Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:6]3[O:7][C:3]([C:2]#[N:1])=[CH:4][CH:5]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: N#Cc1ccc(CN)o1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(C#N)o1
Yield: 72 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use 5-(aminomethyl)furan-2-carbonitrile in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J=5.6 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.52 (d, J=3.6 Hz, 1H), 7.45-7.30 (m, 5H), 6.55 (d, J=3.6 Hz, 1H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.6 Hz, 1H), 5.16 (s, 2H), 4.44 (d, J=5.6 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:31][CH2:30][CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCCCOc1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CCCOc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-phenoxy-1-bromopropane as described for compound 8. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60°-80° C.). M.p. 78°-81° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure IVa. Obtained as a pink solid (1.88 g, 97%). MS (ISP) 485.3 [(M+H)+]; mp 194° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:7]([O:26][CH2:27][CH3:28])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[N:19][CH:20]=2)[C:9]([C:13]#[N:14])=[C:10]([CH3:12])[CH:11]=1)(=[O:5])[CH3:4]>CO>[C:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:6]([CH:3]([OH:5])[CH3:4])=[C:7]([O:26][CH2:27][CH3:28])[C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[N:19][CH:20]=1)#[N:14]
Reactant: CCOc1c(C(C)=O)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)O)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 565.9 %

Procedure:
Sodium tetrahydroborate (370 mg, 9.8 mmol) was added to a mixture of 5-(3-acetyl-6-cyano-2-ethoxy-5-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (2.3 g, 6.5 mmol) in methanol (100 mL) at 0° C. The reaction was stirred at 0° C. for 1 h. The reaction was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product 5-[2-cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamide as a clear oil (13 g, 99%). LCMS calculated for C20H24N3O3(M+H)+: m/z=354.1; found: 354.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[C:15](O)=[O:16])=[O:7]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:7])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][OH:16]
Reactant: O=C(CCCCCCC(O)C(=O)O)c1ccco1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC(O)CCCCCCC(O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 640 ml. of 1.0 M. boranetetrahydrofuran complex in tetrahydrofuran is added a solution of 81 g. of 8-(2-furoyl)-2-hydroxyoctanoic acid in 240 ml. of tetrahydrofuran during one hour while maintaining a temperature of 0°-10° C. After the addition, the solution is stirred at room temperature for 3 hours, is cooled to 0° C., and treated cautiously with 80 ml. of 1:1 aqueous tetrahydrofuran. The resulting mixture is diluted with ethyl acetate. The solution is washed successively with an ice-bold brine-hydrochloric acid mixture, brine, brine-sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate and concentrated to give an oil; pmr (CDCl3) δ 4.70 (triplet).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[CH3:33][O:34][C:35]1[C:40]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][O:34][C:35]1[C:40]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:39][C:38]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:4]([C:20]3[O:21][C:22]([CH2:25][N:26]4[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:23][N:24]=3)[CH:3]=2)=[CH:37][N:36]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCCOCC4)o3)cc(Br)cc21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4CCCOCC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 100 °C

Procedure:
6-Bromo-1-(phenylsulfonyl)-4-[5-(tetrahydro-1,4-oxazepin-4(5H)-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazole (279 mg, 0.538 mmol) was dissolved in 1,4-dioxane (5 ml) and half of the resulting solution was charged to a reaction vessel. N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (114 mg, 0.347 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (39.5 mg, 0.054 mmol), potassium phosphate tribasic (171.5 mg, 0.808 mmol) and water (0.25 ml) were added. The reaction mixture was heated at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was purified by preparative HPLC using the following method:
Reaction SMILES: C[O:2][C:3](=[O:29])[C@H:4]([CH3:28])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].CO.Cl>C(OCC)(=O)C.O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:29])=[O:2])[CH3:28])=[O:27])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](C)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)O

Procedure:
To approximately 0.3 mmol of [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]alanine methyl ester, prepared as in Example 187D, was added 1 mL of 1.39M NaOH in 5:1 methanol: water. The mixture was heated to reflux for 20 minutes, then 1 mL of water, 1.4 mL of 1M aqueous HCl, and 5 mL of ethyl acetate were added sequentially. The biphasic mixture was stirred, then separated, and the aqueous layer was extracted with additional ethyl acetate (2×5 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated to give 4-(3-pyridyloxymethyl)-2-phenylbenzoyl-L-alanine as a foam. 1H NMR (300 MHz, d6-DMSO) δ 1.11 (d, J=7.1 Hz, 3H), 4.14 (quintet, J=7.3 Hz, 1H), 5.21 (s, 2H), 7.22-7.45 (m, 1H), 8.10 (d, J=4.1 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.46 (d, J=7.5 Hz, 1H), 12.42 (br s, 1H); MS (DCI) m/e 377 (M+H)+, 394 (M+NH)+. Anal calcd for C22H20N2O4.0.15HCl: C, 69.19; H, 5.32; N, 7.34. Found: C, 69.22; H, 5.01; N, 7.07.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2ncccc2c1
Yield: 457.8 %

Procedure:
A suspension of 6-nitro-quinoline (8.7 g, 5 mmol), palladium on charcoal (10%) (0.1 g) in methanol (0.2 L) was hydrogenated at room temperature for 24 with stirring. The catalyst was filtered and the solvent evaporated to yield a yellow solid. Crystallisation from ethyl acetate yielded the pure title compound as a pale yellow solid (3.3 g, 46%). MS m/z: 145 [M+H+]. 1H NMR (270 MHz, CHCl3-d) δ ppm 3.89 (s, 2H) 6.87 (d, J=2.64 Hz, 1H) 7.14 (dd, J=8.97, 2.64 Hz, 1H) 7.25 (dd, J=8.44, 4.22 Hz, 1H) 7.88 (dd, J=7.92, 1.58 Hz, 1H) 7.90 (d, J=8.97 Hz, 1H) 8.63 (dd, J=4.22, 1.58 Hz, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>C(Cl)(Cl)Cl>[NH2:9][C:10]1[C:19]([Br:1])=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(I)ccc1N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(I)cc(Br)c1N
Reaction time: 8 h
Yield: 81.9 %

Procedure:
N-Bromosuccinimide (13.5 g, 76.0 mmol) was added in portions over 1.5 h to a stirred solution of methyl 2-amino-5-iodobenzoate (20 g, 72 mmol) in CHCl3 (320 mL) at RT. This was stirred overnight and then silica gel chromatography (step gradient elution with hexane containing 10 to 30% DCM) afforded impure methyl 2-amino-3-bromo-5-iodobenzoate (21 g) as a white solid that was used as such. A flask containing a mixture of 3- (trifluoromethyl)phenylboronic acid (3.73 g, 19 6 mmol), methyl 2-amino-3-bromo-5-iodobenzoate (7.0 g, 16 mmol), K2CO3 (6.85 g, 49 6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.4 g, 1 7 mmol), dioxane (140 mL), and water (28 mL) was degassed and flushed with N2 twice and then heated at 70° C. for 3 h. It was cooled to RT, diluted with EtOAc, washed with water (2×), brine, and then dried over Na2SO4. Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0 to 7% MeOH) afforded impure methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (6.2 g, 10.44 mmol, 63.2% yield) as a white solid that was used as such. A mixture of 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (303 mg, 1.00 mmol), methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (250 mg, 0.668 mmol), tetrakistriphenylphosphine palladium(0) (77 mg, 0.067 mmol), K2CO3 (369 mg, 2.67 mmol) in a microwave vial was flushed with nitrogen and DMF (2.7 mL) was added. The vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried over sodium sulfate, and the solvent removed. Silica gel chromatography (step gradient elution with hexane containing 0, to 20% EtOAc) afforded methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (150 mg, 0.532 mmol, 80% yield). MS (ESI) m/z 470.20 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=2.14 Hz), 7.81 (1H, s), 7.73-7.78 (1H, m), 7.49-7.56 (3H, m), 7.37 (2H, d, J=8.55 Hz), 7.05 (2H, d, J=8.55 Hz), 6.15 (2H, br, s.), 3.95 (3H, s), 3.26-3.38 (4H, m), 2.60-2.69 (4H, m), 2.39 (3H, s).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:17].O.[C:21](O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]=[C:6]1[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:21])=[O:15])[C:9]=2[N:5]1[CH2:4][CH:3]=[O:2]
Reactant: COC(Cn1c(=O)[nH]c2cccc(C(=O)[O-])c21)OC
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc2[nH]c(=O)n(CC=O)c12
Yield: 61 %

Procedure:
The solution of 3-(2,2-dimethoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.4 g, 1.4 mmol) in methylene chloride (10 mL) with water (3 mL) and TFA (3 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-oxo-3-(2-oxoethyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.2 g, 61%): 1H NMR (500 MHz, DMSO-d5) δ 11.43 (s, 1H), 9.61 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 1H), 4.95-4.94 (m, 2H), 3.79 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12])([F:5])[F:4].[N:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:31]=2[Cl:32])[NH:28][C:27](=[O:33])[C:26]([C:34]2[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=2)=[C:25]3[OH:42])=[O:21])=[N:15][CH:14]=1.C(=O)(O)[O-].[K+].[I-].[Na+]>>[N:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:31]=2[Cl:32])[NH:28][C:27](=[O:33])[C:26]([C:34]2[CH:35]=[C:36]([CH3:41])[CH:37]=[C:38]([CH3:40])[CH:39]=2)=[C:25]3[O:42][CH2:2][C:3]([F:5])([F:4])[C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH3:12])=[O:21])=[N:15][CH:14]=1
Reactant: CN1CCCC[C@H]1C(F)(F)CCl
Reactant: Cc1cc(C)cc(-c2c(O)c3cc(C(=O)Nc4ccncn4)c(Cl)cc3[nH]c2=O)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Product: Cc1cc(C)cc(-c2c(OCC(F)(F)[C@@H]3CCCCN3C)c3cc(C(=O)Nc4ccncn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a solution of (S)-2-(2-chloro-1,1-difluoroethyl)-1-methylpiperidine (39 mg in 1.5 mL N,N-dimethylformamide) was added 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (64 mg), potassium bicarbonate (32 mg) and sodium iodide (25 mg) then heated to 80° C. on an oil bath. After 16 hours, the reaction was cooled to room temperature and concentrated in vacuo. Purification of the crude product by preparative tic on silica gel (chloroform:2M ammonium in methanol, 97:3) gave the title compound (56 mg). MASS: 582 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)C(=O)[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].[NH:34]1[CH2:37][CH2:36][C:35]1=[O:38]>>[NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([CH2:6][C@H:7]2[C@H:15]([OH:14])[C@@H:11]([NH:12][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:25])[CH3:26])[CH:19]=3)[CH2:10][S:9](=[O:28])(=[O:29])[CH2:8]2)=[CH:30][C:31]=1[N:34]1[CH2:37][CH2:36][C:35]1=[O:38]
Reactant: O=C1CCN1
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c(N)c(N4CCC4=O)c3)[C@@H]2O)c1

Procedure:
The title compound was prepared in analogous manner as described for example 4 from (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexa-hydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1k) and azetidin-2-one: HPLC RtC=2.99 min; ESIMS [M+H]+=504; NMR (400 MHz, CDCl3+0.5% D2O): δ 7.65 (m, 2H), 7.56 (t, 1H), 7.47 (m, 3H), 6.30 (m, 2H), 4.20 (q, 2H), 3.80 (m, 2H), 3.59 (m, 2H), 3.35, (m, 2H), 3.18 (m, 2H), 2.95 (m, 1H), 2.85 (m, 1H), 2.75 (m, 2H), 1.30 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:56]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:62][S:59]([CH:56]6[CH2:58][CH2:57]6)(=[O:61])=[O:60])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 29 (85 mg, 0.14 mmol) and CDI (47 mg, 0.29 mmol) in dry THF (7 mL) is heated at reflux for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate (RT=5.37). The reaction mixture is cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) is added. Then, DBU (50 μL, 0.33 mmol) is added and the reaction mixture is stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. Solvent is evaporated, and the residue partitioned between AcOEt and acidic water (pH=3). The crude material is purified by column chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1). The residue is crystallized in Et2O, filtered to give the target compound contaminated with the cyclopropyl-sulfonamide. This material is triturated in 3 ml of water, filtered, washed with water and dried overnight in the high vacuum pump to give the target compound 30 as a white powder: m/z=708 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:33][C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=3)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]2)=[CH:10]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1COCCO1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCC4COCCO4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 71 (part C) starting with 0.06 g (0.19 mmol) of 1-(2-[1,4]dioxan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole and 0.060 g (0.26 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard purification, 0.037 g (75% of yield) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]#[N:30])=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7].[CH2:31](N)[CH2:32][NH2:33]>CC(O)=O.CCO>[Cl:1][C:2]1[C:3]([C:29]2[NH:33][CH2:32][CH2:31][N:30]=2)=[N:4][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]([CH3:20])[CH3:19])[C:9]2=[O:28])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C#N)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Reactant: NCCN
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(Cl)c(C2=NCCN2)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
A mixture of 4-chloro-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]-5-methylpyrazole-3-carbonitrile (0.042 g, 0.10 mmol) in ethane-1,2-diamine (1.5 mL), HOAc (0.23 mL) and EtOH (1.25 mL) was stirred at 100° C. for 2.5 hrs. The mixture was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-[4-chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-5-methylpyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.041 g, 87%).
Reaction SMILES: N([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1)=[N+]=[N-].C1C(=O)N([Br:43])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:43][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CBr)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
5-(2-Azidomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole: To 114A (4 g, 9.15 mmol) in chloroform (20 mL) was added NBS (1.711 g, 9.61 mmol) and benzoyl peroxide (30 mg, 0.124 mmol) and the reaction was heated at reflux overnight. Additional NBS and peroxide were added and the reaction was heated an addition 2 h. The reaction was cooled to rt, filtered, and purified by flash chromatography to give 5-(2-bromomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole (3.5 g, 74.1%). 1HNMR (400 MHz, CDCl3) δ: 4.78 (s, 2H), 7.04-7.14 (m, 5H), 7.24-7.35 (m, 11H), 7.40 (d, J=2.02 Hz, 1H), 8.06 (d, J=8.34 Hz, 1H). This intermediate (1.57 g, 3.04 mmol) and sodium azide (0.198 g, 3.04 mmol) in DMF (8 mL) were stirred for two days. The reaction was partitioned with EtOAc/water/brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and purified by flash chromatography to give 114B. LCMS m/z 195.2 (M+H−N3)+; 152.1 (M+H−N6)+.