Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[IH:19]>>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([I:19])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(Cl)ncn2)CC1
Reactant: I
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(I)ncn2)CC1

Procedure:
2.0 g (7.5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-chloropyrimidine were heated at reflux for 5 hours in 20 ml of aqueous hydroiodic acid (57% strength). After cooling the mixture was filtered with suction, the solid was suspended in water and the suspension was rendered basic using ammonia solution. It was extracted with dichloromethane and the organic phase was dried and concentrated, to leave 1.2 g (44.5% of theory) of colorless resin which gradually crystallized.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:8][C:3]([CH3:9])([CH2:2][NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CNS(C)(=O)=O
Reaction time: 48 h
Yield: 31.2 %

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (249 mg, 1.90 mmol) and Et3N (0.80 mL, 5.70 mmol) in 2 mL CH2Cl2 was added methanesulfonyl chloride (0.29 mL, 3.80 mmol). The reaction was stirred for 2 days, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate (124 mg, 31%) as a clear oil. 1H NMR (400 MHz, CDCl3), 4.95 (t, 1H, J=6.8 Hz), 3.69 (s, 3H), 3.16 (d, 2H, J=6.8 Hz), 2.95 (s, 3H), 1.24 (s, 6H). Methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate was hydrolyzed using aqueous NaOH to provide 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoic acid, which was used without further purification. 1H NMR (400 MHz, CDCl3), δ 10.28 (br. s, 1H), 5.56 (br. s, 1H), 3.14 (s, 2H), 2.94 (s, 3H), 1.25 (5, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:21])=[C:12]([C:14]2[CH2:18][CH:17]([CH2:19]Cl)[O:16][N:15]=2)[CH:13]=1>CS(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:21])=[C:12]([C:14]2[CH:18]3[CH:17]([CH2:19]3)[O:16][N:15]=2)[CH:13]=1
Reactant: Fc1ccc(Br)cc1C1=NOC(CCl)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccc(Br)cc1C1=NOC2CC12
Yield: 87.9 %

Procedure:
Potassium t-butoxide (176 mg, 1.572 mmol, Aldrich) was added in small portions over a time period of 20 min to a solution of 3-(5-bromo-2-fluorophenyl)-5-(chloromethyl)-4,5-dihydroisoxazole (200 mg, 0.684 mmol, 1d rac) in DMSO (4 mL) cooled with a water bath. After completed, the reaction was quenched by the addition of ice. EtOAc was added and the organic phase was separated. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography, eluting with 3% to 5% EtOAc in hexane, to provide the title compound as a colorless oil (154 mg, 0.601 mmol, 88% yield). MS m/z=257.9 [M+H]+. Calculated for C10H7BrFNO: 256.07.
Reaction SMILES: [Cu][C:2]#[N:3].N(OC(C)(C)C)=O.[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:13]=1N>CS(C)=O>[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:13]=1[C:2]#[N:3]
Reactant: N#C[Cu]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: N#Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A solution of copper(I) cyanide (2.6 g, 29.0 mmol, Eq: 2) in DMSO (5 mL) was heated at 60° for 1 hr. Tert-butyl nitrite (5.98 g, 6.9 ml, 58.0 mmol, Eq: 4.00) and a solution 2,6-dichloro-4-nitroaniline (3 g, 14.5 mmol, Eq: 1.00) in DMSO (5 mL) was added and the reaction was stirred for 3 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate 3×. The organic extract was washed with brine and dried over sodium sulfate. Chromatography (200 g Analogix, 100% hex to 5% EtOAc/hex) gave 515 mg (16%) of desired product as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C@@H:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2ccccc2CN1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: C[C@H]1Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19].O>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:18]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
L-proline methyl ester hydrochloride (0.300 g, 1.81 mmol) was dissolved in dichloromethane (5 ml). Triethylamine (0.202 g, 1.99 mmol) and 1,1′-carbonylbis-1H-imidazole (0.352 g, 2.17 mmol) were added, and the mixture was stirred at room temperature for five days. Water was added to the reaction solution, followed by extraction with dichloromethane. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, 0.404g of the title compound was obtained as a colorless oily substance (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>>[O:26]1[CH2:27][CH2:28][N:1]([C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:24][CH2:25]1
Reactant: BrCCOCCBr
Reactant: Nc1ccc2sc3ccccc3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c2ccccc2sc2ccc(N3CCOCC3)cc12
Temperature: 180 °C

Procedure:
2-Aminothioxanthone (4.9 g.), anhydrous potassium carbonate (4.5 g.) and di(ethylene-glycol) diethyl ether (150 ml) were heated to reflux (180° C.) and 5.2 g. of 2-bromoethyl ether was added. The reaction was held at reflux for 24 hours, filtered hot and the solvent removed under vacuum. The residue was recrystallized from acetone to give 2-morpholinothioxanthone, mp 166-167° C. Structure was confirmed by IR, NMR, C-13 NMR and MS.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:34]=[N+:35]=[N-:36])(C)C.C(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[NH:36][N:35]=[N:34][N:15]=2)[N:6]=1
Reactant: N#Cc1nc(Cc2ccccc2F)n2ccccc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccccc1Cc1nc(-c2nnn[nH]2)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 188 mg (0.75 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carbonitrile from example 18A, 18.6 mg (0.075 mmol) of dibutyltin oxide and 172 mg (1.50 mmol) of trimethylsilyl azide in 5 ml of toluene is heated under reflux for 20 h. Cooling is followed by addition of 5 ml of ethanol and stirring at RT for 15 h. The mixture is then concentrated, mixed with water and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is purified by preparative HPLC. The product is taken up in ethyl acetate and clarified with activated carbon. The solid obtained after concentration is crystallized from dichloromethane. 40 mg (18% of theory) of the title compound are obtained as pale reddish crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19]C2CCCCO2)=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[N:33]1([CH2:38][CH2:39][OH:40])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:40][CH2:39][CH2:38][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: CC1=C(c2ccc(F)cc2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Reactant: OCCN1CCCC1
Product: CC1=C(c2ccc(F)cc2)C(c2ccc(OCCN3CCCC3)cc2)Oc2ccc(O)cc21

Procedure:
The title compound was synthesized as described in Example 30 using 3-(4-fluorophenyl)-2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromene and 2-(pyrrolidin-1-yl)ethanol as starting materials. 1H NMR (DMSO-d6; TFA salt): δ 9.65 (br s, 1H), 8.99 (br s, 1H), 7.32 (m, 2H), 7.22 (m, 4H), 6.86 (d, 2H), 6.76 (m, 1H), 6.50 (m, 2H), 5.96 (s, 1H), 4.21 (t, 2H), 3.54 (m, 4H), 3.08 (m, 2H), 2.02 (s, 3H), 1.99 (m, 2H), 1.84 (m, 2H); LCMS: 446 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[ClH:18]>>[ClH:18].[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2cccc(N)c2)cc1
Agent: Cl
Product: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
A mixture of 1-4 (500 mg, 2.20 mmol) and 6N HCl (50 mL) was heated at 60° C. for 20 h. Evaporative removal of the solvent provided 1-5 (530 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].N[C:16]1[N:24]([CH3:25])[C:23]2[C:18](=[N:19][C:20]([Cl:27])=[N:21][C:22]=2[Cl:26])[N:17]=1>N1C=CC=CC=1>[Cl:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]([CH3:25])[C:16]([NH:14][S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([O:3][CH3:4])=[O:2])(=[O:13])=[O:12])=[N:17]2)=[C:22]([Cl:26])[N:21]=1
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Reactant: Cn1c(N)nc2nc(Cl)nc(Cl)c21
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1nc2nc(Cl)nc(Cl)c2n1C
Reaction time: 3 h

Procedure:
At 70° C., 6.60 g (28 mmol) of 2-carbomethoxybenzenesulfonamide was added to a suspension of 3.00 g (14.0 mmol) of 8-amino-2,6-dichloro-7-methylpurine in 150 ml of pyridine. After 3 hours at 70°-80° C., the reaction mixture was evaporated down in a rotary evaporator, and the residue was stirred into ice/H2O and acidified with dilute HCl. The desired product was obtained in the form of a brown powder having the following physical data (active ingredient 1.020)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([CH2:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:18])[CH:7]=1)=[O:5])C.Cl>>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([CH3:18])[CH:7]=[C:6]2[C:4]([OH:5])=[O:3])[CH3:17]
Reactant: CCOC(=O)c1cc(C)nc2c(CC)cccc12
Agent: Cl
Product: CCc1cccc2c(C(=O)O)cc(C)nc12
Reaction time: 7 h
Yield: 107.5 %

Procedure:
8-Ethyl-2-methylquinoline-4-carboxylic acid ethyl ester (0.205 g) and 5N HCl combined and the solution boiled for 7 h. Solvent was removed at reduced pressure to give the title compound (0.195 g) as a yellow solid. m/z (API+): 216 (MH+), 214 (API−) 214(M-H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=3[CH:21]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCCBr)cc21
Reactant: COc1ccc(S)cc1OC
Product: COc1ccc(SCCCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 1 from 6-(6-bromohexyloxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxythiophenol.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:34]5[C:35]6[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:31]=[CH:32][CH:33]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc5ccccc45)ccc32)n1)c1ccccc1
Reaction time: 15 h

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 271) (50 mg), 1-naphthyl boronic acid (22 mg), potassium carbonate (31 mg), and tetrakis(triphenylphosphine)palladium(0) (5 mg) were dissolved in degassed n-propanol (2.6 mL) and water (0.4 mL) and stirred at 80° C. under argon atmosphere. for 15 hours. Upon cooling, the reaction mixture was filtered through Celite® (the ppt was washed with 10 mL of EtOAc) and evaporated. The residue was purified by preparative thin layer chromatography eluted with 5% MeOH/CH2Cl2 giving 43 mg of the title compound. 1H NMR (500 MHz, CDCl3), δ 8.58 (br s, 1H), 8.40 (s, 1H), 7.96-7.90 (m, 4H), 7.59-7.27 (m, 10H), 6.85 (d, 1H, J=5.5 Hz), 6.45 (br s, 1H), 5.25 (s, 1H), 1.67 (d, 3H, J=7.0 Hz); Mass spectrum (ESI) 442.2 (M+1).
Reaction SMILES: C([NH:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1)([C:19](=[O:25])NC(C)(C)C)[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14]C(C)(C)C(C)(C)[O:11]1)(=O)C.[ClH:38].[OH2:39]>O1CCOCC1>[ClH:38].[ClH:38].[NH2:4][C@@:5]([C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:11])[OH:14])[C:19]([OH:25])=[O:39]
Reactant: O
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@](CCCCB(O)O)(C(=O)O)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
In a 50 ML round bottom flask, tert-butyl (3R)-3-[1-acetamido-1-(tert-butylcarbamoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentyl]pyrrolidine-1-carboxylate (1.41 g, 2.69 mmol) was dissolved in 1,4-dioxane (10 mL). To this solution was added a 6M aqueous solution of hydrogen chloride (10 mL) in a single portion and the reaction was heated under refluxing conditions for 18 h. At the end of 18 hours the reaction mixture was cooled to room temperature prior to dilution with water (10 mL). The aqueous layer was washed with ethyl acetate (20 mL) and concentrated in vacuo prior to lyophilization to afford (R)-2-amino-6-borono-2-((R)-pyrrolidin-3-yl)hexanoic acid dihydrochloride (0.657 g) as a mixture of diastereomers. The crude foam was used without purification in the next step. ESI MS found for C10H21BN2O4 m/z 227.2 (M+H-water)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)[CH3:2].[H-].[Na+].[CH2:25](I)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]([CH3:25])[CH:4]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc(N2CCCC2=O)c2[nH]cc(CC)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCCC2=O)c2c(c1)c(CC)cn2C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 3-ethyl-7-(2-oxo-1-pyrrolidinyl)-1H-indole-5-carboxylate (B141) (658 mg, 2.3 mmol, 1 equiv) in DMF (10 ml) at room temperature was added NaH (60% dispersion in mineral oil, 120 mg, 3.0 mmol, 1.3 equiv) and the resulting mixture was stirred 15 min at this temperature. Ethyl iodide (187 μl, 3.0 mmol, 1.3 equiv) was added and the resulting solution was stirred for 30 min then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane to give ethyl 3-ethyl-1-methyl-7-(2-oxo-1-pyrrolidinyl)-1H-indole-5-carboxylate (620 mg, 90%) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:9][C:8]=1[O:22][C:23]([F:26])([F:25])[F:24]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[CH2:1])=[CH:14][CH:13]=2)=[CH:9][C:8]=1[O:22][C:23]([F:26])([F:25])[F:24]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.9 g, 10.92 mmol) in dry THF (20 mL) was added n-butyllithium (6.8 mL, 10.88 mmol) dropwise at −78° C. for 0.5 h, the mixture was stirred for 1 h, and then was added a solution of 4-(4-chloro-3-(trifluoromethoxy)phenoxy)benzaldehyde (2.8 g, 8.84 mmol) in THF (5 mL). The reaction was warmed slowly to room temperature, stirred for overnight, and quenched with water. The aqueous layer was extracted with DCM. The organic phase was dried with anhydrous Na2SO4, concentrated and purified via flash chromatography to afford the title compound (1.2 g, 3.81 mmol, 43.1% yield). LCMS: rt=4.42 min, [M+H+]=315
Reaction SMILES: O[C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:23])=O>CN(C)C=O>[Cl:23][C:2]1[C:3]2[N:4]([N:13]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2c1c(O)nc1c(C)nn(C)c12
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c1c(Cl)nc1c(C)nn(C)c12

Procedure:
92.5 gms. of 5-hydroxy-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid, ethyl ester, together with 300 ml. of phosphorus oxychloride and 3 ml. of dimethylformamide are refluxed for 5 hours. After distilling off the phosphorus oxychloride, the reaction mixture is poured onto ice and the crude 5-chloro-1,3-dimethyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acid ethyl ester, is filtered under suction, then recrystallized from acetone, yield 83 gms. of white crystals, m.p. 130°-132°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[CH:24][N:23]=1>CN1C(=O)CCC1.CO>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:27]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ccn3)CC1)C(=O)N2

Procedure:
350 mg (1.27 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 180 mg (0.600 mmol) 6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred overnight in 3 mL NMP at 120° C. The reaction mixture was diluted with MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[O:15][CH3:16].O.I([O-])(=O)(=O)=O.[Na+].[Cl-].[Na+]>CO.O1CCCC1>[CH3:16][O:15][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[CH2:3][CH:2]=[O:1])[NH:11][C:10](=[O:14])[CH2:9][CH2:8]2
Reactant: COc1cc2c(cc1CC(O)CO)NC(=O)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1CC=O)NC(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
110 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 2 ml of methanol and 1 ml of tetrahydrofuran. Thereafter, 2 ml of water containing 0.16 g of sodium metaperiodate was added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 30 minutes. A saturated sodium chloride aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 87 mg of (6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde. This compound was directly used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].Cl.Cl.[CH3:21][N:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1.N12CCCN=C1CCCCC2>C(#N)C>[ClH:1].[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([CH:23]3[N:22]([CH3:21])[CH2:28][CH:27]4[NH:29][CH:24]3[CH2:25][CH2:26]4)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CN1CC2CCC(C1)N2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C3C4CCC(CN3C)N4)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 0.54 g (2.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.50 g (2.5 mmol) of 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride [P. A. Sturm, et al, J. Med. Chem., 17, 481 (1974)], 0.75 ml (5.0 ml) 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile was heated under reflux for 1.5 hours and stirred overnight at room temperature. The reaction mixture was filtered and the solid washed with ethanol to give 0.46 g of the title compound, mp>310°.