Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([CH:15]1[CH2:19][CH:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]1=[O:30])[CH3:14].ICC.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([C:15]1([CH2:1][CH3:2])[CH2:19][CH:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:16]1=[O:30])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCC1CC(C)N(Cc2ccc(OC)cc2)C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(CC)CC(C)N(Cc2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a solution of diisopropylamine (2.1 g) in tetrahydrofuran (20 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 13 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., a solution of 3-ethyl-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one (2.5 g) obtained in Step B in tetrahydrofuran (10 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hr. Iodoethane (2.5 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:21][CH:22]3[O:24]C3)[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][S:12]2(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:25](O)C.C(Cl)(Cl)Cl.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CC(C)=O>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[CH3:25][CH:15]1[CH2:14][CH2:13][S:12](=[O:19])(=[O:20])[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:21][CH2:22][OH:24])[S:16]1(=[O:17])=[O:18]
Reactant: CCO
Reactant: COc1ccc(C2(CC3CO3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: COc1ccc(C2(CCO)S(=O)(=O)CCC(C)S2(=O)=O)cc1OC

Procedure:
3.76 g of 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraoxide are heated at reflux for 18 hours under argon with 50 ml of ethanol, 30 ml of chloroform and 1.95 g of N-methyl-homovetratrylamine. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/ethanol (98:2). The oil obtained is dissolved in acetone and treated with an equivalent amount of anhydrous oxalic acid. The precipitate is filtered off and recrystallized from methanol/acetone. The racemic α- (3,4-dimethoxyphenethyl)-methylamino!-methyl-2-(3,4-dimethoxyphenyl)-m-dithiane-2-ethanol-1,1,3,3-tetraoxide oxalate (1:1) obtained crystallizes with 1 mol of acetone and melts at 162°-164° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(O[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[C:31]([CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])[CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=O)=O.Cl>O.CO>[C:41]([NH:40][CH2:39][CH2:38][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=3)=[CH:7][CH:8]=1)[CH:37]=[CH:36]2)(=[O:43])[CH3:42]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)NCCc1cccc2ccc(OCCCOS(C)(=O)=O)cc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc2)cc1
Reaction time: 0.33 h

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, 0.06 g of sodium is added in small portions. When the sodium has been completely used up, 0.0033 mol of methyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate is added and the mixture is stirred for 20 minutes. The methanol is removed by evaporation under reduced pressure, the residue is taken up in 15 ml of DMF, and then 0.0027 mol of the compound obtained in Step B is added. The reaction mixture is then heated at reflux for 12 hours and subsequently cooled and poured into 100 ml of water and 10 ml of 3M HCl. After extraction with ethyl acetate, the organic phase is washed with a 10% sodium hydroxide solution and then with water. After drying over MgSO4 and removal of the solvent by evaporation under reduced pressure, the title compound is purified by chromatography on silica gel.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[N:7][C:8](=[O:10])[CH2:9][C:4]2=[CH:3][CH:2]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[I:11][C:3]1[CH:2]=[N:1][N:5]2[C:4]=1[CH2:9][C:8](=[O:10])[N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1Cc2ccnn2C=N1
Solvent: CN(C)C=O
Product: O=C1Cc2c(I)cnn2C=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Pyrazolo[1,5-c]pyrimidin-5(4H)-one (1.0 g, 7.4 mM, 1.0 equiv) and N-iodosuccinimide (1.67 g, 7.4 mM, 1.0 equiv) were combined with 20 mL of DMF and warmed slightly. Within minutes a heavy precipitate formed. The reaction mixture was stirred an additional 1 h at ambient temperature then cooled on an icewater bath and filtered. The collected solid was washed with 20 mL of dichloromethane and air dried to give 1.66 g (86%) of 3-iodopyrazolo[1,5-c]pyrimidin-5(4H)-one. LCMS (ESI) m+H=262.2; 1H NMR (400 MHz, DMSO-d6) δ: 12.1 (s, 1H), 8.5 (d, 1H, J=7.6), 7.84 (s, 1H), 6.01 (d, 1H, J=7.1).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:38][C@H:36]([C:33]4[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=4)[CH3:37])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cn1
Temperature: 130 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A suspension of 6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile (Method 32, 5.75 g, 22.0 mmol), in n-BuOH (28.75 ml) was prepared at room temperature in a 48 ml sealed tube. DIEA (4.98 ml, 28.6 mmol) was then added, followed by the addition of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 4.0 g, 28.6 mmol). The tube was then sealed, and the suspension was heated to 130° C. over 45 minutes. The reaction was then allowed to stir at 130° C. for 18 hours. The reaction was then cooled to room temperature and concentrated by rotary evaporation at 60° C. to remove n-BuOH. The remaining oil was then taken up in DCM (100 ml) and washed with water (2×100 ml). The combined aqueous fractions were then extracted with DCM (100 ml), and the combined organic fractions were dried over Na2SO4, filtered and concentrated. The resulting oil was then purified by column chromatography (DCM, then DCM-MeOH=100:1) to give the title compound (5.2 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=2.5 Hz, 1H), 7.60-7.34 (m, 3H), 6.09-5.63 (m, 1H), 5.24 (q, J=7.0 Hz, 1H), 1.91 (septet, 1H), 1.58 (d, J=6.6 Hz, 3H), 1.08-0.90 (m, 2H), 0.79-0.70 (m, 2H). MS: Calcd.: 381. Found: [M+H]+ 382.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:24]([CH3:23])(=[O:26])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(Nc1ccc(F)cc1)c1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1cccnc1)N(c1ccc(F)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 10.8 g. portion of 3-[1-(4-fluorophenylamino)ethyl]pyridine was dissolved in 50 ml. of dichloromethane and 10.4 g. of potassium carbonate was added, followed by 5.9 ml. of methanesulfonyl chloride. The mixture was stirred for two days at ambient temperature, 1.8 ml. more methanesulfonyl chloride was added, and the mixture was then stirred under gentle reflux for four days. It was then cooled, extracted twice with water, dried and concentrated to an oil. The oil was dissolved in dichloromethane and chromatographed on silica gel, eluting with dichloromethane, then with chloroform, and finally with chloroform:acetone to obtain 10.7 g. of oily product. It crystallized upon seeding, m.p. 82°-85°.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=[O:3])N.[OH-:32].[Na+].Cl>C(O)C>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH:23]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([OH:32])=[O:3]
Reactant: [OH-]
Reactant: NC(=O)c1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1

Procedure:
A mixture of 7-carbamoyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.15 g), 1N sodium hydroxide solution (5 ml) and ethanol (5 ml) was stirred under reflux for 10 hours. After cooling, 1N hydrochloric acid (6 ml) was added and the precipitated crystals were collected to give 7-carboxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.[CH3:35][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)([CH2:23][C:24]([OH:26])([CH3:35])[CH3:25])[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[Mg+]
Reactant: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (0.0303 g, 0.0648 mmol) in THF (5 mL) was added MeMgBr (1.4 M in toluene/THF, 1 mL, 1.4 mmol) at 0° C. The mixture was warmed to it and stirred for 1 h before quenching with satd aq NH4Cl (1 mL). The mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by preparative HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.91 min, m/z 484 (MH+), 426; 1H NMR (400 MHz, CD3OD) δ 7.36-7.20 (m, 5H), 7.02-6.92 (m, 6H), 5.52 (q, J=7.0 Hz, 1H), 3.05-3.00 (m, 1H), 2.49-2.35 (m, 2H), 2.22-2.15 (m, 1H), 2.06 (s, 2H), 1.48 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.90 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −113.78 (m), −115.82 (m), −117.50 (m).
Reaction SMILES: O.OO.[O:4]1CCCC1.[F:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13](B(O)O)=[CH:12][N:11]=1>O>[F:9][C:10]1[N:11]=[CH:12][C:13]([OH:4])=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1cc(B(O)O)cnc1F
Reactant: C1CCOC1
Agent: OO
Solvent: O
Product: Cc1cc(O)cnc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Hydrogen peroxide water (4.37 ml, 42.8 mmol) was added to a tetrahydrofuran solution (50 ml) of 2-fluoro-3-methylpyridine-5-boronic acid (5.1 g, 32.9 mmol), and stirred overnight at room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with aqueous 5% sodium thiosulfate solution and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-fluoro-5-methylpyridin-3-ol (4.03 g, yield: 96%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[N:26]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[O:38][C:39]2[N:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41][CH:40]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[O:38][C:39]2[N:44]=[CH:43][C:42]([C:45]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:25][C:7]=4[S:8][C:9]=3[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=3)=[O:46])=[CH:41][CH:40]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)nc1
Product: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)nc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) and (±)-6-[[trans-2-(1-piperidyl)cyclohexyl]oxy]-3-pyridinecarboxylic acid (Part A) by essentially following the procedures detailed in Example 20, Parts D and E.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-:20].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Br)cc1

Procedure:
A 3.5 g. portion of ethyl 1-(4-bromophenyl)-5-cyano-4-pyrazolecarboxylate was reacted with 2.15 g. of potassium hydroxide in 50 ml. of ethanol under reflux for 2 hours to obtain 2.45 g. of the desired product, m.p. 251°-252.5°. The elemental analysis was as follows.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1([C:16]2[O:20][N:19]=[C:18]([CH2:21][N+:22]#[C-:23])[N:17]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[O:20][N:19]=[C:18]([C:21]3[N:22]=[CH:23][N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:11]=[C:2]([CH3:1])[C:3]=34)[N:17]=2)[CH2:15][CH2:14]1
Reactant: Cc1nc2ccccc2nc1O
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Product: Cc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 165°-167° C., from 3-methyl-2-quinoxalinol and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole. (Compound 7)
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[F:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Ni].CO>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[F:21])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.91 ml of hydrazine monohydrate and about 1 g of developed Raney nickel catalyst were added to a methanol (60 ml) solution of 4.94 g of 4-benzyloxy-3-fluoronitrobenzene, and the reaction liquid was stirred at room temperature for 2 hours. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:17]2([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[C:19]([NH2:27])=[N:18]2)[CH:14]=[CH:15][CH:16]=1>>[F:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([NH2:27])=[N:18][C:17]2([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:13]2[CH:12]=[CH:11][CH:16]=[C:15]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[CH:14]=2)=[CH:21][CH:22]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(F)ccc21
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cncnc3)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared as described in Example 78 (Scheme #14, N) using pyrimidin-5-ylboronic acid and 1-(3-bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine (Example 82) (26% yield): 1H NMR (CDCl3) δ 9.19 (s, 1 H), 8.87 (s, 2 H), 8.55 (m, 2 H), 7.53-7.45 (m, 4 H), 7.36 (m, 1 H), 7.29-7.25 (m, 3 H), 7.20 (m, 1 H); MS (ESI) m/z 382 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][S:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:41][CH:40]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (112 mg, 0.3 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (45.5 mg, 0.45 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-methylsulfanyl-benzene (59.4 mg, 0.36 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide as a white solid (Yield 0.13 g, 80%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([CH2:15][CH2:16][O:17][C:18]([N:20]1[C:29]2[C:24](=[N:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C@@H:23]([N:34]([CH2:41][C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=2)[C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[CH2:22][C@H:21]1[CH2:56][CH3:57])=[O:19])#[N:14].Cl>C1(C)C=CC=CC=1>[N:1]1[NH:2][N:3]=[N:14][C:13]=1[CH2:15][CH2:16][O:17][C:18]([N:20]1[C:29]2[C:24](=[N:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C@@H:23]([N:34]([CH2:41][C:42]2[CH:43]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=2)[C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[CH2:22][C@H:21]1[CH2:56][CH3:57])=[O:19]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCC#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCc1nn[nH]n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
Add sodium azide (16 mg, 0.24 mmol) and triethylamine hydrochloride (33 mg, 0.24 mmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid 2-cyano-ethyl ester (77 mg, 0.12 mmol) in toluene (2.4 mL). Stir the mixture at 80° C. for 1.5 h and at 100° C. overnight. Add more sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) and stir the mixture for 8 h at 100° C. Add more sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) and stir the mixture for 6 h at 100° C. Cool down to room temperature. Add 1 M HCl and extract the aqueous phase with dichloromethane. Wash the organic layers with water and brine, then dry over Na2SO4, filter, and concentrate. Purify the crude material by silica gel chromatography (elution with dichloromethane/methanol) to afford the title compound (55 mg, 66%). MS (ES+): 694 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:15]/[CH:16]=[C:17](\[CH3:23])/[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH3:2].[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:15]/[CH:16]=[C:17](\[CH3:23])/[CH2:18][CH2:19][C:20]([O:22][CH3:24])=[O:21])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CO
Product: CCc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (E)-6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in methanol (200 ml) was treated with p-toluenesulfonic acid (0.8 g) and stirred at 25° C. for 16 hours. The reaction mixture was cooled to 0° C. Methyl (E)-6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, m.p. 116.5°-117.6, was collected by filtration.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[O:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>ClCCl>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[O:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(-c3ccccc3)c(C(F)(F)F)o2)cc1)c1ccccc1Cl
Yield: 82.2 %

Procedure:
to a solution of 4-(4-phenyl-5-(trifluoromethyl)oxazol-2-yl)benzenamine (178 mg, 585 μmol) and pyridine (473 μl, 5850 μmol) in 5 mL dichloromethane at room temperature was added 2-chlorobenzoyl chloride (78.0 μl, 614 μmol) all at once by pipet. After one hour the reaction was concentrated under reduced pressure then taken up in 25 mL dichloromethane and washed with 25 mL saturated aqueous sodium bicarbonate solution. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow oil. The product was isolated by chromatography on silica gel, eluting with 15-40% ethyl acetate in hexane, to yield a colorless foamy solid (213 mg, 82%). ESI+ m/z=443.0 [MH]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1([CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCCO)C.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:22]1[CH2:23][CH2:24][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21]1
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCOCCO
Solvent: O
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(Cl)ccc2n1

Procedure:
4,6-Dichloro-2-methylquinoline (0.1 g) and 3-phenylpyrrolidine (0.15 g) in 2-ethoxy-ethanol (1.5 mL) was heated in a microwave at 240° C. for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane. Evaporation of the desired fractions gave the title compound as a white solid.