Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.Cl[C:21]([F:27])([F:26])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH:21]([F:27])[F:26])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (1.8 g) obtained in Reference Example 132-(1) was dissolved in dimethylformamide (15 ml), and added thereto were methyl 2-chloro-2,2-difluoroacetate (1.63 ml) and potassium carbonate (2.28 g), and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction mixture was acidified with 2N aqueous HCl solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl methyl) benzene (695 mg) as a colorless solid. GC-Mass m/Z 402/404 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1ccncc1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccncc1)CC3
Yield: 53 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 4-pyridinecarboxaldehyde. Yield 53%; mp 119°-122° C.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:47]=[CH:46][C:17]([C:18]([O:20][CH2:21][N:22]2[C:31]3[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[CH:23]2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][N:22]2[C:31]3[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)=[CH:23]2)=[O:19])=[CH:46][CH:47]=1
Reactant: [H][H]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)c3ccc(OCc4ccccc4)cc3)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)c3ccc(O)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
10% palladium/carbon (260 mg) was added to a THF (30 ml) and ethanol (15 ml) solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-benzyloxybenzoate (2.6 g, 4.6 mmol). The mixture was subjected to hydrogen substitution and stirred at room temperature for 3 hours. After completion of the reaction, the catalyst was removed by conducting filtration using Celite, and the mixture was concentrated to dryness under reduced pressure, giving a pale yellow powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-hydroxybenzoate (2.22 g, yield: quantitative).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[C:34]([NH2:35])=[C:33]([NH2:36])[C:31](=[O:32])[NH:30][C:28]1=[S:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:35][C:34]1[N:27]([CH2:26][C:25]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:24]=2)[C:28](=[S:29])[NH:30][C:31](=[O:32])[C:33]=1[NH:36][C:10](=[O:11])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OCc1ccccc1
Reactant: CC(C)(OCc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(N)c(NC(=O)C(C)(C)OCc3ccccc3)c(=O)[nH]c2=S)cc1OCc1ccccc1
Yield: 75.3 %

Procedure:
A solution of 2-benzyloxy-2-methyl-propionyl chloride (30.70 g, 144 mmole) in THF (100 ml) was added at 0-5° C. over 15 minutes to a stirred suspension of 1-(3-benzyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil (40.58 g, 100 mmole) and triethylamine (31.4 ml, 225 mmole) in THF (400 ml). After 1 hour the solid was filtered off and the solution evaporated to dryness in vacuo. The residue was suspended in a mixture of diethyl ether (400 ml), water (100 ml) and saturated sodium bicarbonate solution (60 ml). After crystallization for 60 hours the solid was collected and washed with ether and water to give 6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-5-(2-benzyloxy-2-methyl-propionylamino)-2-thiouracil (42.23 g, 75.3%). Crystallization from ethyl acetate gave mp 123-125/184-187° C.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C([Li])CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1.C(O)(=O)C>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[O:23][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncoc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of Ethyl isocyanoacetate (1.00 mL, 9.15 mmol) in Tetrahydrofuran (43 mL) at −78° C. was added 2.5 M n-Butyllithium (9.15 mmol, 9.15 mmol) in hexanes under argon. The mixture was stirred for 20 min. 4-Chlorophenylacetyl chloride (0.753 g, 3.98 mmol) in Tetrahydrofuran (11 mL, 130 mmol) was added at the same temperature. After 1 h, the temperature was raised to rt and then quenched by acetic acid (0.38 g, 6.3 mmol). The mixture was washed with saturated sodium bicarbonate and brine. The organic layer was collected and dried over sodium sulfate. After evaporation, the mixture was purified by chromatography to afford ethyl 5-(4-chlorobenzyl)-1,3-oxazole-4-carboxylate (0.83 g, 78%). LCMS: (FA) ES+ 266.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:4]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:33])=O>ClCCl>[Cl:33][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC2CCN(C)CC2)c2c(=O)[nH]cnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (3.00 g, 10.4 mmol) and diisopropyl ethylamine (5 ml) in dichloromethane (300 ml) was stirred at ambient temperature under an atmosphere of nitrogen. Phosphoryl chloride (10 ml) was added, and the resultant orange solution was heated at reflux for 20 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. Residual phosphoryl chloride was then removed by azeotrope with toluene to give the crude product as an orange oil. Purification by chromatography on silica gel, eluting with 5% triethylamine in dichloromethane, gave an orange solid, which was further purified by trituration under acetonitrile, and then dried in vacuo to yield 4-chloro-5-(N-methylpiperidin-4-yloxy)-7-methoxyquinazoline (2.4 g, 75% yield) as a pale yellow amorphous solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH2:33][NH:34][C:35]([NH:37][CH3:38])=[O:36])[C:30](O)=[O:31])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH:60]([C:30](=[O:31])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]([NH:20][C:10]2[CH:11]=[C:12]([C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)[CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])=[CH:28][CH:27]=1)[CH2:33][NH:34][C:35]([NH:37][CH3:38])=[O:36])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CNC(=O)NCC(C(=O)O)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
2-[4-({[2-[(tert-Butoxycarbonyl)amino]-5-(3-thienyl)phenyl]amino}-carbonyl)phenyl]-3-{[(methylamino)carbonyl]amino}propanoic acid (104 mg, 0.19 mmol), EDCI (54 mg, 0.28 mmol), and HOBT (34 mg, 0.25 mmol) were combined in DMF (3 mL) and stirred for 10 minutes before adding aniline (26 μL, 0.28 mmol). The reaction was then stirred at room temperature for 2 h. The mixture was directly purified by reverse phase HPLC (45-95% MeCN/water) to give the title compound as a white solid. MS (ESI) calcd [M+H]+ 614.2, found 614.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (0.344 g; 1.41 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.19 g; 1.41 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.298 g; 1.56 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-(1-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-propionamide (0.67 g; 1.42 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropyletylamine (0.242 mL; 1.41 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (20 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%;30 mL), an aqueous solution of sodium hydrogen carbonate (pH 8; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue as chromatographed on silica (3×30 cm) using methylene chloride/ethyl acetat (1:1) as eluent to afford 0.81 g of ((3E)-1,1-dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2(1-naphtyl)ethyl)-carbamoyl)but-3enyl)carbamic acid tert butylester.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:22][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[OH:23][C@H]1CC[C@@]2(C)[C@@]3(O[C@@H]3C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1.CC(O)C>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[OH:22][C@:4]12[CH2:3][C:2](=[O:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 75 %

Procedure:
To a solution of a 1/1 mixture of 3β-hydroxy-5α,6α-epoxyandrostan-17-one and 3β-hydroxy-5β,6β-epoxyandrostane-17-one (2.10 g, 6.90 mmol) in acetone (38 mL), Jones reagent (8.35 mL) was added dropwise, maintaining the temperature below 40° C. 5 min after completion of the addition, i-PrOH (10 mL) was added and, after further 10 min, the suspension was filtered and the filtrate evaporated to dryness. The residue was treated with H2O (300 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (100 mL), 5% aqueous NaHCO3 solution (100 mL), H2O (100 mL), dried over Na2SO4 and evaporated to dryness to give 5α-hydroxyandrostane-3,6,17-trione as a white solid (1.65 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.00 (s, 1H), 2.85 (m, 2H), 2.45-1.25 (m, 17H), 1.06 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([OH:22])[CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1C(C)O)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1ccccc1C(C)OC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate (63 g, 0.2 mol) and pyridine (50 ml) in dichloromethane (400 ml) were stirred at 0° C. and treated with benzoyl chloride (50 ml) in dichloromethane (100 ml) added at such a rate to keep the reaction temperature below 10° C. The cooling bath was removed and the mixture was stirred at ambient temperature for 2 hours. The solution was washed with 2M hydrochloric acid (x2), saturated sodium hydrogen carbonate solution, water and brine, dried (anhyd. MgSO4), filtered and evaporated to an orange oil (70 g, 83%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].O=[CH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][CH:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[S:6]1
Reactant: COC(=O)CCC=O
Reactant: SCC(S)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCC1SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure in Example 1 using 1,2,3-trimercaptopropane (4.21 g, 0.03 mol), methyl 4-oxobutanoate from Example 73 (3.5 g, 0.03 mol) and boron trifluoride etherate (1 ml) in methylene chloride (75 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 2.5 g (35%) of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH:16]([C:19]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2=[CH:33][CH:34]=[CH:35][N:21]2[N:20]=1)[CH2:17][CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][NH:15][CH:16]([C:19]1[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:32])[C:22]2=[CH:33][CH:34]=[CH:35][N:21]2[N:20]=1)[CH2:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
(1,1-Dimethyl-3-oxo-propyl)-carbamic acid tert-butyl ester (19 mg, 0.564 mmol) and 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 120 mg, 0.376 mmol) were stirred in CH3OH (10 mL) for 1 h at 25° C. The mixture was then treated with NaBH(OAc)3 (119 mg, 0.564 mmol) and stirred for 12 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 30×100 mm column affording the desired material (100 mg, 57%) as a colorless oil: 13C NMR (CDCl3 100 MHz) δ 161.54, 154.93, 154.42, 144.72, 135.84, 129.53, 128.58, 127.27, 121.99, 117.28, 114.95, 111.94, 110.48, 79.81, 58.05, 51.12, 44.61, 43.07, 35.91, 28.17, 27.07, 26.53, 8.55; LC/MS (ESI+) 468 (M++H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].C(O)C>O>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:10][CH:11]([OH:12])[CH2:13][OH:14])[CH3:2]
Reactant: OCC1CO1
Reactant: CCNc1ccccc1
Solvent: CCO
Solvent: O
Product: CCN(CC(O)CO)c1ccccc1
Temperature: 120 °C
Yield: 94.7 %

Procedure:
A mixture of N-ethylaniline (1.21 g, 10 mmol), glycidol (1.11 g, 15 mmol) and ethanol (1 ml) was heated by microwave irradiation for 10 min at 120° C. The mixture was dissolved in water (10 ml) and extracted with ethyl acetate (3 times 25 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/heptane=1:2) to yield a colorless liquid (1.85 g, 94%); MS (ISP): 196.3 ((M+H)+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:20][O:21][C:22](=[O:45])[C@@H:23]([NH2:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:21][C:22](=[O:45])[CH:23]([NH:44][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N1CC(C)CC(C)C1
Yield: 78.1 %

Procedure:
A solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g, 0.933 mmol) in DMF (4.0 mL) was reacted with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol), and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM (+20% hexane) to give 0.435 g (62%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050 g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 584 (M+1)+. 1H NMR (CDCl3) 11.20 [d, 1H], 8.21 [d, 1H], 7.45 [m, 2H], 7.39 [m, 2H], 7.23 [m, 8H], 7.02 [m, 2H], 6.86 [m, 2H], 4.90 [m, 1H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1H], 2.80 [m, 2H], 2.16 [t, 1H], 2.04 [t, 1H], 1.70 [m, 2H], 1.43 [m, 1H], 0.76 [m, 6H], 0.58 [m, 1H].
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[C:5]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl-].[Na+].CS(C)=O>O>[Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethyl-1-ethoxycarbonylcyclopropane carboxylate (5.0 g.), sodium chloride (0.95 g.), and `wet` dimethylsulphoxide (6.0 ml.) was heated at a temperature of 175° to 180° C. under a nitrogen atmosphere for a period of 6 hours, after which it was cooled to the ambient temperature poured into water and extracted with petroleum ether (boiling range 60° to 80° C.). The extracts were dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent to yield a residue comprising about 60% of the cis-isomer and 40% of the trans-isomer of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylate in about 80% yield, identification of which was confirmed by comparison with authentic samples using infra-red spectroscopy and gas-liquid chromatography.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]1[C:33]2[N:34]([C:38]([CH:57]3[CH2:60][CH2:59][CH2:58]3)=[N:39][C:40]=2[C:41]2[CH:42]=[C:43]([CH:54]=[CH:55][CH:56]=2)[O:44][CH2:45][C:46]2[CH:47]=[C:48]([CH2:52]O)[CH:49]=[CH:50][CH:51]=2)[CH:35]=[CH:36][N:37]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:31][C:32]1[C:33]2[N:34]([C:38]([CH:57]3[CH2:60][CH2:59][CH2:58]3)=[N:39][C:40]=2[C:41]2[CH:42]=[C:43]([CH:54]=[CH:55][CH:56]=2)[O:44][CH2:45][C:46]2[CH:47]=[C:48]([CH:49]=[CH:50][CH:51]=2)[CH2:52][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:35]=[CH:36][N:37]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(CO)c4)c3)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(CN5C(=O)c6ccccc6C5=O)c4)c3)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phthalimide (44 mg, 0.25 mmol), PS-triphenylphosphine (169 mg, 0.37 mmol) and {3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-phenyl}-methanol (100 mg, 0.25 mmol) were added to a dry rbf and dissolved with THF (1.25 mL), which was then evacuated and purged three times with nitrogen. DIAD (61 mg, 0.30 mmol) was added slowly to the reaction mixture and allowed to slowly stir for 24 h at rt. LC/MS analysis indicated that the reaction was nearly finished with some starting material left, but mostly product. Therefore, 0.2 eq. of DIAD and phthalimide were added and the reaction was left to proceed. The reaction mixture was filtered through a glass frit and washed with CH2Cl2 multiple times. The filtrate was concentrated to a red/brown oil and purified using silica gel column chromatography (1% NH3 in MeOH:CH2Cl2) to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.09 (m, 1H), 2.11-2.23 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1H), 4.87 (s, 2H), 5.11 (s, 2H), 6.99-7.02 (m, 2H), 7.10 (d, J=5.2 Hz, 1H), 7.23-7.26 (m, 2H), 7.35-7.42 (m, 4H), 7.49 (s, 1H), 7.69-7.73 (m, 2H), 7.82-7.87 (m, 2H); MS (ES+): m/z 530.14 (100) [MH+].