Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[C:13](=O)([O-])O.[Na+].CI.Cl>CN(C)C=O>[CH3:13][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.9 %

Procedure:
9.00 g (55 mmol) 2-methyl-2-phenyl-propionic acid was dissolved in 90 ml N,N-dimethylformamide, 11.51 g (2.5 eq.) of sodium hydrogencarbonate was added followed by 6.89 mL (15.72 g 2 eq.) of methyl iodide. The mixture was stirred at rt for 40 hours, then poured into ice water, the pH was adjusted to ˜3.0 with aq. HCl (1N) and the mixture extracted 3 times with ether; the organic phases were washed with water, dried over MgSO4, filtered and evaporated to give 7.34 g of the crude title compound as yellow oil. MS: 178.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12](OCC)=[O:13])=[CH:4][C:3]=1[Cl:17].O.[NH2:19][NH2:20]>C(O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:19][NH2:20])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(Cl)c(N)c2c1OCCO2

Procedure:
38.4 g (0.149 mol) of ethyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylate suspended in 150 ml of ethanol are introduced into a 1 l reactor, 149 g (2.98 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 1 h.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:6][CH:5]=1)([O-])=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([O:14][C@H:15]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)=[CH:6][CH:5]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(NS(=O)(=O)c3ccc(Cl)cc3)c3ccccc23)C1
Yield: 50.8 %

Procedure:
The compound was prepared from tert-butyl (3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.23 g (50%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (d, J=4.52 Hz, 9H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H) 6.62-6.71 (m, 2H) 7.17-7.23 (m, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43 (m, 2H) 7.62-7.64 (m, 2H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53 Hz, 1H) MS (ESI+) for C25H27ClN2O5S m/z 520.2 (M+NH4)+, 447.0 (M−tBu)+. HPLC 100%, RT=2.772 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)OCC1.Cl.O1CCC[CH2:42]1>C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([OH:1])[CH2:10][CH2:9]2)[C:12]2[N:13]([N:37]=[C:38]([CH3:42])[N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: C1CCOC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (14 g), 3N hydrochloric acid (50 mL) and tetrahydrofuran (50 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (40 mL) and methanol (40 mL), sodium borohydride (1.5 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (12 g, 93%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH3:3][CH:2]([CH3:4])[CH2:1][NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)CN
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 18.20 g (0.25 mol) isobutylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 26.93 g (0.17 mol, 72% yield) of a white solid.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[CH:10][CH:9]=1>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1.[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: BrCCc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCc1ccc(Br)cc1
Temperature: 106 °C
Yield: 79.6 %

Procedure:
Sodium sulfite (4.75 g, 37.68 mmol) was added to a suspension of 1-bromo-4-(2-bromo-ethyl)-benzene (5.00 g, 18.94 mmol) in water (60 mL). The reaction mixture was heated at 105-107° C. for 18 hours and then cooled to −5° C. The formed precipitate was removed by filtration, washed with water (50 mL) and dried under vacuum to give 4.33 g (86% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2ccccc2c1-c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2ccccc2c1-c1cccc(CO)c1

Procedure:
A solution of 13.2 g (50 mmol) of 3-(2-aminonaphthalen-1-yl)benzoic acid in 300 ml of THF is added dropwise to a solution of 3.8 g (100 mmol) of lithium aluminium hydride in 500 ml of THF. When the addition is complete, the mixture is stirred under reflux for a further 2 h and allowed to cool, 4 ml of water, 4 ml of 15% by weight NAOH solution and 12 ml of water are then added dropwise, the mixture is stirred for a further 30 min., the precipitated salts are filtered off with suction and washed three times with 100 ml of THF each time, and the THF is removed in vacuo. Yield: 11.2 g (90 mmol), 89.8%; purity according to 1H-NMR about 95%.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C1CCCCC1>N1C=CC=CC=1>[C:20]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(-c2nc3c(O)cccc3s2)cc1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: CC(=O)Oc1cccc2sc(-c3ccc(C(=O)O)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
The 4-(4-hydroxybenzothiazol-2-yl)benzoic acid (6.9 g) obtained in Example 3 was dissolved in 15 ml of pyridine, and 2.6 g of acetic anhydride was added dropwise. The mixture was stirred at room temperature for 2 hours, and 160 ml of cyclohexane was added. The precipitated crystals were collected by filtration, washed with cyclohexane and then diethyl ether, and recrystallized from acetonitrile to give 4.0 g of 4-(4-acetoxybenzothiazol-2-yl)benzoic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F)([O-:20])=[O:19]>O.C(O)C>[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:20])=[O:19]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 liters ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.84) which is well resolved from the starting materials under the same conditions.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([N:33]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([N:33]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:31][CH2:32]3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (690 mg, 2.04 mmol) and t-butyl trans -[4-aminocyclohexyl-N-(t-butoxycarbonyl)amino]acetate (670 mg, 2.04 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/3) to give 493 mg of t-butyl trans-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]cyclohexyl-N-(t-butoxycarbonyl)amino]acetate as a colorless solid (37%).
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([F:14])=[CH:12][C:11]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[C:13]([F:14])=[CH:12][C:11]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 55.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (118 mg, 0.190 mmol) prepared in Example 107f, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (50 mg, 56%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[H-].[Na+].CN(C)C=O.Cl[CH2:38][C:39](=[O:41])[CH3:40]>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:38][C:39](=[O:41])[CH3:40])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC(=O)CCl
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (3 g), sodium hydride (0.47 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-chloropropan-2-one (0.75 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 14%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1-c1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Product: ClCc1ccccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3′-benzyloxybiphenyl-2-yl)methanol from Example 4, Step E (247 mg, 0.851 mmol) in dry CH2Cl2 (5 mL) was added thionyl chloride (1.01 g, 8.51 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated to dryness in vacuo. The residue was concentrated twice from cyclohexane in vacuo to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:24])[CH:32]([CH3:34])[CH3:33])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 39A (100 mg, 0.314 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (85 mg, 0.44 mmol) to yield 80 mg (53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28].Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH3:28])=[O:25])=[C:17]3[N:16]=2)[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B; 5.01 g, 14.0 mmol) in MeOH (150 mL) was added dropwise TMSCHN2 (8.41 mL, 16.8 mmol). The reaction was stirred for 30 minutes, and then quenched with 1 mL of acetic acid. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give the crude methyl ester. To the crude methyl ester was added 4N HCl in dioxane (100 mL) and the reaction was sealed and heated to 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100 mL) and washed with saturated NaHCO3 (40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude desired product (4.67 g, 93.2% yield). MS (apci) m/z=357.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[H-].[Na+].C(O)(=O)C[C:28](CC(O)=O)(C(O)=O)[OH:29]>CN(C)C=O>[C:1]([O:5][C:6]([C@@:8]1([CH2:28][OH:29])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.5 h

Procedure:
5-Oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4 g, 13.82 mol) was dissolved in N,N-dimethylformamide (40 mL), and paraformaldehyde (0.83 g, 27.65 mmol) was suspended in the solution. Sodium hydride (0.60 g, 13.82 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Then, the reaction solution was poured into a 10% citric acid solution (150 mL) at 0° C. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (30% ethyl acetate/hexane→80% ethyl acetate/hexane) to give 1.03 g of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH:33]([CH3:35])[CH3:34].[Cl-].[Na+]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-benzyloxycarbonylamino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (1.00 g, 2.59 mmol) in dimethylformamide (10 mL) was cooled to 0° C. under argon. Sodium hydride (60 wt %, 156 mg, 3.89 mmol) was added followed by isobutyl iodide. Let warm to room temperature and stirred overnight. The reaction was worked up with methylene chloride and saturated sodium chloride. The organic extracts were dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, 5 to 50% ethyl acetate in hexane gradient elution), giving the title compound (0.92 g). MS 442 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.989 min, m/z=403.1; 1H NMR (CDCl3) 1.10 (s, 3H), 1.17 (s, 3H), 1.52 (d, 3H), 2.13-2.28 (m, 6H), 2.47 (m, 1H), 2.87 (m, 1H), 3.95 (s, 3H), 5.70 (m, 1H), 6.79 (d, 1H), 7.02 (d, 2H), 7.21-7.38 (m, 6H), 7.58 (d, 1H), 8.27 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccc(Cl)cc2)n1
Product: Fc1ccc(COc2cc(-c3ccccc3)nc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-phenyl-pyrimidin-4-ol (which was obtained in Intermediate 1) and 4-fluorobenzyl bromide according to Method A; LC retention time 4.35 min; MS: m/z (ESI) 391 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17](=[O:51])[C@@H:18]([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:37])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1>>[NH2:16][C:17](=[O:51])[C@@H:18]([NH:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])=[O:37])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:6]=3[CH:15]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Reactant: COCCn1c(=O)oc2ccc(Br)cc21
Product: COCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)cc21

Procedure:
The sub-title compound was prepared by the method of Example 96 step (a) using 5-bromo-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one and (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate.