Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55]([N:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:63]=1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccn4C(=O)OC(C)(C)C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 31.7 %

Procedure:
DIEA (0.009 mL, 0.053 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.010 g, 0.048 mmol) and HATU (0.02 g, 0.053 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (0.013 g, 0.048 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 29% yield: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br-]>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMF was added bnezyl bromide (60 μL) at room temperature. The resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product (60 mg) was purified by combiflash using hexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl 4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which was then converted to the final compound using procedures analogous to those for example 1. MS(ESI): (M+H)+=462.2
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:33][N:32]=5)[S:30][C:23]=34)=[C:17]([F:43])[CH:16]=2)=[O:13])[CH2:10][CH2:9]1.CO.C(Cl)Cl>C(O)=O>[CH:8]1([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29]([C:31]5[N:32]=[CH:33][C:34]([CH2:37][N:38]([CH2:39][CH2:40][O:41][CH3:42])[CH:1]=[O:3])=[CH:35][CH:36]=5)[S:30][C:23]=34)=[C:17]([F:43])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Solvent: ClCCl
Solvent: O=CO
Solvent: CO
Product: COCCN(C=O)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To solution of acetic anhydride (150 μL, 1.17 mmol) in formic acid (2 mL) stirred at RT for 20 min was added in one portion 1 (150 mg, 0.296 mmol). After 2 hr, 200 μL of acetic anhydride (1.57 mmol) were added dropwise. The reaction mixture was stirred at RT overnight, quenched by addition of MeOH and concentrated. The residue was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV, then 10/90 over 5 CV), to afford the title compound 6 (96 mg, 0.18 mmol, 76% yield) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.75 (s, 1H), 8.60-8.50 (m, 2H), 8.37 and 8.34 (2s, 1H), 8.32-8.23 (m, 114), 8.15 (s, 1H), 7.90-7.77 (m, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (bd, J=10.2 Hz, 1H), 6.67-6.58 (m, 2H), 4.60 and 4.56 (2s, 2H), 3.46-3.36 (m, 4H), 3.21 and 3.19 (2s, 3H), 2.59-2.51 (m, 1H), 0.70-0.60 (m, 2H), 0.47-0.38 (m, 2H). MS (m/z): 536.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@@H:24]4[C:27](O)=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.C([N:34](CC)C(C)C)(C)C.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@@H:24]4[C:27]([NH2:34])=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Cc2ccc(N3CC[C@@H]3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3CC[C@@H]3C(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled 0-5° C. and stirred solution of (R)-1-[5-(3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (I-144, 0.14 g, 0.33 mmol) in THF (2.5 mL) was added N,N-diisopropylethylamine (0.09 g, 0.69 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.05 g, 0.36 mmol) was added, and the reaction stirred at 0-5° C. for 30 min. Ammonium hydroxide solution (28%, 1.0 mL, 8.0 mmol) was added, the reaction warmed to room temperature, and stirred for 0.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane, followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.07 g (47%) of P-617 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.99 (d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.38-7.46 (m, 3H), 7.4 (br s, 1H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm; MS (APCI+): 426.9 (M+1), LC-MS: 100%.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]([F:16])=[C:7]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[N:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CO.Cl>O.C1COCC1>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]([F:16])=[C:7]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(F)c(N2CCCC2)nc1NC1CC1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A solution of ethyl 2-cyclopropylamino-5-fluoro-6-pyrrolidinyl-3-pyridine-carboxylate (Example E-2, 270 mg, 0.92 mmol) and NaOH (360 mg, 9.0 mmol) in water (1 mL), THF (2 mL), and MeOH (1 mL) was refluxed for 3 hours. The mixture was cooled to room temperature, acidified with dilute HCl to pH 6, and evaporated under reduced pressure. The residue was mixed with 10% MeOH/dichloromethane (40 mL), dried on sodium sulfate, filtered, and evaporated. The solid residue was further washed with hexane and dried in vacuo, giving 215 mg of the title compound as powder, mp 64-66° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1([C:27]#[N:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.BrC1C=CC=CC=1[Li].S1C=CN=C1.CC(C)CC(N)C12OCC(C)(CO1)CO2.N[C@H](C(O)=O)CC(C)C>>[C:27]([C:24]1([NH:23][C:16](=[O:18])[CH:15]([NH:14][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:26][CH2:25]1)#[N:28]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)O
Reactant: N#CC1(N)CC1
Agent: CC(C)CC(N)C12OCC(C)(CO1)CO2
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CC(C)NC(C)C
Product: CC(C)CC(N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared by the coupling of (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid with 1-aminocyclopropanecarbonitrile in the presence of HATU and diisopropylamine, in similar manner to that described for the preparation of Example 34. The synthesis of (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid was accomplished via addition of bromophenyllithium (generated in situ from 1,4-dibromobenzene and n-butyllithium) to the imine condensation product between thiazole 2-carboxayldehyde and 3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butylamine (L-leucine OBO ester, prepared according to the method described for Example 34), followed by ortho ester deprotection.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].C1COCC1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[C:2](=[O:3])([O:4][CH:5]([CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)OC(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)OC(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1.0 g (1.18 mmol) of bis(9-fluorenyl)-methyl chloroformate in 15 mL of freshly distilled THF and 15 mL of dry benzene was added 0.21 mL (2.3 mmol) of freshly distilled aniline in one portion at 0° C. The mixture was stirred at 0° C. for 3 hours and quenched with 10 mL of sat'd NH4Cl. The organic layer was washed with water (10mL) and the pooled aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to give 1.13 g (100%) of the crude urethane as a white solid. Recrystallization from chloroform gave 0.93 g (82.03%) of the pure α-F-Fmoc-aniline as white crystals, m.p. 225°-227° C. (dec.); IR (KBr): 3340 (NH), 1705 (C=O) cm-1 ; 1H NMR (DMSO-d6): δ 4.59 (d, 2H, ArCH), 5.70 (t, 1H, CHO), 6.80-7.95 (m, 21H, aryl), 9.38 (b, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]=[C:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>C1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[C:8]([CH3:21])=[CH:7][C:6]=2[CH:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(cc1Br)CC(C)=NN=C2c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Br)C=C(C)N(C(=O)C1CC1)N=C2c1ccc([N+](=O)[O-])cc1

Procedure:
0.5 g of 7-bromo-1-(4-nitrophenyl)-4-methyl-8-methoxy-5H-2,3-benzodiazepine (Example 3, Step C) is suspended in 15 ml of benzene, mixed with 0.53 g of potassium carbonate and 0.17 ml of cyclopropylcarboxylic acid chloride and then refluxed for 5 hours. Then, the mixture is stirred with water, the organic phase is separated, washed in succession with soda solution and water, dried, filtered and concentrated by evaporation. The residue is purified by absorptive precipitation in ethanol, and 0.38 g of 7-bromo-3-cyclopropylcarbonyl-1-(4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzodiazepine of the title compound with a melting point of 231-223° C. is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[N:2]1.CN1CCOCC1.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.C(OCC)(=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:28][C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[O:15])=[N:2]1
Reactant: Nc1nc[nH]n1
Reactant: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1nc[nH]n1)c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
A solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (30 mg, 0.11 mmol) obtained in Step 1 of Example 47 in THF (0.50 mL) was sequentially added with 4-methylmorpholine (25 μL, 0.23 mmol), 3-amino-1,2,4-triazole (14 mg, 0.17 mmol), EDC (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole monohydrate (20 mg, 0.15 mmol) followed by stirring at room temperature for 2.0 hours. The reaction mixture was added organic layer and aqueous layer and the organic layer was with water and ethyl acetate to separate the mixture into concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain Compound 139 (17 mg, 45%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CCCc1cnc(Cl)nc1
Product: CCCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-propyl-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=1.86 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]2C(=O)NC(=O)NC2=O)=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:12][CH:11]=1
Reactant: O=C1NC(=O)C(CCc2ccc(Cl)cc2)C(=O)N1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(CCCc2ccncc2)cc1
Temperature: 200 °C

Procedure:
A mixture of 3 g (0.02 m) of 4-chloropyridine hydrochloride and 5.3 g (0.02 m) of 5-[2-(4-chlorophenyl)-ethyl]barbituric acid was thoroughly mixed with a mortar and pestle, heated in a 200° C. oil bath for 15-20 minutes, and then cooled. To the resulting product was added 5 g of NaOH and 40 mL of water, and the mixture was refluxed for several hours. After cooling the mixture, it was acidified with concentrated HCl, again refluxed for 45 minutes, and then cooled. The resulting material was diluted into water; the pH of the aqueous solution was adjusted to 7-8 with dilute NaOH; then the product was extracted into CH2Cl2. The CH2Cl2 layer was separated, filtered through phase separating paper, and concentrated. The residue was adsorbed onto silica gel and chromatographed using 5% EtOAc/CH2Cl2 >10% EtOAc/CH2Cl2 >5% MeOH/EtOAc (wash). Yield 0.82 g.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:16][CH:2]([OH:1])[CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH2:34][CH2:35]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
5 g (˜25 mmol) 2-(3,4-epoxybutyl)-isoindolin-1,3-dione, 7.5 g (30 mmol) benzhydrylpiperazine and 3.5 g (25 mmol) potassium carbonate are stirred in DMF for 6 hours 80° C. After cooling, the reaction mixture is filtered and concentrated under vacuum. The residue is taken up in 300 ml acetic acid ethyl ester and washed three times each with 20 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])[O:3]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:23])[O:3][B:4]([C:9]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:10]=2[CH2:11][OH:12])[O:5]1
Reactant: COC(=O)c1ccc(C(=O)OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC1(C)OB(c2cc(CO)ccc2CO)OC1(C)C
Temperature: -10 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Dimethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)terephthalate (CVI) (2.60 g, 8.12 mmol) was dissolved in DCM (25 mL), flushed with argon and cooled to −10° C. A 1 M solution of diisobutylaluminum hydride in DCM (48.73 mL, 48.73 mmol) was then added dropwise and the reaction was stirred at 0° C. for 2 h. 1 N aqueous HCl (50 mL) was carefully added and stirred for 5 minutes. The reaction was extracted with DCM and the combined extracts were washed with brine, dried over anhydrous MgSO4 and concentrated to give (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-phenylene)dimethanol (CVII) (2.0 g, 7.57 mmol). The crude product was used without further purification for step 4.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12]([OH:14])[CH3:13].[ClH:15]>C(OCC)C>[ClH:15].[CH2:12]([O:14][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH3:13]
Reactant: CCO
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)c1cccc(C(C)=O)c1
Reaction time: 48 h

Procedure:
A solution of 7.25 g (0.05 mol) of 3-acetylbenzonitrile (Aldrich, Buchs, Switzerland; Cat. No. 29,221-4) in 150 ml of diethyl ether and 4.5 ml of ethanol is saturated at 0° C. with dry hydrochloric acid gas and then left to stand at 0° C. for 2 days. The product that has crystallized out is filtered off and the title compound is obtained after recrystallization from ethanol/diethyl ether, m.p. 110° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][CH2:41][OH:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][CH:41]=[O:42])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC=O)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.4 %

Procedure:
To a solution of the compound of example 5, step 5 (0.955 g, 1.67 mmol) in 10 ml of DCM under argon was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (7.78 g, 1.84 mmol). The mixture was stirred at room temperature for 3.5 h and then diluted with 40 ml of diethyl ether. The solution was washed three times with a 1 N solution of sodium hydroxide (15 ml) and twice with brine (15 ml). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give 0.965 g of the title compound as a green powder which was directly used in the next step.
Reaction SMILES: CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][N:29]([CH2:33][CH2:34][C@@:35]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:36](O)=[O:37])[C:28](=[O:44])[CH:27]=2)=[C:22]([F:45])[CH:21]=1.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>CC1CCCO1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][N:29]([CH2:33][CH2:34][C@@:35]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:36]([NH:53][O:52][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][O:46]3)=[O:37])[C:28](=[O:44])[CH:27]=2)=[C:22]([F:45])[CH:21]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (54 mL, 491 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (43.1 g, 245 mmol) were added to a solution of (2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (68.7 g, 164 mmol) in 2-methyltetrahydrofuran (1 L) and the reaction was stirred at rt for 2 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (28.8 g, 245 mmol) was added and the reaction was allowed to stir at rt for 1 h. The mixture was filtered and the filtrate was concentrated. The crude residue was purified via column chromatography using silica gel and eluting with 40% EtOAc in n-heptane (4 L) and EtOAc (6 L). The desired fractions were combined and concentrated to afford the title compound as a white gummy solid. (74.82 g, 88%). MS (LCMS) m/z 517.9 (M−1).