Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:23]=3)[S:18][C:11]=12)[NH2:5].[N:33]1[CH:38]=[CH:37][CH:36]=C[CH:34]=1.ClC(OC1C=CC=CC=1)=[O:41].C1(N)CC1>CN(C=O)C>[CH:38]1([NH:33][C:34]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:16]=[C:17]([C:19]5[CH:20]=[N:21][N:22]([CH2:24][CH2:25][N:26]6[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]6)[CH:23]=5)[S:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)=[O:41])[CH2:36][CH2:37]1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cn2)CC1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
To a stirred solution of 153 (203 mg, 0.449 mmol) and pyridine (0.109 mL, 1.346 mmol) in DMF (10 mL) at 0° C. under nitrogen was added phenyl chloroformate (1.76 mg, 1.121 mmol) and the reaction mixture was stirred at 0° C. for 2 hrs. Cyclopropylamine (128 mg, 2.243 mmol) was added and the reaction mixture was heated at 55° C. for 5 hrs. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution, then washed with a saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (eluent EtOAc to 30% MeOH in EtOAc) to afford title compound 154 (30 mg, 12% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43 (s, J=5.48 Hz, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.74 (m, 1H), 7.67 (s, 1H), 7.60 (bs, 1H), 7.32 (t, J=8.99 Hz, 1H), 7.22 (m, 1H), 6.63 (d, J=5.48 Hz, 1H), 4.25 (t, J=6.46 Hz, 2H), 2.73 (t, J=6.46 Hz, 2H), 2.55 (m, 1H), 2.45 (m, 4H), 2.28 (m, 4H), 2.12 (s, 3H), 0.61 (m, 2H), 0.40 (m, 4H). MS (m/z)=536.54 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])OCC)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[CH2:13]([PH:8](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)[PH](=O)Cc1ccccc1

Procedure:
By a procedure analogous to that of Example 1, but using 1.96 g of ethyl diethoxymethylphosphinate and 20 ml of a molar solution of benzylmagnesium chloride in diethyl ether and adding 4.14 g of potassium carbonate in 5 ml of water to precipitate inorganic salts, benzyl (diethoxymethyl) phosphine oxide is obtained as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.C(O[C:13]([NH:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[F:25])C)=O)(C)(C)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]([C:36](Cl)=[O:37])[C:28]2=O.Cl.O1CCOCC1>ClCCCl>[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[N:16]1[C:36](=[O:37])[C:29]2[C@@H:30]3[C:33]([CH3:35])([CH3:34])[C@@:27]([CH3:26])([CH2:32][CH2:31]3)[C:28]=2[N:15]1[CH3:13]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(NC(=O)OC(C)(C)C)c1cccc(F)c1F
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c2c(c(=O)n1-c1cccc(F)c1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution of N′-(2,3-difluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (360 mg, 1.4 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 800 mg, 3.72 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified by preparative HPLC and dried under high vacuum to give (4S,7R)-2-(2,3-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (129 mg, 29%) as a white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[N:5]=[C:4]([O:10][C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:3]=1.[F:21][C:22](F)(F)[C:23]1C=CC(I)=C[CH:24]=1.C(N[CH:36]([CH3:38])[CH3:37])(C)C>CCCCC.C(OCC)(=O)C.[Cu](I)I>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:37]2[CH:36]=[CH:38][C:22]([F:21])=[CH:23][CH:24]=2)[N:5]=[C:4]([O:10][C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1cc(C)cc(Oc2cc(C(F)(F)F)nn2C)n1
Agent: I[Cu]I
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C#Cc2ccc(F)cc2)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 70 °C
Yield: 81 %

Procedure:
To a solution of 4-methyl-6-ethynyl-2-(1-methyl-3-trifluorome-thylpyrazol-5-yloxy)pyridine (1 g, 3.55 mmol) in diisopropylamine (20 ml) under a nitrogen atmosphere are added 4-trifluoromethyl-iodobenzene (1.11 g, 5 mmol), bistriphenylphosphine palladium dichloride (0.12 g, 0.177 mmol) and copper iodide (0.02, 0.1 mmol) and the mixture is heated at 70 ° C. for 30 min. After cooling, the reaction mixture is diluted with pentane : ethyl acetate 1:1 and the organic phase is washed with water, diluted hydrochloric acid and a saturated aqueous solution of sodium bicarbonate and dried. 81% of the product (1.1 g, mp. 86-87° C.) is obtained by flash chromatography.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:53]1[CH:52]=[CH:51][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=1)=[O:57]
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Yield: 62.2 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.) followed by 4-dimethylaminobutylamine (0.31 g, 2.63 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil that later crystallized. The solid was purified via silica gel flash chromatography using 5% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (4-dimethylamino-butyl)-amide (0.63 g, 62% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2.Br>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Cl)CCC(=O)N2
Agent: Br
Product: O=C1CCc2cc(Cl)c(O)cc2N1
Yield: 89.2 %

Procedure:
The thus-obtained 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyril are dispersed in 300 ml of 47%-hydrobromic acid aqueous solution and heated for 4 hours under refluxing condition. After cooling of the reaction mixture, the insoluble matter is separated by filtration, washed with water and dried. Recrystallization from methanol-chloroform obtains 25 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 264°-266° C.
Reaction SMILES: C(OCC=CCOC(=O)C)(=O)C.C(O)(=O)C.C([O:20][CH2:21][CH:22]([CH:29]=O)[CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])(=O)C>C1C=CC=CC=1>[CH:21]([C:22]([CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])=[CH2:29])=[O:20]
Reactant: CC(=O)OCCC(C=O)COC(C)=O
Agent: CC(=O)OCC=CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: C=C(C=O)CCOC(C)=O
Yield: 90.3 %

Procedure:
A solution of 1,4-diacetoxy-2-butene (170 g.) and hydridocarbonyltris(triphenylphosphine) rhodium (I) (0.5 g.) in benzene (340 g.) was heated in a bomb at 75° C. under 2000 psig of a synthesis gas (50% by volume H2 and 50% by volume CO gas). After a few hours, the bomb was cooled and vented and the benzene was removed from the reaction product by distillation. The resulting crude 1,4-diacetoxy-2-formylbutane was then heated to 120°-130° C. in a distillation apparatus under a vacuum of 5 mm Hg. and a distillate (190.3 g. b.p. 60°-80° C.) was collected. The distillate on redistillation gave acetic acid, 2-formyl-4-acetoxybutene (127.1 g., 90.3% yield, b.p. 77°-79° C./ 6 mm Hg) and 1,4-diacetoxy-2-formyl butane (12.5 g., 6.2% yield, b.p. 110°-113° C./ 1 mm Hg.
Reaction SMILES: C([O:8][C:9](=[O:36])[C@@H:10]([NH:26][C@H:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[C:32]([O:31][C:29]([C@@H:27]([NH:26][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:17]=1)[C:9]([OH:36])=[O:8])[CH3:28])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
Step 4′: A suspension of (S)-2-((S)-1-tert-Butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester (580 mg, 1.10 mmol) and 5% Pd on carbon (0.146 g) in EtOAc (10 mL) was treated with H2 (balloon) and stirred at rt for 1.5 hour. The resulted precipitate was dissolved in methanol and filtered through celite pad. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallized from EtOAc to give (S)-2-((S)-1-tert-butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid (438 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (d, 3H, J=7.1 Hz), 1.35 (s, 9H), 2.84 (dd, 2H, J=7.3, 13.6 Hz), 2.95 (dd, 2H, J=6.1, 13.6 Hz), 3.20 (dd, 1H, J=6.8, 13.6 Hz), 3.48 (dd, 1H, J=6.1, 7.3 Hz), 7.33 (d, 2H, J=8.6 Hz), 7.37 (d, 2H, J=8.3 Hz), 7.42-7.49 (m, 2H), 7.60 (d, 2H, J=8.6 Hz); MS: m/z (MH+) 438.
Reaction SMILES: C(O[C:4](=O)[CH:5]([F:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1COCC1.[H-].[Na+].C(OC(=O)/C=C/[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)C>O.C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[F:11])=[CH:4]\[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)[CH3:10]
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(F)=C\c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
2-fluoro malonic acid diethyl ester (670 μL) was added to a THF (8 mL) suspension of sodium hydride (170 mg) under ice-cooling, and the reaction solution was agitated under ice-cooling for 20 minutes and further agitated at room temperature for 1 hour. After dropping the THF (2 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid ethyl ester (1 g) obtained above to the reaction solution over 10 minutes and the reaction solution was agitated at room temperature for 30 minutes, and heated to reflux for 8 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and water was added and the organic layer was washed with a saturated ammonium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: from hexane to hexane:ethyl acetate=1:1), and 593 mg (56%) of (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1(C2CCCCCCCCCC2)CCCCCC[CH2:18][CH2:17][CH2:16]N1.Br[CH:37]([CH3:39])[CH3:38]>C1C=CC=CC=1>[CH:17]([N:3]1[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]1[Br:1])([CH3:18])[CH3:16].[Br:1][C:2]1[N:6]([CH:37]([CH3:39])[CH3:38])[C:5]([CH3:7])=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[N:3]=1
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: CC(C)Br
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Solvent: c1ccccc1
Product: Cc1c(C(=O)OC(C)C)nc(Br)n1C(C)C
Product: Cc1nc(Br)n(C(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Yield: 70 %
Yield: 20 %

Procedure:
To a solution of 2 g (8.1×10-3 moles) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate in 20 ml of benzene was added 1.2 ml (8.2× 10-3 moles) of diazabicycloundecane, followed by 1.0 g (8.1×10-3 moles) of 2-bromopropane. The resulting mixture was heated to reflux overnight, cooled to room temperature and filtered. Concentration in vacuo gave a golden oil. This residue was purified by medium pressure liquid chromatography on silica gel to yield 1.6 g (70%) isopropyl 1-isopropyl-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil and 466 milligrams (mg) (20%) of the desired product, isopropyl 2-bromo-3-isopropyl -4-methyl-5-imidazolecarboxylate, also a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].CI.[C:18](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)c(C=O)cn2C
Yield: 99 %

Procedure:
5-Methoxyindole-3-carboxaldehyde (300 mg, 1.71 mmol) was added in portions over 5 min to a suspension of sodium hydride (82 mg, 2.05 mmol, 60% dispersion in mineral oil) in DMF (8 mL) stirring under argon. The mixture was stirred for 30 min, methyl iodide (0.13 mL, 2.05 mmol) was added and the mixture was stirred for 1 h. Sodium bicarbonate (10%, 40 mL) was added and the mixture was extracted with EtOAc (4×). The combined organic layers were washed with sodium bicarbonate (10%, 2×) and saturated NaCl, dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (50:50 EtOAc:hexanes) afforded 43 (320 mg, 99%) as a light yellow solid; Rf=0.35 (50:50 EtOAc:hexanes); mp=130-132° C.; lit mp=132-133° C.53; 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.79 (d, 1H, J=2.4 Hz), 7.62 (s, 1H), 7.25 (d, J=8.8 Hz), 6.96 (dd, 1H, J=2.4 and 8.9 Hz), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:30]([NH:33][C:34](=[O:38])[C:35](O)=[O:36])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35](=[O:36])[C:34](=[O:38])[NH:33][CH:30]([CH3:32])[CH3:31])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)NC(=O)C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)NC(C)C)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (53 mg, 0.14 mmol) and 2-(isopropylamino)-2-oxoacetic acid (18 mg, 0.14 mmol). Yield 42 mg (62%).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.CO[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[C@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C@H:29]2[C@@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:19][C:15]4[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=4)[C:12]([NH:9][C:7]4[NH:6][N:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[CH:8]=4)=[O:21])[C:32]3=[O:40])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1cc(C2CC2)n[nH]1
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-cyclopropyl-1H-pyrazol-5-amine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C30H25ClN4O2: 508, observed (M+H)+: 509.21H NMR (400 MHz, MeOD-d4) δppm 0.66-0.77 (m, 2 H) 1.02 (dd, J=8.34, 1.77 Hz, 2 H) 2.24 (d, J=8.59 Hz, 2H) 2.47-2.57 (m, 1 H) 3.26-3.32 (m, 1 H) 5.07-5.25 (m, 2 H) 5.65 (s, 1 H) 6.09 (d, J=7.58 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.96 (d, J=7.83 Hz, 1 H) 7.07-7.14 (m, 1 H) 7.20 (d, J=8.34 Hz, 2 H) 7.31 (d, J=8.34 Hz, 2H) 7.49 (t, J=7.83 Hz, 1 H) 7.55-7.63 (m, 1 H) 7.80 (d, J=7.83 Hz, 1 H) 7.83 (s, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[C:19]1([N:25]2[C:29]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:36]([O-])(O)=O.[Na+].CN(C=O)C>O>[CH2:28]([O:35][C:7](=[O:17])[CH3:36])[CH3:29].[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:32]2[CH2:31][CH2:30][C:29]3([N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][NH:27][C:28]3=[O:35])[CH2:34][CH2:33]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C([O-])O
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(C)=O
Product: CN1CC(CCN2CCC3(CC2)C(=O)NCN3c2ccccc2)c2nc3ccccc3n2C1=O

Procedure:
A mixture of 4.0 g (0.015 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazole-1(2H)-one, 3.46 g (0.015 mol) of 1-phenyl-1,3,8-triazaspiro[4,5]-decan-4-one, 9 g of NaHCO3, 0.5 g of Kl, and 35 mL of DMF was heated on a steam cone for 24 h. The reaction mixture was poured into 500 mL of H2O and extracted with 3×100 mL of CH2Cl2. The combined organic extracts were washed with 2×100 mL of H2O, dried (NaSO4), filtered and concentrated by rotary evaporation. The residue was purified by preparative HPLC using acetone and the eluent and silica gel as the stationary phase. Like fractions were combined and concentrated by rotary evaporation to a glass which crystallized upon treatment with ethyl acetate to give 4.3 g (52%) of analytically pure material, mp 173°-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[Cl:22].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)c(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (12.7 g) and triethylamine (6.72 ml) in THF (150 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (2.76 ml). The reaction mixture was then stirred at room temperature for 60 min to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (28.4 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 min and then poured into EtOAc and washed sequentially with dilute aq. HCl, water and saturated brine. The organic phase was separated and was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate (9.32 g, 77%) as a yellow oil. MS (ISP): 324.0 ([{81Br37Cl}M+H—C4H8]+), 321.9 ([{81Br35Cl or 79Br37Cl}M+H—C4H8]+), 319.9 ([{79Br35Cl}M+H—C4H8]+), 279.9 ([{81Br37Cl}M+H—C4H8—CO2]+), 277.9 ([{81Br35Cl or 79Br37Cl}M+H]—C4H8]—CO2]+), 276.0 ([{79Br35Cl}M+H—C4H8—CO2]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.C(O)(=O)[CH:10]([CH2:12][C:13](O)=O)[OH:11].[S:18](=[O:22])(=[O:21])([OH:20])[OH:19]>>[S:18](=[O:20])(=[O:19])([OH:22])[OH:21].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([OH:11])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Product: Nc1ccc2ccc(O)nc2n1

Procedure:
In step 1 of the method, commercially available 2,6-diaminopyridine (e.g., Aldrich, Milwaukee, Wis.) is reacted with malic acid in sulfuric acid to provide 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt. It is noted that 2-amino-7-hydroxy-1,8-naphthyridine free base is described in S. Carboni et al., Gazz. Chim. Ital., 95, 1498 (1965).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>>[ClH:1].[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2nc[nH]c12
Product: Cl
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2nc[nH]c2n1

Procedure:
Following the procedure described in Example 9, the title compound was prepared from 6-chloropurine and 5-aminoindole (70%). TS-MS: 251 (MH+); anal. RP18-HPLC RT: 2.44 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[CH3:19][O-:20].[Na+]>CN(C)C=O>[C:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:5]1[N:6]=[C:2]([O:20][CH3:19])[S:3][CH:4]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(CSCCNC(=O)OC(C)(C)C)cs1
Temperature: 45 °C
Reaction time: 72 h
Yield: 32.7 %

Procedure:
To a solution of 2-bromo-4-[(2-tert-butoxycarbonylaminoethyl)thiomethyl]-1,3-thiazole (650 mg, 1.85 mmol) in N,N-dimethylformamide (5 mL) was added sodium methoxide (300 mg, 5.56 mmol) and stirred at 45° C. for 3 days. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with aqueous lithium chloride and concentrated. The residue was chromatographed on silica gel (10% ethyl acetate-hexane), affording 184 mg of the title compound. 1H NMR (CDCl3) δ 1.54 (9H), 2.78 (t, 2H), 3.42 (m, 2H), 3.74 (s, 2H), 4.18 (s, 3H), 5.24 (br s, 1H), 6.60 (s, 1H).