Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=4[F:31])=[C:19]([C@H:32](F)[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=3)[C:10]=2[F:38])[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.C1([C@@H](C2C=CC=C(OCC3C=CC(C4C=C(OC)C=CC=4F)=C([C@@H](F)C(C)(C)C)C=3)C=2F)C[C:44](O)=[O:45])CC1.C1([C@H](C2C=CC=C(OCC3C=CC(C4C=C(OC)C=CC=4F)=C([C@H](F)C(C)(C)C)C=3)C=2F)CC(O)=O)CC1.C1([C@H](C2C=CC=C(OCC3C=CC(C4C=C(OC)C=CC=4F)=C([C@@H](F)C(C)(C)C)C=3)C=2F)CC(O)=O)CC1>>[CH:1]1([C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=4[F:31])=[C:19]([C@@H:32]([O:45][CH3:44])[C:33]([CH3:34])([CH3:35])[CH3:36])[CH:18]=3)[C:10]=2[F:38])[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1ccc(F)c(-c2ccc(COc3cccc([C@@H](CC(=O)O)C4CC4)c3F)cc2[C@H](F)C(C)(C)C)c1
Reactant: COc1ccc(F)c(-c2ccc(COc3cccc([C@@H](CC(=O)O)C4CC4)c3F)cc2[C@@H](F)C(C)(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3F)cc2[C@@H](F)C(C)(C)C)c1
Agent: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3F)cc2[C@H](F)C(C)(C)C)c1
Product: COc1ccc(F)c(-c2ccc(COc3cccc([C@H](CC(=O)O)C4CC4)c3F)cc2[C@@H](OC)C(C)(C)C)c1
Yield: 88 %

Procedure:
(3S)-3-Cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1R)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid or (3S)-3-cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1S)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid or (3R)-3-cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1R)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid or (3R)-3-cyclopropyl-3-(2-fluoro-3-(((2′-fluoro-2-((1S)-1-fluoro-2,2-dimethylpropyl)-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)phenyl)propanoic acid (83.9). The alkylation and hydrolysis were conducted in an analogous manner to Example 66.6 (using 83.B and 66.30G or 66.30H derived from peak two from the chiral separation of 66.30D from the OD-column, described herein) to yield 83.8 (0.0256 g, 88% yield). MS ESI (neg.) m/e: 525.3 (M−H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([NH2:11])(=[O:10])[CH:8]=[CH2:9]>ClC(Cl)C>[ClH:4].[CH:8]([C:7]1[O:10][C:1](=[O:5])[C:2](=[O:3])[N:11]=1)=[CH2:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC(N)=O
Solvent: CC(Cl)Cl
Product: C=CC1=NC(=O)C(=O)O1
Product: Cl
Yield: 99.7 %

Procedure:
Oxalyl chloride (130 g; 1.02 mol) was charged in a reactor, and a warm solution of acrylamide (71 g; 1.0 mol) in dichloroethane (250 ml) was dropwise added thereto (reaction temperature, 10° to 30° C.). After completion of the dropwise addition, the solvent and excess of the oxalyl chloride were removed by distillation under reduced pressure to obtain 2-vinyloxazoline-4,5-dione hydrochloride (161 g) as a yellow oil. Viscosity, 100,000 cp. Yield, 100%.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[Cl:25])[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccc(F)cc1Cl)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccc(F)cc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 52.6 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (100 mg, 0.28 mmol) and (1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (62.4 mg, 0.308 mmol) and 21% by wt. ethanolic sodium ethoxide (0.157 ml, 0.42 mmol) were heated together in a microwave reactor in EtOH (1.5 ml) at 140° C. for 10 min. The mixture was worked up by partitioning between EtOAc and 2M HCl. The organic phase was evaporated and purified by MDAP to afford the title compound as a solid (73 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Product: COc1cc(C(=O)O)cc(CCCOCc2ccccc2)c1OC
Yield: 68 %

Procedure:
3-(3-Benzyloxypropyl)-4,5-dimethoxybenzoic acid was prepared from 3,4-dimethoxy-5-hydroxypropylbenzoic acid (Example 10, Step 1) and benzyl bromide in 68% yield by following Method I and used without further purification.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:14][NH2:15].[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38]([NH:15][CH2:14][C:13]3[CH:12]=[C:11]([F:10])[CH:18]=[C:17]([F:19])[CH:16]=3)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cc(F)cc(F)c1
Yield: 45 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 3,5-difluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 45% yield: mp 208-209° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.23 (m, 5H), 6.82 (s, 1H), 6.80 (s, 1H), 6.66 (t, J=8.7 Hz, 1H), 6.24 (t, J=5.7 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H), 4.44 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.43 (t, J=8.4 Hz, 2H), 2.58 (s, 3H); 11C NMR (75 MHz, DMSO-d6) δ 164.6, 162.6, 161.5, 161.4, 157.4, 155.3, 142.3, 135.4, 128.9, 128.2, 128.0, 116.7, 110.3, 102.8, 47.9, 43.0, 42.0, 41.6, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])=[C:4]([F:6])[F:5].S(=O)(=O)(O)[OH:10]>O>[F:1][CH2:2][C:3]([OH:10])([CH2:7][F:8])[CH:4]([F:6])[F:5]
Reactant: FCC(CF)=C(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: OC(CF)(CF)C(F)F

Procedure:
As another example, the 2-fluoromethyl-1,1,3-trifluoro-2-propanol may be prepared by oxidizing commercially available 1,3-difluoro-2-propanol to 1,3-difluoro-2-propanone which may then be reacted with a CF2 carbene to form 2-fluoromethyl-1,1,3-trifluoro-1-propene. The 2-fluoromethyl-1,1,3-trifluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,3-trifluoro-2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:3][CH:4]=2)[N:11]=1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)CNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 362.2 %

Procedure:
A mixture of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (100 mg) prepared in a similar manner according to Step 6 of Production Example 1, ((tert-butoxycarbonyl)amino)acetic acid (74 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 1-hydroxybenzotriazole (57 mg) and dichloromethane (5 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate, and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica-gel with 3% methanol/chloroform as an eluent. The crystalline residue was collected and washed with ethyl acetate to give tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]-2-oxoethylcarbamate (580 mg).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([NH2:15])=[O:14])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:32])[CH:29](O)[OH:30].C(O)(=O)CCCC(O)=O>O>[ClH:1].[ClH:1].[ClH:1].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:32])[CH:29]([NH:15][C:13](=[O:14])[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:30]
Reactant: N=C(N)NCCCCCC=CC(N)=O
Reactant: NCCCNCCCCNC(=O)C(O)O
Agent: Cl
Agent: O=C(O)CCCC(=O)O
Solvent: O
Product: N=C(N)NCCCCCC=CC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C
Yield: 87.9 %

Procedure:
A mixture of 202.4 mg (0.86 mmole) of 8-guanidino-2-octenamide hydrochloride, 302.4 mg (1.04 mmoles) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, 113.9 mg (0.86 mmole) of glutaric acid and 0.2 ml of water was heated at 60° C. for 24 hours. After completion of the reaction the reaction mixture was purified in a manner similar to that in Example 1 using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 128.3 mg (29.2% yield) of N-[4-(3-aminopropyl)aminobutyl]-2-(8-guanidino-2-octenamido)-2-hydroxyethanamide trihydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4](=[C:20]([CH3:23])[O:21][N:22]=2)[N:5]=[C:6](C(O)=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].C([N:26]([CH2:29]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:38])C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]2=[N:22][O:21][C:20]([CH3:23])=[C:4]2[N:5]=[C:6]2[NH:26][C:29](=[O:38])[N:8]([C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])[C:7]=12
Reactant: Cc1onc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)nc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1onc2c(F)c3c(nc12)[nH]c(=O)n3-c1ccc(I)cc1F
Temperature: 25 °C

Procedure:
To a suspension of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylisoxazolo[4,3-b]pyridine-5-carboxylic acid (241 mg, 0.56 mmol) in toluene (10 ml) is added triethylamine (0.23 ml, 1.68 mmol) and diphenylphosphoryl azide (0.26 ml, 1.21 mmol). The reaction is heated at reflux for 4 h. The mixture is cooled to room temperature and concentrated to dryness. Silica gel chromatography yields the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][NH:2][C:36]([C:33]1([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=3)[CH2:35][CH2:34]1)=[O:37])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)NCCc3c(-c4ccccc4)c4cc(OC)ccc4c(=O)n3C)CC2)cc1
Reaction time: 3 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (70 mg, 0.20 mmol) in 3 mL of dimethylformamide was added 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (0.39 mg, 0.20 mmol), triethylamine (0.085 mL, 0.61 mmol), 1-hydroxybenzotriazole hydrate (37 mg, 0.24 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (47 mg, 0.24 mmol). After three hours, the mixture was partitioned between EtOAc and water, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was triturated with ether-hexane solution to provide the titled product. HRMS (ES) exact mass calculated for C30H30N2O4 (M+H+): 483.2258. Found 483.2279.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.I[C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[N:30]([C@H:38]2[CH2:43][CH2:42][C@@H:41]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:29]=[C:28]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=5[N:6]=4)=[CH:15][CH:14]=3)[C:36]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccc(Cl)cc6s5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
Procedure for Suzuki coupling: A mixture of N-(6-chloro-1,3-benzothiazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.116 g, 0.30 mmol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.106 g, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.012 mmol) in ethylene glycol dimethyl ether (3.0 mL), sodium carbonate (0.064 g, 0.60 mmol), and water (1.5 mL) in a sealed Schlenk flask were heated at 90° C. for 24 h. The mixture was cooled, diluted with water (10 mL) and extracted with methanol/dichloromethane (1:19, 3×20 mL). The combined organic fractions were dried (magnesium sulfate), filtered, concentrated and purified by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.8-10.0 min) to afford cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-6-chloro-1,3-benzothiazol-2-amine as a yellow powder (0.036 g, 0.062 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.42 min; MS (MH)+ 574.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][O:14]CC1C=CC=CC=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[CH3:9][C:2]([NH:10][C:11](=[O:31])[C@@H:12]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][OH:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(NC(=O)[C@H](COCc1ccccc1)NC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(NC(=O)[C@H](CO)NC(=O)c1ccccc1)c1ccccc1
Yield: 89.3 %

Procedure:
2.0 g of (2S)-N-(α,α-dimethylbenzyl)-2-benzoylamino-3-benzyloxypropionamide (prepared as described in Example 5) was catalytically reduced with hydrogen gas in the presence of 0.4 g of 10% w/w palladium-on-carbon in a mixture of 4 ml of acetic acid and 60 ml of ethanol. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. Recrystallization of the resulting residue from acetic acid and hexane gave 1.4 g of the title compound, melting at 152°-153° C.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:38])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:22]3=[O:24])[CH2:15][N:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:38])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CN(S(C)(=O)=O)C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N2[C@H](C(=O)NC2CC(=O)OC2O)C1
Reaction time: 0.5 h

Procedure:
A solution of (4S,6S,10aS)-6-benzoylamino-2-methanesulfonyl-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide, 15, (70 mg, 0.13 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford the desired product. 1H NMR (CD3OD) δ 7.90–7.88 (d, J=6.9 Hz, 2H), 7.52–7.55 (t, J=7.2 Hz, 1H), 7.52–7.47 (d, J=6.9 Hz, 2H), 5.14–5.11 (m, 2H), 4.69–4.67 (m, 1H), 4.54–4.49 (broad, d, J=12.6 Hz, 1H), 4.34–4.30 (m, 1H), 4.24–4.19 (broad d, J=12.9 HZ, 1H), 3.69–3.65 (d, J=12 Hz,1H), 3.40–3.28 (m, 3H), 3.09–3.04 (m,1H), 3.01 (s, 3H), 2.71–1.28 (m, 11H); MS 522.8 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:5]=1[CH3:19])(=[O:3])[CH3:2].Cl[C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]([C:8]1[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:19])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[C:7]=1[CH3:9])=[O:29]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(=O)CCCC(=O)OC)c2C)cc1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) and methyl 5-chloro-5-oxovalerate (0.63 mL, 4.5 mmol) reacted to give 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.05 (d, 2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.65 (s, 3H), 2.75 (t, 2H), 2.41 (s, 3H), 2.40 (t, 2H), 2.11 (s, 3H), 2.01 (s, 3H), 2.00 (quintet, 2H), 1.45 (t, 3H); MS (ESI) 386 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16](C=O)=[CH:15][CH:14]=2)[N:8]=1.O1CCN(C2CCC=CC2)CC1.[C:34]12(CS(O)(=O)=O)[C:41](C)(C)[CH:38](C[CH2:40]1)[CH2:37][C:35]2=[O:36].Cl>C(OCC)(=O)C.O.C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([CH:40]=[C:34]3[CH2:41][CH2:38][CH2:37][C:35]3=[O:36])=[CH:17][CH:18]=2)[N:8]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(C=O)cc3)n2)c(C)[nH]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C1=CCC(N2CCOCC2)CC1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccc(-c3ccc(C=C4CCCC4=O)cc3)n2)c(C)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask equipped with Dean-Stark trap topped with a condenser and N2 inlet were added 552 mg (2.0 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-formylphenyl)-pyridine, 20 mL benzene, 0.384 mL (2.4 mmol) 4-morpholino-1-cyclohexene, and 10 mg camphorsulfonic acid. The solution was refluxed with removal of water for 13 hours cooled, and 25 mL 3N hydrochloric acid added. The mixture was stirred at room temperature for 1 hour then diluted with ethyl acetate and water. The organic layer was separated, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated. The crude oil solidified on standing, 460 mg (˜100%), and was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]2[O:23][C:10]3[C:11](=[O:22])[N:12]([C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=O)[CH2:13][C:9]=3[CH2:8][C:7]=2[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][N:60]=1>O1CCCC1.O>[Cl:65][C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:15](=[O:17])[C@@H:14]([N:12]2[CH2:13][C:9]3[CH2:8][C:7]4[C:6]([O:25][CH3:26])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:24]=4[O:23][C:10]=3[C:11]2=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:60][CH:61]=1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: Nc1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 90 °C
Yield: 18.5 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.24 mmol), in tetrahydrofuran (10 mL) was treated with N-methylmorpholine (760 mg, 0.69 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (263 mg, 0.69 mmol) and commercially available 2-amino-5-chloropyridine (42 mg, 0.33 mmol). The mixture was heated in a sealed tube was heated for 16 hours at 90° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide (21 mg, 16.2%), as an off white solid. 1H NMR (DMSO-d6) δ: 11.09 (br. s., 1H), 8.40 (br. s., 1H), 8.05 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.05 (br. s., 1H), 4.38 (d, J=19.1 Hz, 1H), 4.03 (d, J=18.6 Hz, 1H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.82 (br. s., 1H), 1.67 (br. s., 1H), 1.45 (br. s., 1H), 0.93 (t, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[O:8][CH2:9][C:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([C:27]#[C:28][CH3:29])[CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Cl.O>C1COCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[O:8][CH2:9][C:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([C:27]#[C:28][CH3:29])[CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CC(CC(=O)OC)c1ccc(OCC2(COc3cccc(C(C)(C)C)c3)CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3cccc(C(C)(C)C)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
410 mg of methyl 3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoate were dissolved in a mixture of THF/MeOH/2N NaOH=1:1:1 (5 ml of each) and stirred at room temperature. After 45 min, the mixture was acidified to pH 1 by adding 4N HCl. 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by means of RP-HPLC. This gave 148 mg of 3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoic acid.