Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:64][C@:65]1([C:70]([NH:72][S:73]([C:76]2([CH2:79][F:80])[CH2:78][CH2:77]2)(=[O:75])=[O:74])=[O:71])[CH2:67][C@H:66]1[CH:68]=[CH2:69]>ClCCl>[F:80][CH2:79][C:76]1([S:73]([NH:72][C:70]([C@@:65]2([NH:64][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:67][C@H:66]2[CH:68]=[CH2:69])=[O:71])(=[O:74])=[O:75])[CH2:77][CH2:78]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(CF)CC1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(CF)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.7 g, 13.82 mmol) in dichloromethane (60 mL) was added HATU (5.78 g, 15.2 mmole) followed by DIPEA (7.13 mL, 41.4 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(1-(fluoromethyl)cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (4.34 g, 16.58 mmole) was added to the reaction mass and stirred at room temperature for 6 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (5% methanol in chloroform) to get 6.6 g (73%) of desired product as white solid. MS: MS m/z 658.3 (M++1).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16].O>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([I:3])=[CH:5][CH:6]=2)[C:14]=1[C:15]#[N:16]
Reactant: OCc1ccc(I)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Sodium hydride (60%; 432 mg; 10.8 mmol) was suspended in DMF (5 mL) and cooled to 0° C. under inert atmosphere. 4-Iodobenzyl alcohol (2.53 g; 10.8 mmol) was dissolved in DMF (5 mL) and added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 15 minutes. The solution was then cooled to 0° C. 2,6-Difluorobenzonitrile (1 g; 7.2 mmol) in DMF (20 mL) was added dropwise to the alcohol solution and stirred for 2 hours. The solution was poured over 100 mL of cooled water. The solution was cooled for 1 hour and a precipitate was evident. The solid was collected by vacuum filtration and washed with water. Purification by recrystallization in cyclohexane yielded 1.49 grams of 2-fluoro-6-(4-iodobenzyloxy)benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:16][C:15](=[O:17])[O:14][C:8]4([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: O=C1Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C2(CCCCC2)O1

Procedure:
Prepared from 6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 245-246° C. 1H-NMR (CDCl3) δ8.39 (t, 1H, J=1.9 Hz), 8.20 (dd, 1H, J=8.2, 1.4 Hz), 8.11 (s, 1H, D2O exchangeable), 7.86 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.1 Hz), 7.50 (dd, 1H, J=8.2, 1.9 Hz), 7.39 (d, 1H, J=1.8 Hz), 6.93 (d, 1H, J=8.2 Hz), 2.25 (d, 2H, J=12.7 Hz), 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M−H]−, 100%). Anal. Calc. For C19H18N2O4.0.35H2O: C, 66.21, H, 5.47, N, 8.13. Found: C, 66.22, H, 5.43, N, 7.86.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:15]1[N:16]=[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:18]2[C:19](=[O:22])[C:20]=1[I:21])[CH2:13][CH3:14].C(N(CC)C(C)C)(C)C>C(O)C>[I:21][C:20]1[C:19](=[O:22])[N:18]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:17]2=[N:16][C:15]=1[CH:12]([NH:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2)[CH2:13][CH3:14]
Reactant: CCC(N)c1nc2cccc(C)n2c(=O)c1I
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-9H-purine (1.65 g, 0.008270 mol), 2-(1-aminopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.58 g, 0.00752 mol), and N,N-diisopropylethylamine (1.571 mL, 0.009022 mol) in ethanol (60 mL) was refluxed under nitrogen overnight. The mixture was concentrated and the resulting residue was purified on silica gel, eluting with 0 to 10% methanol in methylene chloride, to provide the desired product (2.86 g, 82.5%). LCMS calculated for C17H17IN7O (M+H)+: m/z=462.1. Found: 462.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.31 (2H, m), 8.19 (1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.7 and 6.9 Hz), 7.44 (1H, d, J=8.7 Hz), 6.99 (1H, d, J=6.9 Hz), 5.69 (1H, m), 2.89 (3H, s), 1.91 (2H, m), 0.95 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: [C:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([C:21]([F:24])([F:23])[F:22])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(OCC)(=O)C>C1COCC1>[C:1]1([C:7]2[C:16]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]([F:24])([F:22])[F:23])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc2c(c1)C1OCCCC1C(c1ccccc1)N2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCc1cc2cc(C(F)(F)F)ccc2nc1-c1ccccc1
Reaction time: 8 h

Procedure:
0.50 g (1.50 mmol) of 5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 3 was dissolved in THF (15 ml), 1.65 g (3.00 mmol, 2 eq) of cerium(IV) ammonium nitrate were added at RT, and stirring was continued overnight at RT. When the reaction was complete, 50 ml of ethyl acetate were added, and the mixture was extracted 2× with 50 ml of water. The org. phase was dried and evaporated to dryness. The residue was recrystallised from ethyl acetate/diethyl ether, giving a pale-yellow solid (compound 4).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[F-].[K+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1>[O:28]1[CH2:29][C@H:27]1[CH2:26][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinoline (10 g, 0.15 mol) in THF (100 mL) was cooled to 0° C. and potassium fluoride (22 g, 0.3 mol) was added. After 1 h, (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.4 g, 0.17 mol) was added; the mixture was warmed to 25° C. and stirred for 16 h. The solution was filtered, washed with THF and concentrated. The crude product was used in next step without further purification. (15 g, yield 53%) MS (ESI+) e/z: 190.1 [M+1]+.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5][C:4]([CH3:43])([CH3:42])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH3:42][C:4]1([CH3:43])[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:24][CH:25]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 85.3 %

Procedure:
A solution of 3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.40 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.44 g) in dichloromethane (4 mL) was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate 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 (0.34 g, 86%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)Cl)c1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#Cc1cccc(C(=O)Oc2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 692 mg (7.35 mmol) of phenol and 3.4 ml (42 mmol) of pyridine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to obtain 0.55 q of phenyl 3-ethynylbenzoate which is a desired product as yellow solid. (Yield: 35%)
Reaction SMILES: Cl.[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[SH:11][CH2:12][C:13](OCC)=O.[OH-].[K+]>>[OH:5][C:4]1[CH:6]=[C:12]([CH3:13])[S:11][C:3]=1[C:2]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1sc(C)cc1O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Dry hydrogen chloride gas was bubbled through a mixture of ethyl acetoacetate (0.2 moles) and ethyl 2-mercaptoacetate (b 0.4 moles) at -10° C. until saturated. The oil was allowed to stand 4 days at room temperature. Then, 350 ml of 2N ethanolic KOH, was added drop-wise. The resultant mixture was added to 2 liters of ice-water, and acidified with 6M HCl until the pH was approximately 1. The precipitated oil was extracted with benzene, washed with water and dried with sodium sulphate. After removal of solvent the residue was distilled, b.p. 70°-75° C. (0.5 mm).
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCC1.[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26]N=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:9]1([C:14]([NH:16][C:17]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([O:33][C:24]3[C:23]4[C:28](=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=4)[N:27]=[CH:26][CH:1]=3)=[CH:35][CH:36]=2)=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(N=C=S)C1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
1-Cyclopentanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopentanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopentanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 57%).
Reaction SMILES: Cl.[C:2](=[N:5][OH:6])([NH2:4])[CH3:3].[H-].[Na+].[I:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=O)=[CH:12][CH:11]=1>O1CCCC1>[CH3:3][C:2]1[N:4]=[C:14]([C:13]2[CH:19]=[CH:20][C:10]([I:9])=[CH:11][CH:12]=2)[O:6][N:5]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(N)=NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(I)cc2)n1
Temperature: 65 °C
Yield: 29 %

Procedure:
Acetamidoxime hydrochloride (1.5 g) was added portionwise to an ice-cooled suspension of sodium hydride (1.18 g of a 60% dispersion in oil) in dry tetrahydrofuran (40 ml) under an atmosphere of argon. Molecular sieves (type 4A, 8-12 mesh) were added to the reaction mixture, followed by a solution of ethyl 4-iodobenzoate (3.73 g) in tetrahydrofuran (10 ml). The reaction mixture was heated at 65° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 70:30 (v/v) mixture of ethyl acetate/hexane as eluent to give 3-methyl-5-(4-iodophenyl)-1,2,4-oxadiazole (1.12 g) as a solid, m.p. 136°-137° C.; microanalysis, found: C, 38.2; H, 2.5; N, 9.5%; C9H7IN2O requires: C, 37.8; H, 2.47; N, 9.79%; NMR: 2.41(3H,s), 7.84(2H,d), 8.02(2H,d); m/z 287(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:17]#N)([CH:14]([F:16])[F:15])[C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:32]C(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:14]([F:16])[F:15])([CH:17]=[O:32])[C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 3 h
Yield: 39 %

Procedure:
Method LLL To a stirred solution of 7-chloro-5-cyano-5-(difluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (92) (747 mg, 2.55 mmol) in anhydrous methylene chloride (40 mL) at −78° C. was added DIBAL (1.0 M in CH2Cl2, 7.67 mL) dropwise. After 3 h at −50° C., the reaction was quenched with 1.0 N HCl (40 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 30% EtOAc-hexane) furnished 93 (299 mg, 39% yield) as a yellow solid.
Reaction SMILES: CN(CCCN=C=NCC)C.[C:12]([O:16][C:17](=[O:26])[CH2:18][C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20]([OH:22])=O)([CH3:15])([CH3:14])[CH3:13].ON1C2N=CC=CC=2N=N1.Cl.[NH2:38][C@@H:39]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]([NH:42][C@@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])=[O:41].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:53][C:51]([CH3:52])([CH3:54])[C@H:39]([NH:38][C:20]([C@H:19]([CH2:23][CH:24]=[CH2:25])[CH2:18][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:26])=[O:22])[C:40]([NH:42][C@@H:43]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH3:44])=[O:41]
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
N-(Dimethylaminopropyl)-N′-ethylcarbodiimide (4.21 g, 22.0 mmol) was added to a stirred mixture of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]pent-4-enoic acid (A. L. Castelhano, S. L. Bender, J. G. Deal, S. Homer, T. J. Liak, Z. Yuan, World Patent WO96/16027 (1996)) (3.80 g, 17.8 mmol) and 1-hydroxy-7-azabenzotriazole (2.49 g, 18.3 mmol) in anhydrous dimethylformamide (60 mL) under nitrogen at 4° C. After 1 h, (2S)-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(5.10 g, 18.8 mmol) was added, followed by diisopropylethylamine (2.42 g, 19.2 mmol). After another 30 min, the mixture was allowed to warm to room temperature. After 17 h at room temperature, the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (400 mL) and water (400 mL). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2×100 mL). The combined organic solutions were concentrated under reduced pressure, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (6.70 g, 88%), as a colourless solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH:37]1([CH2:40][C:41](O)=[O:42])[CH2:39][CH2:38]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:41](=[O:42])[CH2:40][CH:37]2[CH2:39][CH2:38]2)[CH2:7]1)#[N:2]
Reactant: O=C(O)CC1CC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)CC2CC2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and cyclopropylacetic acid. LCMS (M+H)+: m/z=578.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]([Zn]CC)[CH3:15]>O1CCOCC1>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH2:14][CH3:15])[CH:3]=[N:4][CH:5]=1
Reactant: CCOC(=O)c1c(Cl)cncc1Br
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)cncc1CC
Temperature: 70 °C
Yield: 54.9 %

Procedure:
To a solution of ethyl 3-bromo-5-chloropyridine-4-carboxylate (5.84 g, 22.08 mmol) in anhydrous dioxane (40 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (323 mg, 0.441 mmol). Then, diethylzinc (2.72 g, 18 mL, 22.09 mmol, 15% solution in toluene) was added dropwise and the reaction was heated at 70° C. for 45 minutes. The mixture was cooled to room temperature, quenched with MeOH, and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water, 0.1 N HCl, and brine, and then dried over anhydrous sodium sulfate. The filtered solution was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate in hexane to provide ethyl 5-chloro-3-ethylpyridine-4-carboxylate as a pale yellow oil (2.59 g, 55% yield); 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.45 (t, 3H), 2.65 (q, 2H), 4.47 (q, 2H), 8.41 (s, 1H), 8.49 (s, 1H); M+ 214.5.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester according to the method of Example 21. 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, 1H, J=3.5 Hz, 1.17 Hz), 7.41 (dd, 1H, J=5.1 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08 (dd, 0.1H, J=5.1 Hz, 3.91 Hz), 6.81 (d, 2H, J=8.6 Hz), 6.75-6.62 (m, 3H), 4.17 (t, 2H, J=6.6 Hz), 3.26 (d, 1H, J=13.7 Hz), 3.14 (d, 1H, J=13.69 Hz), 2.98 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 1.45 (s, 3H). HRMS (ES+) m/z exact mass calcd for C26H25FNO5S 482.1437, found 482.1454.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[OH:32])(=[O:40])=[O:41])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccccc3O)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-hydroxybenzenesulfonamide [Synth. Commun., 1994, 24, 671]: 1H-NMR (CDCl3) δ 7.74-7.70 (1H, m), 7.48-7.24 (9H, m), 7.15 (2H, d, J=8.2 Hz), 7.02 (1H, d, J=7.7 Hz), 6.93 (1H, t, J=7.6 Hz), 6.16 (1H, br.s), 3.47-3.40 (2H, m), 2.81 (2H, t, J=6.5 Hz), 2.32 (3H, s), 2.23 (3H, s).