Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][CH:28]=3)=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>CCCCO>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][CH:28]=3)=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cncc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Solvent: CCCCO
Product: Cc1cncc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Temperature: 160 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (172 mg, 0.859 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide (100 mg, 0.286 mmol) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness, and then the residue was purified by chromatography (SP4, 25M, water/ACN 90/10 to 10/90, 30CV) to yield (R)-tert-butyl 1-(5-bromo-3-(5-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (47 mg, 31.0% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+:21]>O>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]([O-:16])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Na+:21]
Reactant: COc1cccc2cc(C(=O)O)oc(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cccc2cc(C(=O)[O-])oc(=O)c12
Reaction time: 0.75 h

Procedure:
To a stirred suspension of the carboxylic acid of Example 5 (3.7529 g., 17.05 mM) in 225 ml. of distilled water is added 1.4324 g. (17.05 mM) of sodium bicarbonate. After stirring 0.75 hour, the solution is filtered and freeze-dried to give a pale green solid. The solid is dried at 100° under vacuum for four hours to give sodium 8-methoxy-1-oxo-1H-2-benzopyran-3-carboxylate as a pale green solid, m.p. 244°.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[NH4+:24].Cl>ClCCl>[NH2:24][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of alcohol 20 (500 mg, 2.1 mmol) in dichloromethane at room temperature was added thionyl chloride (0.25 mL, 3.14 mmol) and the resulting reaction mixture is allowed to stir at room temperature for half hour. Thereafter concentrated ammonium hydroxide (10 mL) was added and the resulting reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was poured onto 1N HCl and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 35% EtOAc-Hexanes eluant) provided 310 mg of 24 as a white solid (500 mg theoretical, 62% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:31][C:32](=[O:44])[C:33]4[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[C:35]([Cl:43])[CH:34]=4)[CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:20][CH2:19][C@@H:18]([NH:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[C:35]([Cl:43])[CH:34]=1)[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:3]3[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of N-{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide (1.5 mmol) in ethanol (10 mL) was added hydrazine monohydrate (7.6 mmol). The reaction stirred for 18 h at 50° C. upon which a white precipitate formed and was filtered. The filtrate was concentrated in vacuo. The resultant light yellow solid was used directly in the next reaction without further purification. ESMS [M+H]+: 533.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:27]=[CH:26][C:17]3[O:18][C:19]([CH3:25])([CH3:24])[C@@:20]4([CH3:23])[O:22][C@H:21]4[C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]([OH:36])=[N:30]1.N1C=CC=CC=1>O1CCOCC1>[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]([O:36][C@H:21]2[C@@:20]([OH:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18][C:17]3[CH:26]=[CH:27][C:14]([S:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:13])=[O:12])=[CH:15][C:16]2=3)=[N:30]1
Reactant: Cn1nc(O)ccc1=O
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H]2O[C@]2(C)C(C)(C)O3)cc1OC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H](Oc2ccc(=O)n(C)n2)[C@](C)(O)C(C)(C)O3)cc1OC
Yield: 42.8 %

Procedure:
(3S,4S)-3,4-Dihydro-6-(3,4-dimethoxyphenyl)sulphonyl-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (3.0 g) (see Preparation 25) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (2.0 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (30 ml), pyridine (0.61 g) was added and the mixture heated under reflux (a calcium chloride drying tube was attached to the flask) for 2 days. The solvent was removed under reduced pressure, the residue stirred with 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the crude product chromatographed on silica eluting with 2.5:97.5 methanol: dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-6-(3,4-dimethoxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.7 g) as a yellow foam.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH3:23]
Reactant: CCN
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCC)s1
Yield: 55 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using ethylamine (2M solution in THF) instead of rac-2-amino-1-butanol, to the title compound (91 mg, 55%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=334.2 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:10]=1
Reactant: CS(=O)(=O)Nc1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 70 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
(Step 3) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.77 g), N-[2-(aminomethyl)-4-fluorophenyl]methanesulfonamide hydrochloride obtained in Step 2 (1.0 g) and potassium carbonate (1.36 g) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.04 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:15]C)=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=[O:17])[CH3:2].Cl.N1C=CC=CC=1>O>[CH2:18]([C:3]1([CH2:1][CH3:2])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([OH:15])=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=[O:17])[CH3:19]
Reactant: CCC1(CC)C(=O)c2cc(OC)c(C)c(C)c2C1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC1(CC)C(=O)c2cc(O)c(C)c(C)c2C1=O
Temperature: 180 °C

Procedure:
A mixture of 2,2-diethyl-4,5-dimethyl-6-methoxy-indan-1,3-dione (5.5 g., 0.021 mole) and pyridine hydrochloride (50 g.) is heated at 180°C. for six hours then poured into water (1 l) affording 4.0 g. of 2,2-diethyl-4,5-dimethyl-6-hydroxy-indan-1,3-dione which melts at 141°-142°C. after recrystallization from methanol-water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.S(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2CCCC2)C1=O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC(C(O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
3-Cyclopentanecarbonyl-2-oxopyrrolidine-1-carboxylic acid t-butyl ester (1.2 g, 4.4 mmol) was dissolved in THF (3.5 mL, 43.7 mmol) under nitrogen. 2M BH3.Me2S in THF (6.6 mL, 13.1 mmol) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 24 hours. After an additional 48 hours, the mixture was placed on an ice bath and the reaction slowly quenched with cold MeOH (100 mL). The mixture was stirred for 15 minutes, then diluted with EtOAc (30 mL), and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg). The oil was purified by preparative HPLC (2″ column; 5-50% MeCN/H2O; 0.1% TFA buffer; at 40 mL/min over 80 minutes). The desired fractions were collected, frozen and lyophilized to yield the title compound (939 mg). MS m/z: [M+H]+ calcd for C15H27NO3, 269.3; found 270.4.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:12]([CH3:13])=[N:11][C:10]2[C:5]1=[N:6][C:7]([C:14]#[N:15])=[N:8][CH:9]=2.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:13][C:12]1[N:4]([CH2:3][C:2]([CH3:17])([CH3:16])[CH3:1])[C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([C:14]#[N:15])[N:6]=2
Reactant: Cc1nc2cnc(C#N)nc2n1CC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)Cn1c(CBr)nc2cnc(C#N)nc21

Procedure:
A mixture of 1.1 g 9-(2,2-dimethyl-propyl)-8-methyl-9H-purine-2-carbonitrile, 1.7 g of N-bromosuccinimide and 116 mg dibenzoylperoxide was heated for 18 hours under reflux in 5 ml of CCl4. The mixture was evaporated and the residue was chromatographed on silicagel using hexanes/ethylacetate yielding 8-bromomethyl-9-(2,2-dimethyl-propyl)-9H-purine-2-carbonitrile as pale yellow wax.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
Prepared from 4-fluorobenzaldehyde and 1,4-dioxa-8-aza-spiro{4.5}decane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O.P(Br)(Br)([Br:20])=O>>[Br:20][C:1]1[C:2]2[C:3]([N:8]=[C:9]3[C:17]=1[CH:16]=[CH:15][CH:14]=[C:10]3[CH3:11])=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=P(Br)(Br)Br
Reactant: Cc1ccccc1Nc1ccccc1C(=O)O
Product: Cc1cccc2c(Br)c3ccccc3nc12
Temperature: 120 °C
Yield: 83.5 %

Procedure:
2-(2′-Methylphenylamino)benzoic acid 7 (1.0 g, 4.4 mmol) was suspended in 11.0 g (38 mmol) of phosphorus oxybromide, and the mixture was heated to 120° C. for 2 hours. Excess phosphorus oxybromide was removed by distillation and the residual solution was poured into a 1:1 mixture of aqueous ammonium hydroxide:CH2Cl2. The CH2Cl2 solution was separated, dried, filtered, and the combined organic layers were dried in vacuo to give 9 (1.0 g, 85%) as a yellow powder. 1H-NMR δ=2.94 (s, 3H), 7.53 (dd, J=8.5 Hz, J=8.8 Hz, 1H), 7.59-7.69 (m, 2H), 7.78 (ddd, J=1.4 Hz, J=8.5 Hz, J=8.5 Hz, 1H), 8.28 (dd, J=8.5 Hz, J=8.5 Hz, 2H), 8.43 (dd, J=1.4 Hz, J=8.8 Hz, 1H). 13C-NMR δ=19.48, 126.37, 128.49, 128.76, 129.07, 129.28, 129.72, 130.95, 131.15, 131.88, 135.87, 138.12, 148.43, 148.71. Anal. calcd. for C14H10NBr: C, 61.79; H, 3.70; N, 5.15. Found: C, 61.40; H, 3.72; N, 5.05.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:35]=[CH:36][CH:37]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@H:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:38]([BH3-])#N.[Na+]>CO.C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:35]=[CH:36][CH:37]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@H:28]([N:30]([CH2:31][CH2:32][O:33][CH3:34])[CH3:38])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COCCN[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COCCN(C)[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Add to a solution of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-N—[(R)-6-(2-methoxy-ethylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide (0.13 g, 0.20 mmol) in 5 mL MeOH formalin (0.3 mL) and sodium cyanoborohydride (51 mg, 0.82 mmol). Stir the mixture at room temperature for 2 h. Add sat. NH4Cl to the mixture to quench any unreacted sodium cyanoborohydride. Concentrate the mixture, concentrate and purify via preparative HPLC to afford 0.06 g, 58% yield of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-N-{(R)-6-[(2-methoxy-ethyl)-methyl-amino]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-benzamide. MS, ES+ 528.44 (M+H), rt 5.33 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)C)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCC(NC(C)=O)CC2)cc1OC
Agent: Cl
Product: COc1ccc(CCN2CCC(N)CC2)cc1OC

Procedure:
The acetamido compound of Example 3 (2.5 g.) in 2N hydrochloric acid (25 ml.) was heated under reflux for 3.5 hours. The cooled solution was basified and extracted with chloroform. Evaporation of the washed and dried extracts gave an oil which was treated with ethanolic hydrogen chloride to provide 1.67 g. of the title compound as its dihydrochloride, m.p. 260°-263° C. (Found: C, 53.4; H, 7.7; N, 8.3. C15H24N2O2.2HCl requires C, 53.3; H, 7.8; N, 8.3%).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:16]([NH2:19])([CH3:18])[CH3:17]>CO>[OH:1][CH:2]([CH2:15][NH:19][CH:16]([CH3:18])[CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccccc1OCC1CO1
Reactant: CC(C)N
Solvent: CO
Product: COC(=O)c1ccccc1OCC(O)CNC(C)C
Yield: 63 %

Procedure:
A mixture of 2.1 g (0.01 mole) of methyl 2-(2,3-epoxypropoxy)benzoate, 10 mL of isopropylamine and 10 mL of methanol was heated to reflux for three hours. The reaction medium was then evaporated under reduced pessure to provide the amine as an oil. The oil was treated with hexane:ethyl acetate (9:1) to generate the free amine as a crystalline product in 63% yield: m.p. 78°-79° C. The NMR spectrum and elemental analysis were consistent with the assigned structure.
Reaction SMILES: C1(COC([N:11]2[CH2:14][C:13]3([C@@H:18]([CH3:19])[NH:17][C:16](=[O:20])[O:15]3)[CH2:12]2)=O)C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][C@@H:18]1[C:13]2([CH2:14][NH:11][CH2:12]2)[O:15][C:16](=[O:20])[NH:17]1
Reactant: C[C@H]1NC(=O)OC12CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1NC(=O)OC12CNC2
Yield: 105.5 %

Procedure:
To a solution of (8R)-8-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylic acid phenylmethyl ester (1.84 g, 6.6 mmol) in methanol (66 mL) was added wet 10% palladium on carbon (50% by mass, 500 mg). The resulting suspension was stirred under 1 atm of hydrogen for 1 h. The catalyst was then removed by filtration through celite. The filtrate was concentrated in vacuo to provide (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one as a white solid (0.99 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 5.23 (br s, 1H), 4.07 (d, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 3.79 (d, 1H), 3.58 (d, 1H), 1.38 (d, 3H); MS (EI) for C6H10N2O2: 143 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:33][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C@@H:13]([NH:12][C:8]([C:5]3[O:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=3)=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: COc1ncc(C(=O)O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 16, (98 mg, 0.69 mmol) and (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (210 mg, 0.57 mmol) in DMF (10 mL) and CH2Cl2 (4 mL) is added HATU (272 mg, 0.72 mmol) and TEA (0.50 mL, 3.58 mmol). The crude is stirred at room temperature for 2 hrs. The crude is quenched with water and diluted in EtOAc. The organic layer is washed with water 3×, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate (122 mg). HPLC retention time=1.89 minutes (condition A); MS (m+1)=443.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H), 2.52-2.66 (m, 2 H), 2.94 (dd, 1 H), 3.08 (dd, J=13.6, 6.3 Hz, 1 H), 4.12 (s, 3 H), 4.14-4.23 (m, 2 H), 4.60-4.71 (m, 1 H), 6.81 (d, J=8.8 Hz, 1 H), 7.25-7.32 (m, 3 H), 7.35 (t, J=7.7 Hz, 1 H), 7.42 (s, 1 H), 7.43-7.47 (m, 1 H), 7.48-7.54 (m, 2 H), 7.55 (t, J=1.6 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10](=[O:19])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]([N:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:31]=[CH:30][C:5]=2[N:6]=1)=[O:19]
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(N)cc3s2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(NS(C)(=O)=O)cc3s2)cc1OC
Yield: 24.8 %

Procedure:
A mixture of 33.2 mg (0.07 mmol) N-(6-Amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide in 0.7 ml DCM, 18.2 mg (0.18 mmol) NEt3 and 10.3 mg (0.091 mmol) methanesulfonyl chloride in 0.2 ml DCM was reacted for 16 h at room temperature. After evaporation of all volatiles the residue was taken up in DMF/acetonitrile and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield 9.6 mg (25%) of the title compound. MS (m/e): 552.1 (MH+, 100%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]=[CH:7][C:6]2=[O:14].Br[CH:18]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]1Br.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[C:8]3[C:7](=[CH:19][C:20]4[C:21]([CH:18]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:6](=[O:14])[C:5]=2[CH:4]=1
Reactant: BrC1c2ccccc2C1Br
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
5.65 g (25 mmol) of 6-(trifluoromethyl)-1,4-naphthoquinone, 9.82 g (about 37 mmol) of 1,2-dibromobenzocyclobutene (contaminated with a little 2-bromo-1-iodobenocyclobutene) and 100 ml of xylene are kept under reflux for 16 hours, using a water separator. The mixture is cooled and the precipitate is filtered off and washed with xylene. Yield 5.82 g (71%); melting point 253°-254° C. The procedure in Examples 58 to 61 is analogous.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:17][C:16]=1[C:33]([F:36])([F:35])[F:34])=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:33]([F:36])([F:35])[F:34])=[O:13]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(N2CCC[C@@H]2C(=O)O)cc1C(F)(F)F)c1c[nH]c2ccccc2c1=O
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2R)-1-[4-[(4-oxo1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylate (35 mg, 0.06979 mmol) in DCM (500 μL) was added TFA (1 mL) at room temperature and the reaction mixture was stirred for 3 h. The solvents were evaporated under reduced pressure and the residue was purified via reverse phase HPLC to give (2R)-1-[4-[(4-oxo-1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic acid. LC/MS: m/z 466.3 (M+H)+ at 1.46 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).