([C:2]2[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CC(=O)c1ccnc(N2CCNCC2)c1
Yield: 21 %

Procedure:
1-(2-Chloro-4-pyridyl)ethanone (156 mg, 1 mmol), piperazine (861 mg, 10 mmol) and pyridine (5 ml) were placed in a Radley vial and heated at reflux overnight. The mixture was concentrated under reduced pressure to dryness, the residue was mixed with toluene and evaporated under reduced pressure to remove excess of piperazine. The last step was repeated several times. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 51 mg of a solid (0.21 mmol, yield 21%) MS (multi-mode) m/z=206.2 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]([OH:15])=[CH:5][CH:4]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C1C=CN=CC=1.O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:15][C:6]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(O)c(-c2ccccn2)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COc1cc2nccc(Oc3ccc(SC)nc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
6-Methylsulfanyl-[2,2′]bipyridin-3-ol (6 mg), 4-chloro-6,7-dimethoxyquinoline (18 mg), 4-dimethylaminopyridine (10 mg), and cesium carbonate (27 mg) were suspended in N,N-dimethyl sulfoxide (1 ml), and the suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (1 mg, yield 8%).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[OH-].[Na+].[CH:14](=[O:16])[CH3:15]>C(O)(C)C.O>[N:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:15][CH:14]=[O:16])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CC=O
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=CC=O)cc1
Yield: 27.8 %

Procedure:
4-Azidobenzaldehyde (14.71 g, 0.1 mol) was dissolved in a solvent mixture of isopropyl alcohol (50 g) and pure water (15 g). Under cooling in an ice bath, sodium hydroxide (1 g) dissolved in pure water (10 g) was added to the solution, and the resultant mixture was stirred for ten minutes. Acetaldehyde (4.41 g, 0.1 mol) was added to the mixture, and the resultant mixture was stirred for two hours at the same temperature. Subsequently, acetaldehyde (4.41 g, 0.1 mol) was again added to the mixture, and the resultant mixture was stirred for a further three hours. The formed precipitates were collected through filtration and dried, to thereby yield 4.82 g of p-azido-cinnamaldehyde as brown solid (yield: 28%) as a mixture containing acetaldehyde (2.7%).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(O)(=O)C>C(O)C>[CH3:17][N:18]([CH:20]=[C:3]([C:4](=[O:5])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of diethyl oxalacetate sodium salt (100 g, 476 mmol) in ethanol (250.00 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (113 g, 952 mmol) and the reaction was stirred at room temperature for 30 min. Acetic acid (54.5 mL, 952 mmol) was added slowly over a period of 3 h and stirred at room temperature for 24 h. The volatile components were evaporated under reduced pressure and the oily residue was purified by silica gel chromatography (750 g REDISEP® column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104A (43 g, 30.8%). MS(ES): m/z=244 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.18 (q, J=5.4 Hz, 2H), 3.35 (s, 3H), 3.04 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][N:38]([C:46]([O:48][CH2:49][CH:50]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[C@H:37]1[C:63]([OH:65])=O.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:63]([C@H:37]2[CH2:36][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][N:38]2[C:46]([O:48][CH2:49][CH:50]2[C:62]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:56]3[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])=[O:65])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1)[C@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-[4-(2-nitrophenyl)piperazinyl]-2-oxoethyl}(tert-butoxy)-carboxamide (1.4 g, 2.8 mmol) was treated with satd HCl in EtOAc as described in Preparation XVI. The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. This sample (1.05 g, 2.50 mmol), was coupled to N-Fmoc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.1 g, 2.7 mmol) (Peptech), by the procedure for Preparation XIX using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (Aldrich) (1.6 g, 5.5 mmol) and HOAT (370 mg, 2.7 mmol). The crude compound was obtained in a quantitative yield (2.2 g). MS (ESI, pos. ion) m/z: 770 (M+H), (ESI, neg. ion) m/z: 768 (M−H). Calc'd for C44H40ClN5O6: 769.27.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]3[S:18][C:19]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([C:22]4[O:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:21]=[C:17]([NH:16][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[CH:2][N:7]=[CH:6][N:5]=3)[CH2:13][CH2:12]2)=[O:15])[S:18][C:19]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: [H][H]
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCN(c2cc(Cl)ncn2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCN(c2ccncn2)CC1
Yield: 76.7 %

Procedure:
Compound 51 (300 mg, 0.63 mmol) was dissolved in ethanol (10 mL), and 10% palladium-carbon (500 mg) was added thereto, followed by stirring in an atmosphere of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was distilled away under reduced pressure to afford the entitled Compound 52 (213 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[CH2:29](N)[CH2:30][NH2:31].CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[NH:26]1[CH2:29][CH2:30][N:31]=[C:25]1[C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2[C:6]([NH:8][C:9]3[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=3[CH3:15])=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)(=[O:20])=[O:19])=[CH:28][CH:27]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C#N)cc2)c(C)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(C3=NCCN3)cc2)c(C)c1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-benzonitrile (83 mg, 0.21 mmol), prepared by the method described in Example 22, ethylenediamine (0.042 mL, 0.63 mmol), p-TsOH.H2O (59 mg, 0.31 mmol) and toluene (4 mL) was heated at reflux under N2 overnight and then cooled to room temperature. Saturated aqueous NaHCO3 was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (75:25 EtOAc/MeOH) to provide the target compound (14 mg, 15%) as a white solid: mp 240–242° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.27 (br s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 6.92 (s, 2H), 4.80 (br s, 1H), 3.83 (s, 4H), 2.40 (s, 3H), 2.30 (s, 3H), 2.01 (s, 6H); ESI MS m/z 436 [(M+H)+, calcd for C23H26N5O2S, 436.2].
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[CH3:12][O:13][CH:14](OC)[CH2:15][CH:16](OC)OC.FC(F)(F)C(O)=O>>[CH3:12][O:13][CH:14]=[CH:15][CH:16]=[C:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: COC(CC(OC)OC)OC
Solvent: O=C(O)C(F)(F)F
Product: COC=CC=C1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
1,3-Dimethylbarbituric acid (20 g, 0.1 mol; Aldrich) was placed in 100 mL round-bottom one-necked flask equipped with magnetic stir bar and reflux condenser, 1,1,3,3-tetramethoxy-propane, (40 mL, 0.2 mol; Aldrich) and 1 mL of Trifluoroacetic Acid (2 mL, 0.03 mol; Sigma) were added to the reaction mixture. The flask was heated at 100° C. with stirring for 5 hours and then cooled to room temperature. The crystallized product was filtered, washed with methanol and dried. The yield was 23 g (80% of theory).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[Br:17])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Into a 200 ml four necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-tert-butylacetyl chloride (14.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 15.3 g of N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide. M.P., 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COCn1nc2c(I)c(Br)ccn2c1=O
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: C1COCCO1
Solvent: O
Product: COCn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Temperature: 20 °C
Yield: 94.9 %

Procedure:
To a degassed mixture of 7-bromo-8-iodo-2-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.0 g, 7.8 mmol), 4-chlorophenylboronic acid (1.32 g, 8.6 mmol) and K2CO3 (2.16 g, 15.6 mmol) in 1,4-dioxane (42 mL) and H2O (14 mL) under argon at 20° C. was added Pd(PPh3)4 (450 mg, 0.39 mmol). The reaction mixture was refluxed for 40 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (50 mL), then brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was successively triturated with hexanes and Et2O and dried under high vacuum to obtain the title compound as a light yellow solid (2.7 g, 7.4 mmol) in 85% purity along with bis-4-chlorophenyl coupled by-product. The crude product was used without further purification. MS: [M+H]+=368.0.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].Cl>O.O1CCOCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:16]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 64.6 %

Procedure:
To a solution of Na2CO3 (11.7 g, 110.7 mmol) in water (50 mL) and 1,4-dioxane (50 mL) at 60° C. was added 2-amino-4-chloro-benzoic acid (5.0 g, 29.14 mmol) followed by 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (20.15 g, 72.48 mmol) in 3 portions and heated the resulting reaction mixture at 80° C. for 4 hours. 2N HCl Was added until the reaction mixture became acidic (pH=˜2) and obtained white solid was filtered, washed with water, dried under high vacuum to obtain title compound (7.8 g) in 65% yield. MS (ES) M+Na expected 436.0, found 435.8.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:33]=[CH:32][C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:22][C:21]=1[N+:34]([O-:36])=[O:35]>>[N+:34]([C:21]1[CH:22]=[C:23]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:32]=[CH:33][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1)([O-:36])=[O:35]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.3 g) and 4-chloro-3-nitrobenzophenone (0.29 g) using the method of example 1. Yield 0.25 g as a solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: C([O:4][CH:5]([CH:37]([O:43]C(=O)C)[CH2:38][O:39]C(=O)C)[C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:31][O:32]C(=O)C)[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24]C(=O)C)[CH2:19][O:20]C(=O)C)=[O:15])=[O:7])(=O)C.[OH-].[Na+]>>[OH:4][CH:5]([CH:37]([OH:43])[CH2:38][OH:39])[C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:31][OH:32])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([OH:24])[CH2:19][OH:20])=[O:15])=[O:7]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(NC(=O)C(O)C(O)CO)c1I
Yield: 68 %

Procedure:
5-[N′-(2,3,4-Triacetoxybutanoyl)amino]-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (13.8 g, 14.0 mmol) was hydrolysed using sodium hydroxide (4.0 g, 0.10 mol) according to the procedure given in Example 79c. The product was isolated in 68% yield after purification.