Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH:30]4[CH2:32][CH2:31]4)=[CH:28][C:27]([CH3:33])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:30]1([C:29]2[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=[C:27]([CH3:33])[CH:28]=2)[CH2:32][CH2:31]1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C2CC2)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)c(C2CC2)c1
Yield: 22.9 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 129 and by the reaction and treatment in the same manner as in Example 4, the title compound (108 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH:23]S(O)(=O)=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH:4]=1)=[O:23]
Reactant: O=S(=O)(O)O
Reactant: N#CC1=CCSc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=CC1=CCSc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.5 g of 4-cyano-2H-1-benzothiopyrane in 2 ml of benzene are reacted with 2 ml of a 20% solution of diisobutylaluminium hydride in toluene and the mixture stirred for 4 hours at room temperature. The resulting mixture is poured onto 20% H2SO4 and the organic phase separated, washed with saturated aqueous NaCl and dried over MgSO4. After concentration by evaporation the product is purified by chromatography over kieselgel (eluant hexane/ethyl acetate).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:63]([C@@H:61]2[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]2)=[O:64])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (92 mg, 0.24 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (86 mg, 0.22 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (51.9 mg, 0.24 mmol) and DIEA (0.043 mL, 0.24 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (86 mg, 0.22 mmol) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cc(B(O)O)ccn1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: COc1cc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)O)cc4)sc3n2)ccn1
Yield: 37 %

Procedure:
The titled compound (yield=37%, yellow solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 2-methoxypyridin-4-ylboronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 3.93 (s, 3H) 7.54 (s, 1H) 7.67 (d, J=8.59 Hz, 2H) 7.75 (dd, J=5.43, 1.39 Hz, 1H) 8.11 (d, J=8.59 Hz, 2H) 8.25 (d, J=1.52 Hz, 2H) 8.31 (d, J=5.31 Hz, 1H) 13.07 (br. s., 1H); ESI-MS: m/z 421.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:41]=[CH:40][C:17]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CCOCC>[ClH:39].[Cl:39][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:26]([N:23]1[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:17]3[CH:40]=[CH:41][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[CH2:25][CH2:24]1)(=[O:28])=[O:27])[CH:38]=[CH:37]2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(c1ccc(C2CCNCC2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 188 %

Procedure:
To a solution of 1-[4-(N-tert-butoxycarbonylpiperidin-4-yl)benzoyl]-4-(6-chloronaphthalene-2-sulfonyl)piperazine (125 mg) in ethyl acetate (0.5 ml) was added 4 N hydrochloric acid in ethyl acetate solution (4 ml) and the solution was stirred at room temperature for 1 hour, and diluted with ether. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (105 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][O:40][CH3:41])[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([NH:42][C:29]4[C:30]5[O:34][CH2:33][O:32][C:31]=5[C:35]([C:37]#[C:38][CH2:39][O:40][CH3:41])=[CH:36][C:28]=4[F:27])=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: COCC#Cc1cc(F)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCN(C(C)=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 71.6 %

Procedure:
This was prepared using the, method described in the example 4 using 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (150 mg, 0.40 mmol), 5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (97 mg, 0.43 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 0.83 ml) in DMF (2.5 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (162 mg, 72%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.98 (quintet, 2H), 1.99 (s, 3H), 2.34 (m, 2H), 2.40 (m, 2H), 2.50 (t, 2H), 3.37 (s, 3H), 3.44 (m, 4H), 3.94 (s, 3H), 4.20 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 6.91 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 566.
Reaction SMILES: C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3N(C=2C(O)=O)C=CS3)CC1.[CH:27]1([O:32][C:33]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:34]=2[CH:35]=O)[CH2:31][CH2:30][CH2:29][CH2:28]1.[Br-].[CH2:44]([O:46][C:47]([C:49]1[N:56]2[C:52]([S:53][CH:54]=[CH:55]2)=[N:51][C:50]=1[CH2:57][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:48])[CH3:45].[H-].[Na+]>CS(C)=O>[CH:27]1([O:32][C:33]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][C:34]=2/[CH:35]=[CH:57]/[C:50]2[N:51]=[C:52]3[N:56]([C:49]=2[C:47]([O:46][CH2:44][CH3:45])=[O:48])[CH:55]=[CH:54][S:53]3)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cccc(C=O)c1OC1CCCC1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Agent: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OC2CCCC2)nc2sccn12
Yield: 71.7 %

Procedure:
This compound was prepared as described in Intermediate 1 by the reaction of 2-(cyclopentyloxy)-3-methoxybenzaldehyde (1.318 g, 5.984 mmol) with 5-ethyloxycarbonylimidazo[2,1-b][1,3]thiazol-6-yl-methyl(triphenyl)phosphonium bromide (3.0 g, 5.440 mmol) in the presence of sodium hydride (239 mg, 5.984 mmol) in anhydrous DMSO (20 mL) to give 1.610 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40 (t, J=6.9 Hz, 3H), 1.54-1.65 (m, 4H), 1.78-1.85 (m, 4H), 3.81 (s, 3H), 4.39 (q, J=7.2 Hz, 2H), 4.83-4.86 (m, 1H), 6.99-7.02 (m, 1H), 7.09 (t, J=8.1 Hz, 1H), 7.21-7.25 (m, 1H), 7.46 (d, J=4.5 Hz, 1H), 7.67 (d, J=16.2 Hz, 1H), 7.88 (d, J=16.2 Hz, 1H), 8.12 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 413.27 (M+H)+.
Reaction SMILES: [N:1]1([CH2:10][C@@H:11](O)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:55]=[N+:56]=[N-:57])(C2C=CC=CC=2)=O)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:55]([C@H:11]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)=[N+:56]=[N-:57]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@@H](COCc1ccccc1)Cn1cnc2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H](COCc1ccccc1)Cn1cnc2ccccc21
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of Example 441A (1.0 g, 3.54 mmol) and triphenylphosphine (1.39 g, 5.31 mmol) in anhydrous THF (30 mL) was added diphenylphosphoryl azide (1.14 mL, 5,31 mmol) at 0° C. followed by the addition of DEAD (836 μL). The reaction mixture was stirred at 0° C. for 30 mins and at room temperature for 15 hrs. The concentrated residue was then purified by flash column chromatography on silica gel eluting with 60%-80% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>[Cl-].[Na+].O>[Br:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]=2[CH:15]=1
Reactant: COc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1Br)C(C(C)C)CNCC2
Reaction time: 8 h
Yield: 1117.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.013 g, 0.03 mmol) methanol (0.5 mL) was treated with 15% aqueous NaOH (0.5 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.10 g of a clear oil. 1H N (400 MHz, CD3OD) d 7.08 (s, 1 H), 6.64 (s, 1 H), 3.72 (s, 3 H), 3.2-3.10 (m, 3 H), 2.7-2.5 (m, 3 H), 2.3-2.1 (m, 2 H), 0.96 (d, 3 H), 0.63 (d, 3 H). MS calculated for C14H20BrNO+H: 298, observed: 298.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1Nc1ccccc1
Yield: 44 %

Procedure:
By a procedure similar to that of Example 219 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and aniline, the title compound was obtained in 44% yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccccc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: CO
Reactant: Cc1cc(O)c(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(C)cc1O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-hydroxy-4-methylbenzoic acid (6.78 g) in methanol (200 mL) was added dropwise sulfuric acid (6.77 mL), and the mixture was stirred overnight at 70° C. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.56 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]([NH:18][C@@H:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:20]([OH:24])[C:21](O)=[O:22])=[O:17])[NH:13][C:10]2=[CH:11][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:25]([C@H:19]([NH:18][C:16]([C:14]1[NH:13][C:10]2=[CH:11][N:12]=[C:7]([Cl:6])[CH:8]=[C:9]2[CH:15]=1)=[O:17])[C@H:20]([OH:24])[C:21](=[O:22])[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1CCNC1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 12 h

Procedure:
Pyrrolidine (7 μg, 0.084 mmol) was added to a solution of 3-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-4-phenylbutyric acid (EXAMPLE 124, 30 mg, 0.080 mmol), HOBt (14 mg, 0.091 mmol), DIPEA (31 μL, 0.18 mmol) and EDCI (18 mg, 0.094 mmol) in DMF (3 mL). After stirring for 12 h the mixture was added to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with brine (50 mL) and drying (MgSO4), gave, after concentration, a residue which was purified by preparative LCMS to give the title compound as a colourless solid. m/z (ES+)=427.31 [M+H]+; RT=3.27 min.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[C:11]1=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C[OH:21]>>[C:1]([O:9][CH:10]1[CH2:13][CH:12]([CH2:14][OH:15])[C:11]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=C1C(CO)CC1OC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(OC1CC(CO)C1=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A mixture of 2.09 g (9.5 mmol) of 1-benzoyloxy-3-hydroxymethyl-2-methylenecyclobutane from Step G, 112 mL of methylene chloride and 28 mL of methanol was cooled to -78° C. under a nitrogen atmosphere. Ozone was bubbled through the mixture for 10 minutes, until a persistent blue color was observed. Excess ozone was flushed out with nitrogen, 9 mL of dimethyl sulfide was added and the reaction mixture stirred for 0.5 h at -78° C. The reaction mixture was allowed to warm to ambient temperature, stirred for 0.5 h at ambient temperature and evaporated under reduced pressure to a syrup. The syrup (2.5 g) was dissolved to ~2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @ 5 psi with 100 mL of methylene chloride, followed by 250 mL of 1% methanol in methylene chloride and 250 mL of 2% methanol in methylene chloride to give 1.79 g (86% yield) of the title compound; MS DCI-NH3M/Z: 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>>[CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[O:13][CH2:14][C:15]4[CH:21]=[C:20]([NH:22][C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:29])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(NC3=Nc4ccc(N)cc4CO3)c2O1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2c(c1)COC(Nc1cccc3c1OC(C)(C)C3)=N2
Yield: 67.8 %

Procedure:
Prepared from the above described N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (150 mg, 0.49 mmol) and isopropyl isocyanate (42 mg, 0.49 mmol) according to the procedure described for Example 16. Obtained the title compound as a white solid (131 mg, 68%), MS (ISP) m/e=395.3 [(M+H)+].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]([CH3:13])([CH3:12])[C:10]#[CH:11]>C(OCC)C.O.[Cu]>[CH3:12][C:9]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([CH3:13])[C:10]#[CH:11]
Reactant: C#CC(C)(C)Cl
Reactant: OC1CCNCC1
Agent: [Cu]
Solvent: CCOCC
Solvent: O
Product: C#CC(C)(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24 mg cuprous chloride and 15 mg copper powder were added to a mixed solution of 5 ml solution of 7.3 g 4-hydroxypiperidine in diethyl ether (5 ml) and water (2.5 ml) in a nitrogen atmosphere. The mixture was ice-cooled, and 2.5 ml solution of 2.7 ml 3-chloro-3-methyl-1-butyne in diethyl ether was added dropwise thereinto at a bulk temperature of 17 to 22° C. Then, it was stirred at room temperature overnight. Water was added thereto, and the resulting mixture was extracted with diethyl ether for 5 times. The organic layers were combined, and dried over potassium carbonate and then over potassium hydroxide, and filtered. The filtrate was concentrated at normal pressure. The resulting crystalline residues were collected by filtration by adding ethyl acetate/hexane thereto to give 2.54 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:12]([Br:13])=[C:11]([NH:14][C:15]([C@@H:17]2[CH2:19][C@H:18]2[CH3:20])=[O:16])[S:10][N:9]=1.[CH3:21][N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28]2)=[N:23]1>COCCOC>[Br:13][C:12]1[C:8]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][N:22]([CH3:21])[N:23]=3)[CH:28]=2)=[N:9][S:10][C:11]=1[NH:14][C:15]([C@@H:17]1[CH2:19][C@H:18]1[CH3:20])=[O:16]
Reactant: Cn1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Temperature: 83 °C
Yield: 51 %

Procedure:
Add a 2; M aqueous solution of sodium carbonate (606.3; mL, 1.21; mol) to a stirring mixture of (1R,2R)-2-methyl-cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (148.1; g, 0.404; mol) and 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (123.40; g, 0.444; mol) in HPLC grade 1,2-dimethoxyethane (1.21; L) and degas using vacuum and nitrogen. Add bis(triphenylphosphine) palladium(II) dichloride (56.77; g, 80.84; mmol) in one portion, heat at 83° C. for 10; h, cool to room temperature and filter through a pad of Celite® using ethyl acetate to give a biphasic solution. Separate the layers and extract the aqueous layer three times with dichloromethane (200; mL). Combine all the organic layers, wash with brine (200; mL) and concentrate to approximately a volume of 400; mL. Separate into two portions and purify each by silica gel chromatography by gradient 50:50; to 10:90; eluting with n-hexane:ethyl acetate to give the title compound as a light brown solid (107.32; g, 51%). MS (m/z): 391,393; (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH3:10])[NH2:9])=[N:6][CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: COc1ccccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccccc1C(=O)N(N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of 5-bromo-2-hydrazinylpyridine (7.1 g, 38 mmol) and 2-methoxybenzoic acid (7.0 g, 46 mmol) in dichloromethane (DCM, 100 mL) were added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 25.2 g, 57 mmol) and N-methylmorpholine (NMM, 13.4 g, 0.10 mol), and it was stirred at room temperature for 2 h. The mixture was filtered and the solids were washed with DCM (50 mL×3), dried to give the title compound (8.23 g, 67.5% yield) as yellow solids. MS: m/z 322.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=O)[C:14]=3[C:22](O)=[O:23])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[O:29]=[C:28]1[CH:27]([N:26]2[C:22](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][C:13]=3[O:12][CH2:11][C:8]3[S:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=4[CH:9]=3)[C:16]2=[O:18])[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1
Reactant: O=C(O)c1cccc(OCc2cc3c(F)cccc3s2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc5c(F)cccc5s4)c3C2=O)C(=O)N1
Yield: 44.3 %

Procedure:
A mixture of 3-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid (1.2 g, 3.4 mmol), alpha-amino-glutarimide hydrochloride (0.58 g, 3.6 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-isoindole-1,3-dione as a white solid (0.66 g, 44% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.08 min (97.5%); mp, 264-266° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H, CHH), 2.54-2.95 (m, 2H, CHHCH2), 5.11 (dd, J=6, 12 Hz, 1H, CH), 5.73 (s, 2H, CH2), 7.18-7.88 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.95, 48.82, 65.85, 109.57, 109.81, 116.04, 116.91, 118.02, 119.02, 119.07, 120.37, 125.98, 126.08, 127.39, 127.65, 133.38, 137.02, 140.81, 141.98, 142.06, 154.81, 155.10, 158.41, 165.17, 166.71, 169.91, 172.78. Anal Calcd For C22H15N2O5SF: C, 60.27; H, 3.45; N, 6.39; S, 7.31; F, 4.33. Found: C, 60.40; H, 3.26; N, 6.29; S, 7.24; F, 4.32.