Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[C:33]([N:37]=[C:38]=[O:39])([CH3:36])([CH3:35])[CH3:34]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:38]([NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 85.5 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (500 mg, 0.8 mmoles) was dissolved in anhydrous dichloromethane (5 ml) and tert-butyl isocyanate (383.8 mg, 3.2 mmoles) was added. The mixture was stirred under argon at 25° C. for 47 h. Additional tert-butyl isocyanate (191.4 mg, 1.6 mmoles) was added and the reaction was stirred for a total of 144 h. The solution was heated at 74° C. for 5 h and the stirred at 25° C. for an additional 24 h. The solution was chromatographed on silica gel using 2% (10% conc. NH4OH in methanol) dichloromethane as the eluant to give 421.8 mg of the title compound (Yield: 71%).
Reaction SMILES: NC1C=C(C=CC=1Cl)C(C1C=CC=CC=1)=O.[N+:17]([C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]([CH2:31][CH3:32])([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O>>[NH2:17][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]([CH2:31][CH3:32])([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCC(O)(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Nc1cc(C(=O)c2ccccc2)ccc1Cl
Product: CCC(O)(c1ccccc1)c1ccc(Cl)c(N)c1

Procedure:
This compound is prepared from 3-amino-4-chlorobenzophenone as described in Example 1, or by reducing 3-nitro-4-chloro-α-ethyl-benzhydrol as described in Example 7. The product melts at 103° C.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:16]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: O=C1Nc2ccccc2Oc2sccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and butyryl chloride (880 mg) was added. To this reaction system was added portionwise aluminium chloride (4.6 g) under ice-cooling. The mixture was stirred at room temperature for 45 minutes. Insoluble matter was filtrated and the filtrate was poured into ice water, and chloroform was added. The organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and water-ethanol was added. The precipitated crystals were collected by filtration. The obtained crystals were washed with chloroform-diisopropyl ether to give 2-butyrylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9]1.C[O:21][C:22](=[O:46])[CH:23]([NH:34][C:35](=[O:45])[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=1[CH3:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH:23]([NH:34][C:35](=[O:45])[C:36]3[C:37]([CH3:44])=[CH:38][C:39]([CH3:43])=[CH:40][C:41]=3[CH3:42])[C:22]([OH:46])=[O:21])=[CH:26][CH:27]=2)[CH2:9]1
Reactant: COC(=O)C(Cc1ccc(B(O)O)cc1)NC(=O)c1c(C)cc(C)cc1C
Reactant: c1ccc(NCC2CNC2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(N3CC(CNc4ccccn4)C3)cc2)C(=O)O)c(C)c1
Reaction time: 20 h

Procedure:
153 mg (0.203 mmol) TFA salt of (10) together with 150 mg (0.406 mmol) 2-(2,4,6-trimethylbenzoylamino)-3-(4-boronophenyl)propionic acid methyl ester (12), 844 μl (6.1 mmol) triethlamine and 74 mg (0.406 mmol) Cu(OAc)2 were stirred in 2.5 ml DCE for 20 min under ultrasonification and then stirring was continued for another 20 h at room temperature. The reaction mixture was filtered over a pad of Celite, the solvent was removed under reduced pressure and the residue was dissolved in acetonitrile to be filtered over another pad of Celtite. After the solvent was removed, the crude methyl ester was dissolved in 9 ml methanol and stirred with 4 ml 0.5 M NaOH over the weekend. Solids were removed by filtration and the reaction mixture was purified by reversed phase HPLC using a water/acetonitrile gradient containing 0.1% TFA yielding the TFA salt of (11) after lyophilization as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(NC(=O)CCl)C=CC=CC=1>>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C(CCl)Nc1ccccc1
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
Indoline-2,3-dione (I-D) is either N-alkylated with benzylchloride (I-E) or N-phenyl-2-chloro-acetamid (I-F) to yield the 1-benzylindoline-2,3-dione (I-G) or with the 1-phenylcarbamoylmethylindoline-2,3-dione (I-H), respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([NH:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[NH:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:35]2[CH:34]=[C:33]([NH:41][S:42]([C:45]3[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[C:32]([NH:31][CH2:29][CH3:30])=[N:37][CH:36]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CCNc1ncc(B(O)O)cc1NS(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 45 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (25 mg, 0.06 mmol) was treated with 6-(ethylamino)-5-(4-methoxyphenylsulfonamido)pyridin-3-ylboronic acid (30 mg, 0.09 mmol), 2M cesium carbonate (60 μl, 0.12 mmol) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3 mg, 0.01 mmol) according to the method described in Example 3 to give 18 mg (48% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[NH2:36][C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.C(C1C=CC(N=C=S)=CC=1)#N>>[C:37]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:2][CH:7]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: N#Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(C#N)cc4)cc3)cc2C1=O

Procedure:
The compound of example 67 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-cyanophenyl isothiocyanate. The compound of example 67 was used directly without isolation for the preparation of compound of example 66.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][O:13][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([Cl:17])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(OCc2cccc(OCc3ccccc3)c2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 3-benzyloxybenzyl alcohol (3.46 g, 16.2 mmol), K-t-BuO (1.69 g, 15.1 mmol) and 2,6-dichloropyrazine (1.97 g, 13.2 mmol). The yield of the title compound was 2.64 g (61%) and was obtained as a semisolid. Anal. (C18H15ClN2O2) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][N:28]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[O:9])=[N:22][C:21]=2[CH:34]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2nccs2)c(C(=O)O)c1
Product: Cc1ccc(-c2nccs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-2-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 481 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][S:12]S(=O)(=O)O)=[CH:2]1.CCOCC>P(=O)(O)(O)O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][SH:12])=[CH:2]1
Reactant: O=S(=O)(O)SCCc1c[nH]c2ccccc12
Agent: O=P(O)(O)O
Solvent: CCOCC
Product: SCCc1c[nH]c2ccccc12

Procedure:
Thiosulfuric acid S-[2-(1H-indol-3-yl)-ethyl]ester, O-sodium salt (5.04 g, 18 mmol) was suspended in 105 ml of 50% phosphoric acid and covered with a layer of 160 ml of ether. The mixture was refluxed for 6 hours. After cooling, the phases were separated and the aqueous phase was extracted with ether and the organic phases were concentrated to dryness by evaporation. The crude product was obtained in a yield of 3.2 g (100%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10]([Br:28])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(-c2cccc3c2c(=O)ccn3Cc2ccccc2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(Br)cn3Cc2ccccc2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
1-Benzyl-5-mesitylquinolin-4(1H)-one (0.52 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0° C. N-bromosuccinimide (0.27 g, 1.5 mmol) was added and the reaction stirred for 1 hr. The reaction was quenched with water (100 mL) and the precipitate was collected by vacuum filtration. 0.57 g (90%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([CH3:35])[C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:33])[C:31]([F:36])([F:30])[CH3:35])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(Cl)cc3)c2)[C@H](C)N)c1
Reactant: CC(F)(F)C(=O)O
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: CN1CCCC1=O
Solvent: O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(Cl)cc3)c2)[C@H](C)NC(=O)C(C)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (126a) (256 mg, 0.63 mmol) dissolved in NMP (3.5 mL) was added to a solution of 2,2-difluoropropanoic acid (111 mg, 1.00 mmol), HATU (382 mg, 1.00 mmol) and DIPEA (0.438 mL, 2.51 mmol) in NMP (1.5 mL). The reaction mixture was stirred at r.t. for 2 h. Additional 2,2-difluoropropanoic acid (80 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (0.25 mL, 1.4 mmol) in NMP (1.5 mL) was added. The reaction mixture was stirred at r.t. for another h. Water (50 mL) was added, the mixture was extracted with EtOAc (2×50 mL), the organic phase was washed with 10% NaHSO4 (aq), brine, dried over MgSO4, filtered and evaporated to give a crude product that was purified by HPLC. The fractions containing the product was combined and freeze dried. Yield 197 mg (62%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:29][C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[CH:31][CH:30]=2)[C:3]1=[O:18]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC#N
Product: COCCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)C1=O
Temperature: 130 °C
Yield: 90.6 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-morpholinoaniline (0.53 mmol, 94 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was subjected to microwave heating single node 130° C. for 10 min and purified on SiO2 (EtOAc:heptane, 1:1) to give 96 mg (89%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 7.73 (bs, 1H), 7.17-7.04 (m, 3H), 6.98-6.93 (m, 2H), 6.70-6.64 (m, 2H), 6.59-6.54 (m, 2H), 3.75-3.70 (m, 6H), 3.58 (t, J=5.6 Hz, 2H), 3.33 (s, 3H), 2.98-2.95 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:37]=1
Reactant: NC(=NO)c1ccccc1F
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3F)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 42.3 mg (0.275 mmol) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 55.6 mg (42% of theory).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10]([O:14]C)[C:11](Br)=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1.[CH3:31][S-:32].[Na+].[BH4-].[Na+].Cl[O-].[Na+]>CCOC(C)=O.O.C(O)(=O)C.CN(C=O)C>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([OH:14])[C:11]([S:32][CH3:31])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)C1
Reactant: C[S-]
Agent: [BH4-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Temperature: 120 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesised by the of WO9616051 for the corresponding 3-butyl-3-ethyl analogue; 40 mg, 0.08 mmol) was added DMF (2 ml), sodium methanethiolate (60 mg, 0.85 mmol) and sodium borohydride (60 mg, 1.6 mmol). The reaction was run overnight at 60° C. Additional sodium borohydride (60 mg, 1.6 mmol) and sodium methanethiolate (60 mg, 0.85 mmol) was added and the temperature was raised to 120° C. The reaction heated at this temperature for 4 hours and then cooled to room temperature. Then acetic acid was added under a flow of nitrogen, through sodium hypochlorite overnight. Water and EtOAc was added and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with HCl (1M), dried and concentrated under reduced pressure. The residue was then purified by flash chromatography [EtOAc:heptane, 1:4] to give the title compound 0.34 g (93%). NMR 0.7–0.9 (m, 6H), 1.0–1.6 (m, 12H), 2.2 (s, 3H), 3.1 (s, 2H), 3.4 (s, 2H), 3.7 (brs, 2H), 6.7 (s, 1H), 6.85–7.05 (m, 2H), 7.2–7.4 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[F:25])=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]#[N:43])=[N:40][CH:41]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(=O)([O-])[O-].[K+].[K+].N#N>C1COCC1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O>[C:42]([C:39]1[N:40]=[CH:41][C:36]([CH2:2][CH2:1][C:3]2[CH:12]=[C:11]3[C:6]([C:7]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[F:25])=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[N:10]3)=[CH:5][CH:4]=2)=[CH:37][CH:38]=1)#[N:43]
Reactant: N#Cc1ccc(Br)cn1
Reactant: C=Cc1ccc2c(-c3ccc(OC)cc3F)cc(C(=O)OC)nc2c1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(OC)cc2F)c2ccc(CCc3ccc(C#N)nc3)cc2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
Methyl 7-ethenyl-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (250 mg, 0.741 mmol) was dissolved in THF (1.3 ml), heated to 60° C. and then added 9-BBN (0.5M THF, 1.85 ml, 0.93 mmol) dropwise over 5 minutes. After 1 hour, allowed to cool to ambient. Added 5-bromopyridine-2-carbonitrile (203 mg, 1.112 mmol), Pd2(dba)3 (33.9 mg, 0.037 mmol), butyldi-1-adamantylphosphine (26.6 mg, 0.074 mmol), potassium carbonate (410 mg, 2.96 mmol) and water (135 degassed 5 minutes with N2 and then heated to 90° C. in a sealed tube for 30 minutes. Reaction proceeded, allowed to cool to ambient. Added brine and then EtOAc. The organic portion was collected, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel, eluting with hexanes to EtOAc to afford methyl 7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (160 mg, 0.362 mmol, 48.9% yield) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:3]=1[C:4]([NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:5].[Cl:29]C1C=CC=C(Cl)C=1C(N[C@H](C(O)=O)CNC([C@@H]1CCC(=O)O1)=O)=O>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:3]=1[C:4]([NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:5]
Reactant: O=C1CC[C@@H](C(=O)NC[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)O1
Reactant: CC(CC(=O)NC[C@H](NC(=O)c1c(F)cccc1Cl)C(=O)O)c1ccccc1
Product: CC(CC(=O)NC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O)c1ccccc1

Procedure:
N-(2-chloro-6-fluorobenzoyl)-3-[(3RS)-3-phenylbutanoyl]amino-L-alanine) or k is 0 (for example N-(2,6-dichlorobenzoyl)-3-[(2S)-5-oxotetrahydrofuran-2-carbonyl]amino-L-alanine;
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Cl)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(OC)c2)cc1
Yield: 96.8 %

Procedure:
3-Chloroanisole (76 mg, 0.54 mmol) reacted with 4-methoxyphenylboronic acid (117 mg, 0.77 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in toluene at 80° C. to give the title compound (112 mg, 97%) as a colorless oil: 1H-NMR (300 MHz CDCl3): δ 7.57 (d, 2H, J=8.7 Hz), 7.37 (t, 1H, J=7.8 and 8.1 Hz), 7.17 (m, 2H), 7.01 (d, 2H, J=8.7 Hz), 6.88-6.97 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 159.86, 159.17, 142.28, 135.51, 129.66, 128.13, 119.21, 114.09, 112.44, 111.93. GC/MS (EI): m/z 214 (M+), 199, 171, 128. Anal. Calcd for C14H4O2: C, 78.48; H, 6.59. Found C, 78.46: H, 6.62.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]([C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:9]=[C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:11]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[NH:10]1
Reactant: NC(=O)c1ccccc1N
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: O=C(O)COc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Yield: 73 %

Procedure:
2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from anthranilamide and 4-formyl phenoxy acetic acid, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (800 mg, 73%) was isolated as a white solid. Selected data: MS (m/z): 296.98; MP 285-287° C.