Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:21](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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]>[C:24]([O:23][C:21](=[O:28])[NH:22][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1nccc2nc(-c3c(Cl)cc(C#N)cc3Cl)sc12
Temperature: 80 °C
Yield: 76 %

Procedure:
A mixture of 4-(4-bromo-thiazolo[5,4-c]pyridin-2-yl)-3,5-dichloro-benzonitrile (0.578 g, 1.50 mmol), tert-butyl carbamate (1.76 g, 15.0 mmol), Pd2(dba)3 (0.069 g, 0.075 mmol), XantPhos (0.087 g, 0.15 mmol) and tribasic potassium phosphate (0.635 g, 3.0 mmol) in toluene (10 mL) and water (1.5 mL) was degassed with argon then heated at 80° C. for 3 hours. The reaction mixture was filtered through Celite® and washed with EtOAc. The filtrate was washed with water then brine, dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-50% EtOAc in pentane) to give the desired compound as an off-white solid (0.48 g, 76% yield). 1H NMR (300 MHz, CDCl3): δ 8.35 (d, J=5.6 Hz, 1H), 7.79 (d, J=5.6 Hz, 1H), 7.75 (s, 2H), 1.56 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:22]2[CH2:24][CH2:23]2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:4]([F:25])[CH:3]=1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:45])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:22]2[CH2:24][CH2:23]2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:45])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:4]([F:25])[CH:3]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 150 mg (0.25 mmol) of the compound from Example 230 in analogy to the synthesis of the compound from Example 235. 75 mg (77% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([CH:11]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10].CN(C=O)C>O>[Br:8][C:18]1[CH:17]=[CH:16][C:15]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[C:14]([O:13][CH2:12][CH:11]([CH2:9][CH3:10])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(CC)COc1ccccc1OCC(CC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(Br)cc1OCC(CC)CCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Solid NBS (26.21 g, 0.147 mol) was added to an ice cold CH2Cl2 solution (250 mL) of 1b under N2 in the absence of light. Just enough DMF was added (30 mL) to disolve the NBS. The reaction mixture was allowed to warm to room temperature and then stirred for 12 h. The mixture was then poured into water. The organic layer was washed with a saturated LiCl solution and water. After drying with MgSO4 the solvent was removed under reduced pressure. The remaining oil was distilled (160° C./0.01 mmHg) to yield 4-bromo-1,2-di(2-ethylhexyloxy)benzene (2b) in 96% yield as a colorless oil.
Reaction SMILES: Cl[Si:2]([CH3:14])([CH2:4][CH2:5][Si:6]([CH3:13])([CH3:12])[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CCOCC>[CH3:14][SiH:2]([CH2:4][CH2:5][Si:6]([CH3:13])([CH3:12])[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH3:3]
Reactant: C[Si](C)(C)C[Si](C)(C)CC[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[SiH](C)CC[Si](C)(C)C[Si](C)(C)C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
About 77.4 g (0.29 mol) of the chlorosilane described above were added dropwise to a suspension containing 3.2 g (0.084 mol) of LiAlH4 in 150 ml of absolute ether while stirring at 10°-30° C. over a period of 3 hours. Continuation of the reaction at room temperature for 4 hours was followed by cautious decomposition of the excess alanate with water, and the mixture was made basic with 10 ml of 5N NaOH and the phases were separated. After working up the ether phase, the distilled residue yielded 62.5 g (92.9% of theory) of 2,5,5,7,7-pentamethyl-2,5,7-trisilaoctane at 82°-83° C. under 134 Pa. C10H28Si3.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:28]([CH3:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:4]([NH:6][C@@H:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16]CC)=[O:15])=[O:9])=[O:5].CO[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][C@H:3]([C:28]([CH3:36])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:4]([NH:6][C@H:7]([C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([OH:16])=[O:15])=[O:9])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:5]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO[C@@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
According to General Procedure II, a 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (1.0 g, 2.0 mmol, from Reference Example 104) is dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). To this solution is added water (5 mL) and lithium hydroxide monohydrate (0.17 g, 4.0 mmol), and the resulting mixture is stirred at 60° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (240 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[(N-[(2R)-2-methoxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a clear colorless oil (80 mg). MS (ES+): (M+H)=475.0
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]([OH:12])=O)[C:4]=2[CH:3]=1.C(Cl)(=O)[C:16]([Cl:18])=O.[N+](=C)=[N-].Cl>>[Cl:18][CH2:16][C:10](=[O:12])[CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=2[S:6][CH:7]=1
Reactant: O=C(O)Cc1csc2ccc(Cl)cc12
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(CCl)Cc1csc2ccc(Cl)cc12
Yield: 97.1 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting 5-chlorobenzo[b]thiophen-3-yl acetic acid (4.00 g, 17.6 mmol) with oxalyl chloride (1.7 mL, 2.5 g, 19 mmol), then ethereal diazomethane, then dry HCl gas. Work-up of the reaction mixture gave pure product as a light golden-yellow solid (4.43 g, 97% yield): 1H NMR (400 MHz, CDCl3) δ 4.12 (s, 2H) 4.15 (s, 2H) 7.35 (dd, J=8.6, 2.1 Hz, 1H) 7.43 (s, 1H) 7.65 (d, J=2.1 Hz, 1H) 7.79 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:28]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][O:24][C:23](=[O:25])[C@H:12]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (S)—N-benzyloxycarbonyl-L-tryptophan 1a (2.45 g, 7.2 mmol) in 10 ml anhydrous CH2Cl2, was added DMAP (0.1 g, 0.82 mmol) and methanol (0.28 g, 11.8 mmol). At 0° C., DCC in CH2Cl2 solution was slowly added to the mixture and then it was allowed to warm to room temperature and stirred overnight. After twice filtration and evaporation, the residue was purified by flash column chromatography (n-hexane/EA, 4:1 to 2:1) and afforded the desired product (S)-2a as a colourless oil (2.5 g, 98%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][O:36][CH2:37][C:38](=[O:40])[CH3:39])[O:7][C@@H:6]1[CH2:41][O:42]C(=O)C)(=O)C.[OH-].[Li+]>C1COCC1.CO.O>[Cl:34][C:22]1[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:41][OH:42])[O:7]2)=[C:20]([CH:21]=1)[CH2:35][O:36][CH2:37][C:38](=[O:40])[CH3:39]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(COCC(C)=O)cc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(C)=O)cc2Cl)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-((2-oxopropoxy)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (36.8 g, 0.057 mmol) (prepared from intermediate J using a Wacker oxidation as described for the preparation of intermediate T-1 below) in THF:MeOH:H2O (2:3:1, 1.2 mL) was added lithium hydroxide (3.71 mg). The reaction was stirred overnight at 20° C. The volatiles were removed and the residue was dissolved in EtOAc (20 mL), washed 1× with brine, 1× with brine containing 2 mL of 5% aqueous KHSO4 and dried over Na2SO4. Concentration gave 16 mg of pure product as a white solid. 1H-NMR (CD3OD, 300 MHz) δ 7.47 (s, 1H), 7.44 (s, 1H), 7.08 (s, 4H), 4.80 (d, J=12.3 Hz, 1H), 4.55 (d, J=9.6 Hz, 1H), 4.22 (s, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.85 (dd, J=11.7 Hz, 2.1 Hz, 1H), 387-3.83 (m, 1H), 3.68-3.63 (m, 1H), 3.50-3.36 (m, 4H), 2.58 (q, J=7.8 Hz, 2H), 2.12 (s, 3H), 1.19 (t, J=7.8 Hz, 3H); LC-MS (m/z) 479 [(M+1)+], 523 [(M+45)−].
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12][CH3:13])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[Cl:1][C:2]1[C:3]([S:12][CH3:13])=[N:4][C:5]([CH:11]=[CH:19][N:20]([CH3:22])[CH3:21])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CSc1nc(C)c([N+](=O)[O-])cc1Cl
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CSc1nc(C=CN(C)C)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
3-Chloro-6-methyl-2-methylthio-5-nitropyridine (D7) (1.35 g, 6.18 mmol) was treated with tert-butoxy-bis(dimethylamino)methane (1.26 ml, 7.41 mmol) and was heated to 100° C. with stirrng. After 0.5 h, the reaction mixture was allowed to cool and was triturated with petroleum ether (60-80) (15 ml). The resultant dark solid was then filtered off and dried in vacuo to give the title compound as a dark red solid (1.56 g, 92%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1.C(O)(=O)C>O>[N:18]1([C:17]2[CH:19]=[CH:20][C:14]([S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)(=[O:13])=[O:12])=[CH:15][CH:16]=2)[CH:23]=[CH:27][CH:26]=[CH:25]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(-n2cccc2)cc1)c1cccc2cnccc12
Yield: 76.1 %

Procedure:
A mixture solution of 4-(5-isoquinolylsulfonyl)aniline 300 mg (1.1 mmol), 2,5-dimethoxytetrahydrofuran 160 mg (1.2 mmol) and acetic acid 2 ml was heated and refluxed for 1 hour. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystalized from ethyl acetate-hexane to give 5-[4-(pyrrole-1-yl)phenylsulfonyl]isoquinoline 280 mg (83.0%).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[C:15]=1[CH3:33])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:1]([CH:8]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Br:32])=[CH:30][CH:31]=2)[C:15]=1[CH3:33])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(Cc1ccccc1)C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76.2 %

Procedure:
To a room temperature solution of the methyl ester from Step 2 (40 mg, 0.08 mmol) in 3 mL THF and 5 mL MeOH was added 1 mL of 1M LiOH. The resulting solution was stirred 30 h at room temperature, then quenched with aqueous NH4Cl and concentrated in vacuo. The residue was partitioned between 1M HCl and EtOAc, washed with brine, dried over Na2SO4 and evaporated to give 30 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:6](=[O:12])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]=1[NH:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1.[C:33]([NH:36][C:37]1[S:38][C:39]([S:43](Cl)(=[O:45])=[O:44])=[C:40]([CH3:42])[N:41]=1)(=[O:35])[CH3:34].C(Cl)Cl.Cl>N1C=CC=CC=1>[C:33]([NH:36][C:37]1[S:38][C:39]([S:43]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C:23]([NH:22][C:3]3[C:4](=[O:21])[N:5]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:6](=[O:12])[N:7]([CH2:8][CH:9]4[CH2:11][CH2:10]4)[C:2]=3[NH2:1])=[O:32])=[CH:30][CH:29]=2)(=[O:44])=[O:45])=[C:40]([CH3:42])[N:41]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Nc1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
A solution of N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-(4-amino-phenyl)-acetamide (prepared as in Example 1, 75 mg, 0.16 mmol) in pyridine (1.6 mL) was stirred at 25° C. for 5 min. This solution was then treated with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (44 mg, 0.17 mmol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then poured into a mixture of methylene chloride (50 mL) and a 1.0N aqueous hydrochloric acid solution (10 mL). This mixture was extracted with a 1/9 methanol/methylene chloride solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 7/93 methanol/methylene chloride) afforded 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (56.4 mg, 54%) as an off-white solid; FAB-HRMS m/e calculated for C29H30FN7O6S2 (M+) 655.1683, found 655.1679
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem, 57, 1992, 5462.) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160° C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:37]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:37].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-benzhydryloxy]azetidine (132) (3.8 mmol) using the procedure described for compound (9) (0.70 g, 60%).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCCC1.C(O)(=O)C>C(O)C>[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: Cc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.2 g of 5-methyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed with 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.2 g (80% yield) of 3-[2-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1cccnc1
Product: COc1ccc2c(-c3cccnc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-pyridinylboronic acid to give (6-methoxy-1-pyridin-3-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 318(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[C:18](/[C:24]([O:26]C)=[O:25])\[CH2:19][C:20]([O:22]C)=[O:21].ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[C:24]([C@:18]1([OH:36])[C@@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:21][C:20](=[O:22])[CH2:19]1)([OH:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C/C(=C\CCCCCCCCc1ccc(Cl)cc1Cl)C(=O)OC
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C[C@](O)(C(=O)O)[C@@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
(E)-Methyl 12-(2,4-dichlorophenyl)-3-methoxycarbonyl-3-dodecenoate (686 mg, 1.65 mmol, described in example 4) and 3-chloroperbenzoic acid (5.7 g of 55% grade, 18.2 mmol) were heated under reflux in dichloromethane (15 ml) for 24 h. The mixture was cooled and poured into aqueous NaHCO3 /Na2SO3. This mixture was stirred for 10 min, then extracted with dichloromethane. The extracts were washed with aqueous NaHC3, water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum, and the residue purified by chromatography on silica gel (20-40% ether/petroleum ether 40-60%) to give the title compound (369 mg, 52%) as an oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[C:25]([F:34])[CH:24]=3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:2].CO.[OH-].[Li+]>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[C:25]([F:34])[CH:24]=3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1)[CH3:2]
Reactant: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (4-{2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}-2-fluorophenyl)acetate (1.4 g, 2.97 mmol) was dissolved in THF (3 ml):MeOH (30 ml) and 1M lithium hydroxide (14.84 ml, 14.84 mmol) added. The mixture was stirred at RT overnight. The mixture was concentrated in vacuo and the residue diluted with water (5 mL). The pH of the solution was adjusted to pH˜5 by addition of 1N HCl and the aqueous phase was extracted with EtOAc (3×10 mL). The organic fractions were combined, washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford the title compound. LC/MS (m/z): 458 (M+H)+.