Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:4][N:3]=1.[CH2:16]([Li])[CH2:17][CH2:18]C.[CH2:21]([Si:24](Cl)(C)[CH3:25])C=C.[NH4+].[Cl-]>C1COCC1>[CH2:16]([C:2]1[C:7]([SiH:24]([CH3:25])[CH3:21])=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:4][N:3]=1)[CH:17]=[CH2:18]
Reactant: Brc1ccc(COC2CCCCO2)cn1
Reactant: [Li]CCCC
Reactant: C=CC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1ncc(COC2CCCCO2)cc1[SiH](C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-[(2-bromopyridin-5-yl)methoxy]tetrahydro-2H-pyran. (5 Scheme 27, 5.1 g, 18.7 mmol) in dry THF (200 mL) at −78° C. was added n-butyllithium (7.5 mL, 2.5 M solution in hexanes, 18.7 mmol). After being stirred for 10 min −78° C., allylchlorodimethylsilane (2.5 g, 18.7 mmol) was added dropwise over a period of 20 min. The reaction mixture was stirred further for 1 h and warmed to room temperature. Concentrated NH4Cl (5 mL) was added to the solution, and the reaction mixture was concentrated. The resulting yellow oil was concentrated, extracted with ethyl acetate/water, and the organic layer was dried, concentrated, and purified by column chromatography (1:7 ethyl acetate/hexanes) to give the desired compound as a liquid (3 g, 55%) 1H NMR (300 MHz, CDCl3) δ 0.31 (s, 6 H), 1.45-1.68(6 H), 1.82 (d, J=8.40 Hz, 2 H), 3.54 (m, 1 H), 3.87 (m, 1 H), 4.47 (d, J=12.30 Hz, 1 H), 4.70 (t, J=3.45 Hz, 1 H), 4.77 (d, J=12.30 Hz, 1 H), 4.80-4.87 (2 H), 7.75 (m, 1 H), 7.46 (d, J=7.50 Hz, 1 H), 7.58 (dd, J=7.50, 1.80 Hz, 1 H), 8.76 (1 H); 13C NMR (75 MHz, CDCl3) −3.8 (2C), 19.4, 22.9, 25.8, 30.6, 62.3, 66.7, 98.1, 113.8, 129.1, 133.0, 133.6, 134.6, 149.9, 165.9. HRMS (EI) calcd for C16H25NO2Si 291.1654, found 291.1556.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[F:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=3)[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4ccccc4F)csc3c2=O)cc1
Yield: 16 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (2.0 ml), p-anisidine (91.17 mg, 0.74 mmol), and acetic acid (0.1 ml) were used to give 22 mg (0.062 mmol, 16% yield) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2].ClS([N:34]=[C:35]=O)(=O)=O.CN(C=O)C>C1COCC1>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[C:27]([C:35]#[N:34])=[CH:28][CH:29]=[C:4]12)[CH3:2]
Reactant: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC1c2ccc(C#N)n2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 250 ml round bottom flask with addition funnel was added 2 g (4.8 mmol) of the product from Example 4 and 50 ml of THF. The solution was cooled to −78° C. and 0.50 ml (5.76 mmol) of chlorosulfonyl isocyanate in 20 ml of THF added dropwise via the addition funnel. After the addition was complete the solution was stirred at this temperature for 3 hr until all of the product had disappeared by TLC. Added 1 ml of DMF and allowed the solution to warm to room temperature, whereupon product begins to form. After stirring overnight the reaction was quenched with saturated sodium bicarbonate solution, then extracted 3 times with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to afford an oil, which was chromatographed on silica gel eluting with 30% ethyl acetate:hexane to afford 1.81 g (83%) of product as a solid, which was recrystallized from ethyl acetate hexane, mp 176-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:27].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:27])[CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCCC3)c1=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCC(=O)C3)c1=O
Yield: 97.9 %

Procedure:
By the method of Example 3, Step A, 0.5 gram (0.0013 mole) of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil was reacted with 1.1 grams (0.0040 mole) of potassium persulfate and 0.3 gram (0.0013 mole) of copper(11) sulfate pentahydrate in 30 mL of acetonitrile and 30 mL of water, yielding 0.5 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-3-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure. This product was combined with another run of this reaction. The combined runs were subjected to column chromatography on silica gel, with 1:4 to 1:2 ethyl acetate:hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-4-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C>Cl.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Clc1ccnc(-c2ccsc2)c1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(c2ccnc(-c3ccsc3)c2)CC1
Temperature: 180 °C

Procedure:
To a microwave tube was added 4-chloro-2-thiophen-3-yl-pyridine (50 mg, 0.26 mmol), 1-methylpiperazine (100 mg, 1 mmol), 2-propanol (0.7 mL) and concentrated HCl (1 drop). The resulting mixture was heated at 180° C. for 40 min using a Personal Chemistry Smith Synthesizer. The resulting mixture was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cnccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cnccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 114.2 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(isoquinolin-5-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-9) (508 mg, 0.70 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (406 mg, 114%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([OH:16])=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>>[CH3:8][O:7][C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=[CH:13]2
Reactant: O=C(O)c1ccco1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(C(=O)O)cccc2c1

Procedure:
This starts from anisole; this is reacted with furan-2-carboxylic acid in the presence of a large excess of aluminium trichloride to give 6-methoxy-naphthalene-1-carboxylic acid (see J. Am. Chem. Soc. 69, page 2262 and European Pat. No. A1-200,840).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH3:7]>O>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6](=[O:8])/[CH:7]=[CH:2]/[C:1]([OH:5])=[O:4]
Reactant: CC(=O)c1cccs1
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(O)/C=C/C(=O)c1cccs1
Temperature: 125 °C
Yield: 52.5 %

Procedure:
A two phase mixture of 18 grams glyoxylic acid (an 80% solution of glyoxylic acid in water) and 25.2 grams of 2-acetylthiophene is heated to 125° C. with stirring, and heating and stirring are maintained for about 5 hours. A clear solution forms at 115° C. and the water formed is removed by means of a Dean-Stark apparatus. On cooling the residue solidifies. It is dissolved in 100 cc ether and extracted with 150 cc of a 20% solution of Na2CO3. This aqueous solution is treated with activated charcoal, filtered and made strongly acid with 20% HCl. The solid is filtered and dissolved in about 1 L ether. The ether is dried over MgSO4 and removed to yield 19.1 g of the title compound, melting point 139°-142° C.
Reaction SMILES: [OH:1][C@H:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=1)[CH2:3][NH:4][C@H:5]([CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](O)=[O:16])[CH:10]=[CH:11][CH:12]=1.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:30]=1[CH2:31][NH2:32].C(N(CC)CC)C>CN(C)C=O>[NH3:4].[Cl:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[C:30]=1[CH2:31][NH:32][C:15](=[O:16])[CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][C@H:5]([NH:4][CH2:3][C@H:2]([OH:1])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=2)[CH3:18])[CH:8]=1
Reactant: C[C@H](Cc1cccc(CCC(=O)O)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Reactant: NCc1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Cc1cccc(CCC(=O)NCc2c(F)cccc2Cl)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Product: N
Yield: 40.2 %

Procedure:
A solution of 3-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}propanoic acid (Preparation 60) (150 mg, 0.29 mmol), O-(1H-benzotrizol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol), 2-fluoro-6-chlorobenzylamine (56 mg, 0.35 mmol) and triethylamine (0.12 ml, 0.88 mmol) were stirred at room temperature for 16 hours in N,N-dimethylformamide (3 ml). The solvent was removed in vacuo and the resulting brown oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 followed by 94:6:0.6 by volume) to give the title compound as a white foam (30 mg).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][SiH:5]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.I[CH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>[Cu]I.C1COCC1>[CH2:8]([Si@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:24][CH2:25][C@H:26]2[CH2:27][CH2:28][C@H:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[C:40]([F:48])[CH:39]=4)=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)[CH2:3][CH2:4]1)[CH2:9][CH3:10]
Reactant: Fc1cc(-c2ccc([C@H]3CC[C@H](CCI)CC3)cc2)ccc1C(F)(F)F
Reactant: CCC[SiH]1CCC(Br)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(C(F)(F)F)c(F)c4)cc3)CC2)CC1

Procedure:
22.1 g (0.1 mol) of 1-bromo-4-n-propyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 47.6 g (0.1 mol) of 4-(trans-4-(2-iodoethyl)cyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 35.5 g (yield 72.3%) of the trans isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15].CN1CCOCC1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])=[CH:21][CH:22]=1
Reactant: CCC(/C=C/C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(/C=C/C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (E)-methyl 4-(4-amino-1H-indazol-1-yl)-4-(4-chlorophenyl)hex-2-enoate (120 mg) and NMM (98 mg) in DCM (5 mL) was added MsCl (45 mg). Then the mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=5/1) to afford the title compound as a pale yellow solid. LC/MS m/z=448.2[M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([NH:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([NH:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])=[CH:46][CH:47]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 79.1 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (1.5 g, 2.78 mmol), [4-(tert-butylaminocarbonyl)phenyl]boronic acid (1.3 g, 5.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (195 mg, 0.28 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 3.5 mL, 7 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (1.2 g, 79.5%) as a light yellow solid: LC/MS m/e calcd for C31H32FN3O3S [M+H]+ 546.69, observed 546.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:19])[CH:14]=[C:15]([NH:17][CH3:18])[CH3:16].N1C=CC=CC=1.Cl.N1C=CC=CC=1>C1COCC1>[CH3:11][O:12][C:13](=[O:19])[CH:14]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)/[C:15](=[N:17]/[CH3:18])/[CH3:16]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNC(C)=CC(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Bromobenzoyl chloride (17.14 g, 78.1 mmol) and 3-methylamino-but-2-enoic acid methyl ester (10.0 g, 78.1 mmol) were combined in THF (600 mL) and cooled to 0° C. Pyridine (6.8 mL, 85.9 mmol) was added by syringe, and the reaction was stirred overnight at room temperature. Solid pyridine hydrochloride was observed on the flask walls, so the solution was decanted and then concentrated to 10% of its original volume. The residue was diluted with EtOAc (400 mL) and washed twice with H2O. The organic layer was dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([N+:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1)[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].S(=O)(=O)(O)O.O>C(Cl)Cl>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:10]([N+:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccccc1
Reactant: CCCCC(C(O)c1ccc(CC)cc1)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCCC(C(c1ccc(CC)cc1)c1ccc(OCC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.1 g of 1-p-ethylphenyl-2-nitro-1-hexanol and 14.6 g of ethoxybenzene are dissolved in 80 ml of methylene chloride, and the solution is added dropwise at 0° C, with vigorous stirring, to 90 g of conc. sulphuric acid and 10 ml of water. After 2 hours' stirring at room temperature, the mixture is poured on to 400 ml of ice water. The product is taken up in methylene chloride and washed with saturated sodium bicarbonate solution. After the solvent has been removed by evaporation, the oil remaining behind is dried in high vacuum at 60° C for 2 hours. There is obtained the compound of the formula ##STR7## as viscous, dark yellow oil having a refractive index of nD22 = 1.5452.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:30]=[C:29]([NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Nc1nc(Cl)nc2ccccc12
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)nc2ccccc12

Procedure:
EXAMPLE 81 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-quinazolin-4-ylamine (2-chloro-quinazolin-4-ylamine was prepared from 2,4-dichloroquinazoline and ammonia in THF at room temperature; N. B. Chapman, G. M. Gibson, F. G. Mann, J. Chem. Soc., 1947, 890–899): MS (m+1)=426.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCNC2
Reaction time: 2 h

Procedure:
To a solution of the intermediate isolated in Step B in 100 mL of dichloromethane was added 25 mL of trifluoroacetic acid. After 2 h at ambient temperature, the reaction was diluted with an equal volume of saturated aqueous NAHCO3. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried (Na2SO4) and concentrated in vacuo, affording the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:24]([N:25](C(OCC(Cl)(Cl)Cl)=O)[C@H:26]([C:31]([O:33]C)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:24]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:23][O:22][N:21]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of methyl N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (1.0 g, 1.55 mmol) in THF (20 mL) was added acetic acid (10 mL) and zinc dust (2.8 g, 42.8 mmol). The mixture was sonicated for 1 min, then stirred 1.5 h at room temperature. The solids were filtered through celite and the filtrate was co-evaporated with heptane. The residue was dissolved in ethyl acetate and washed with aqueous NaHCO3 and brine and concentrated. The residue was dissolved in methanol (25 mL) and 2 M LiOH (5 mL) was added. The mixture was stirred overnight at room temperature, then diluted with ethyl acetate and washed with pH 3 phosphate buffer. The organic phase was washed with brine and dried over MgSO4, and concentrated to give 710 mg of N-(3-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}isoxazol-4-yl)leucine.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[S:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][S:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN1CCC(O)c2sccc2C1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2sccc2C1
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-8-ol (Reference Example 25) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 3,4-dichlorophenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13](=[O:20])[CH2:14][C:15](=O)[CH2:16][O:17][CH3:18]>>[CH3:11][O:12][C:13]([C:14]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][C:15]=1[CH2:16][O:17][CH3:18])=[O:20]
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COCC(=O)CC(=O)OC
Product: COCc1onc(-c2ccccc2)c1C(=O)OC

Procedure:
As described for Example 36c, (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (14.04 g, 90 mmol) was converted, using 4-methoxy-3-oxo-butyric acid methyl ester instead of acteylacetone to the crude title compound (18.76 g) which was obtained as an off-white solid and used directly in the next step without further purification.