Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C=O.[C:14](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][N:3]1[C:8]2[C:9](=[CH:4][CH:5]=[CH:6][N:7]=2)[CH:10]=[CH:11][CH:2]1[Cl:1]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Clc1ccc2c(n1)CCNC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1c2ncccc2C=CC1Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 250 mg of 2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (U.S. Pat. No. 6,169,093) in methylene chloride (6.1 mL) was treated with 0.148 mL of a 37% formalin solution, followed by 0.388 g of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 60 hrs. and quenched by the addition of 2N sodium hydroxide (6 mL). After stirring for 1 hr., the mixture was diluted with water and extracted with methylene chloride (2×). The organic layers were dried over sodium sulfate, filtered, and concentrated. Purification of the residue using silica gel chromatography provided N-methylchloronaphthyridine.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][NH:40][S:41]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1)(=[O:42])=[O:43]
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 33 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with (3-(N-methylsulfamoyl)phenyl)boronic acid (68 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (17 mg, 0.02 mmol) and 1.12 ml 1,2-dimethoxyethane and 0.28 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 40 mg (33% yield, 77% purity) of the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][C:34]([O:36][C:37](C)(C)C)=[O:35].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of 251 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 6 mL of acetonitrile was added 0.108 mL of t-butyl bromoacetate and 0.36 mL of DIPEA. The reaction was heated at 50° C. for 5 hours and then concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried with sodium sulfate, combined and evaporated. The residue was purified by FC (0-2.5% methanol in methylene chloride) to afford 294 mg of title compound. Mass spec (ESI): 564 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([NH2:41])=[O:40]>C1COCC1.CN(C=O)C>[C:39]([CH2:38][NH:41][C:39](=[O:40])[CH2:38][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)(=[O:40])[NH2:41]
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)CNC(=O)COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in THF (1 ml) and DMF (5 drops) on ice was added sodium hydride (0.024 g, 0.6 mmol). To the flask was added bromoacetamide (0.083 g, 0.6 mmol). While warming to room temperature the reaction was allowed to sit for 6 hours. The reaction was quenched with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified by semipreparative HPLC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to yield the title compound (0.008 g, 7.0% yield):1H NMR (CDCl3) 6.6-7.3 (m, 11H), 6.0 (broad s, 2H), 5.55 (broad s, 1H), 4.7 (t, 1H), 4.5 (s, 2H), 4.1 (m, 4H), 3.5 (m, 2H), 3.05 (m, 1H), 2.9 (m, 4H), 2.65 (m, 1H), 2.55 (m, 4H), 1.65 (m, 4H), 1.5 (m, 2H); ES-MS (m/z) 575 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:17][C@H:16]2[C@@H:6]([CH2:7][C:8]3[C:18]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]2=4)[NH:10][CH:9]=3)[N:5]([CH3:19])[CH2:4]1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22]>CO>[CH3:19][N:5]1[C@H:6]2[C@@H:16]([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:18]=3[C:8]([CH2:7]2)=[CH:9][NH:10]4)[CH2:17][C@@H:3]([CH2:2][NH:1][CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[CH2:4]1
Reactant: C=CC(=O)OC
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CO
Product: COC(=O)CCNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
A mixture of 5.1 g of 8β-aminomethyl-6-methyl-ergoline and 1.8 ml of methyl acrylate in 100 ml of methanol was refluxed for four hours. The solvent was evaporated off under reduced pressure, and the residue was crystallized from diethyl ether to give 6 g of 6-methyl-8β-[N-(2-methoxycarbonylethyl)-aminomethyl]-ergoline (II: R1 =R2 =R3 =R7 =R8 =H, R4 =CH3, n=1, A=CH2 --CHR6, R6 =H, B=COOCH3) melting at 130°-132° C. To a solution of 2.86 g of potassium cyanate in 30 ml of water, a solution of 6 g of 6-methyl-8β-[N-(2-methoxycarbonylethyl)-aminomethyl]-ergoline in 120 ml of water and 35 ml of 1N hydrochloric acid was added. This reaction mixture was heated for four hours at 80° C. and allowed to stand overnight at room temperature. The solid separated out and was filtered off and recrystallized from ethanol to give 4.5 g of the title compound melting at 330° C. with decomposition.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:17][F:18])[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>>[F:18][CH2:17][N:8]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CC(C)(C)OC(=O)CN(CF)C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(CF)C(=O)c1ccccc1

Procedure:
Fluoromethylbenzoylglycine t-butyl ester was treated with trifluoroacetic acid for one hour, and the product was purified by thin layer chromatography. Mp 233°-235°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: Nc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)Nc4ccc(O)cc4)cc3)cc12

Procedure:
4-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 4-aminophenol following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (28%). 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.44 (s, 1H), 7.40 (d, 2H), 7.36 (d, 1H), 7.24 (d, 2H), 7.10 (d, 2H), 6.76 (d, 2H), 4.72 (m, 1H) 3.27 (t, 2H), 3.12 (t, 2H), 2.50 (s, 3H), 2.06 (d, 3H). LRMS [M+H]=449.2
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCCc4ccccc4)c3Cl)c2n1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg), 4-phenylbutyric acid (40 mg) and dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50 mg) and 1-hydroxybenzotriazole (41 mg). After being stirred for an hour at ambient temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-(4 -phenylbutyrylglycyl)amino]benzyloxy]-2-methylquinoline (105 mg) as a colorless glass.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)=[N:30][OH:31])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc2ncccc2c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1ccc2ncccc2c1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-quinolin-6-yl-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (5.6:1) as a white foam, MS (ESI+): m/z=445.0907 ([M+H]+, 1Br).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CNc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.8 %

Procedure:
To a solution of N-methylaniline (10.0 g) in DMF (100 ml) was added dropwise a solution of at room temperature N-bromosuccinimide (16.6 g) in DMF (100 ml), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow oil of 4-bromo-N-methylaniline (18.18 g).
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) H-Pro-NHC(CH3)3 were dissolved in 34 ml of dry dichloromethane. After cooling to 0° C., 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution (1×). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH2:19][CH3:20])C.[CH3:21][C@@H:22]([NH2:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[O:8]=[C:7]1[C:6](=[O:9])[C:5]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[CH2:19][CH3:20])=[C:4]1[NH:27][C@H:22]([CH3:21])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOc1c(Nc2ccc(C#N)cc2CC)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCO
Product: CCc1cc(C#N)ccc1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Yield: 52.1 %

Procedure:
4-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-3-ethylbenzonitrile (1.26 g, 4.66 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (9.3 mmol) in ethanol (58 mL) were stirred at room temperature for 24 hours. The resulting yellow solution was concentrated to a yellow oil, which was dissolved in acetonitrile (20 mL) and stirred at room temperature. The yellow solid which precipitated was filtered off and rinsed with ethyl acetate to yield 0.79 g (52%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethylbenzonitrile as an off-white solid: mp 235°-237° C.; [α]D25 =+68.20° (DMSO, c 0.0072); 1H NMR (DMSO-d6): δ 8.04 (br s, 1H), 8.04 (d, 1H), 7.69-7.57 (m, 3H), 4.05 (m, 1H), 2.71 (q, 2H), 1.27-1.16 (overlapping doublet and triplet, 6H), 0.91 (s, 9H). IR (KBr): 3278, 2959, 2222, 1793, 1674, 1598, 1576, 1522 cm-1 ; MS (m/z) 325 (M+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH2:9].[CH2:11]([C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH:9][S:22]([C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:21][C:13]=1[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: CCc1sc2ncccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ncccc2c1S(=O)(=O)Nc1onc(C)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a mixture of NaH (38 mg, 1.6 mmoles) in THF (5 ml) at ambient temperature was added 4-chloro-3-methyl-5-amino isoxazole (84 mg, 0.63 mmoles). The mixture was stirred 1 hr. at ambient temperature then cooled to 0° C. followed by the addition of 2-ethylthieno[2,3-b]pyridine-3-sulfonyl chloride (0.19 g, 0.73 mmoles) via cannula in THF (2 ml). The cooling bath was removed and the brown mixture was stirred 1 hr. at ambient temperature and then diluted with 3% NaOH (50 ml) and washed with CHCl3 (2×75 ml). The aqueous layer was acidified to pH 4 using concentrated HCl, upon which a precipitate formed. The aqueous phase was extracted with EtOAc (50 ml), and the organic layer was dried (MgSO4), filtered and concentrated to collect 0.23 g of a yellow oil. Recrystallization from EtOAc/hexanes provided 0.18 g (79%) of the title compound as a light yellow solid, m.p. 152-154° C.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>[OH-].[Na+].C1COCC1>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:1][CH:2]([CH:6]2[CH2:11][CH2:10][C:9]([F:12])([F:13])[CH2:8][CH2:7]2)[C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NC(C(=O)O)C1CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
The amino(4,4-difluorocyclohexyl)acetic acid (2.68 g, 10.973 mmol) was dissolved in 2N NaOH (20 mL). The solution was cooled to 0° C., 5-chlorothiophene-2-sulfonyl chloride (3.25 g, 12.42 mmol) was added (5 min) dropwise as a solution in THF (10 mL). The solution was allowed to warm up to 25° C. overnight. After 19 h, THF was removed in vacuo and the mixture was acidified to a pH of about 1 to about 2 with 2N HCl (20 mL). The aqueous layer washed with EtOAc (4×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to produce {[(5-chlorothien-2-yl)sulfonyl]amino}(4,4-difluorocyclohexyl)acetic acid as a crude oil (3.8 g, 98.2%). Mass Spectrum (−ESI): 372 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7][CH2:6]2)[CH2:3]1.[BrH:21].[CH2:22]([O:24]CC)[CH3:23]>C(O)(=O)C>[BrH:21].[C:22]([O:1][CH:2]1[CH2:3][C:4]2([CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)[CH2:5]1)(=[O:24])[CH3:23]
Reactant: CCOCC
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(O)C2
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)OC1CC2(CCNCC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.800 g (2.91 mmoles) of benzyl 2-hydroxy-7-aza-spiro-[3.5]nonane-7-carboxylate (WO 9222550) is slowly added to 5 ml of a 5.7N solution of hydrobromic acid in acetic acid cooled to 0° C. After stirring for 1 hr at 0° C., 50 ml of diethyl ether are added and the medium is stirred for 1 hr. The precipitate formed is filtered on a fritted filter and copiously rinsed with diethyl ether. After drying overnight under vacuum at 80° C., 0.380 g of the expected product are obtained in the form of a white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:1])[CH:11]=2)[NH:6][C:5]1=[O:13]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (1.98 g) in acetic acid (10 cm3) was added dropwise to a stirred solution of 3,3-dimethyl-indol-2-one (2.0 g) and sodium acetate (1.01 g) in acetic acid (10 cm3). The mixture was stirred at room temperature for 30 minutes, poured onto water (20 cm3), basified to pH9 with sodium carbonate, and extracted with ethyl acetate (3×50 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:hexane:dichloromethane, 1:10:40 by volume. Combination and evaporation of the appropriate fractions gave the title compound, m.p. 166°-166.5° (2.15 g).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:12]([CH2:20][C:21](=O)[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.C(OCC)C>[NH2:4][C:3]1[C:20]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:21]([CH3:22])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#CC(N)c1ccc(F)cc1
Solvent: CCO
Solvent: CCOCC
Product: Cc1[nH]c(-c2ccc(F)cc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-(p-fluorophenyl)acetonitrile and benzoyl acetone, the open-chain intermediate compound is obtained, b.p. 120° C./0.2 mm Hg. The title compound is obtained in a 66% overall yield, m.p. 209°-10° C. (from ethanol/diethyl ether).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:30]1[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[CH:32][C:31]=1[OH:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C:30]1[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[CH:32][C:31]=1[O:38][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1ccc(O)c(Cc2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Cc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 2-benzyl-4-ethyl-phenol as in Example 18 to afford 0.040 g (13%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H29O4F 484, found 485 (M+1, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[CH:13]=[O:14].[CH:15]1([CH2:20][NH:21][CH2:22][CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][N:21]([CH2:22][CH3:23])[C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[CH:4][C:3]=2[CH:13]=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCNCC1CCCC1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Product: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 100 °C
Reaction time: 8 h
Yield: 178.3 %

Procedure:
6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N-(cyclopentylmethyl)-N-ethylamine (11.70 g, 92.0 mmol) synthesized by the method described in International Patent Publication WO2006/073973 were mixed, and the mixture was stirred at 100° C. for 8 hours in an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to obtain 6-[(cyclopentylmethyl)(ethyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine 5-carbaldehyde (9.96 g, 99%) as yellow oil.