Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-fluoro-4-methyl-2-nitrophenol (2.83 g, 16.5 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (3.4 g, 25 mmol) and iodomethane (1.2 mL, 20 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was then poured into water and stirred until solids crashed out. The solids were filtered and air dried to give 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene without further purification (2.76 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (d, J=8.1 Hz, 1 H), 7.25 (d, J=11.7 Hz, 1 H), 3.89 (s, 3H), 2.19 (d, J=1.5 Hz, 3 H).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][Si](C(C)(C)C)(C)C)[C@H:15]([CH3:25])[O:14][C:13](=[O:26])[C@@H:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1COCC1.C1C=CN=CC=1.F.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[C:30]([O:29][C:28](=[O:34])[NH:27][C@H:12]1[CH2:11][O:10][CH2:9][C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:16]([OH:17])[C@H:15]([CH3:25])[O:14][C:13]1=[O:26])([CH3:32])([CH3:31])[CH3:33]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-((tert-butyldimethylsilyl)oxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (120 mg, 0.24 mmol) in a solution of HF/pyridine/THF (5:3:8 ratio, 1.2 mL) was stirred at room temperature. After 16 h, an additional 0.1 mL HF-pyridine solution was added and the reaction was allowed to stir for 2 h. The crude reaction was diluted with EtOAc (5 mL) and added to sat'd aq Na2CO3 (5 mL) dropwise. Additional sat'd aq Na2CO3 was added until bubbling was no longer observed. The EtOAc layer was separated and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to furnish tert-butyl-(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-ylcarbamate as a colorless oil (82 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 3H), 7.20 (dd, J=8.2, 6.4 Hz, 2H), 5.15 (d, J=8.5 Hz, 1H), 4.88 (m, 1H), 4.65 (d, J=7.6 Hz, 1H), 3.90 (dd, J=11.7, 7.5 Hz, 1H), 3.57 (d, J=10.3 Hz, 1H), 3.44 (m, 2H), 3.33 (m, 1H), 3.11 (dd, J=13.8, 4.3 Hz, 1H), 2.49 (m, 1H), 1.87 (s, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.43 (d, J=4.3 Hz, 9H); ESIMS m/z 378.4 ([M−H]).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:9]([O:24]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:13])=[O:14])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:7]2
Reactant: COc1c(S(=O)(=O)NCc2ccc(Cl)cc2)cc(Cl)c2ccc(C(C)(C)C)nc12
Agent: BrB(Br)Br
Product: CC(C)(C)c1ccc2c(Cl)cc(S(=O)(=O)NCc3ccc(Cl)cc3)c(O)c2n1

Procedure:
The title compound is prepared from 5-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-methoxy-7-quinolinesulfonamide, which is the second title compound of Preparation 9, and 6 equivalents of BBr3 according to the procedure described in Example 18. Crystallization from Et2O/hexane affords 0.035 g of tie title compound as a dark tan solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=CC=C[CH:2]=1.[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[C:18]([CH2:20][NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:17]=[CH:16][C:15]=12.N1C=CN2C=CC(CNC(=O)C3C=CC(C4CCNCC4)=CC=3)=CC=12>>[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[C:18]([CH2:20][NH:21][C:22](=[O:35])[C:23]3[CH:24]=[CH:25][C:26]([CH:29]4[CH2:30][CH2:31][N:32]([S:7]([CH:1]([CH3:6])[CH3:2])(=[O:9])=[O:8])[CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[N:17]=[CH:16][C:15]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1cn2ccnc2cn1)c1ccc(C2CCNCC2)cc1
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Product: CC(C)S(=O)(=O)N1CCC(c2ccc(C(=O)NCc3cn4ccnc4cn3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 682, substituting propane-2-sulfonyl chloride for benzenesulfonyl chloride and N-(imidazo[1,2-a]pyrazin-6-ylmethyl)-4-(piperidin-4-yl)benzamide for N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide. 1H NMR (500 MHz, methanol-d4) δ ppm 9.21 (d, J=1.4 Hz, 1H), 8.67 (d, J=1.4 Hz, 1H), 8.22 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.89-7.82 (m, 2H), 7.40-7.35 (m, 2H), 4.85-4.79 (m, 1H), 4.75 (s, 2H), 3.96-3.85 (m, 2H), 3.12-3.00 (m, 2H), 2.88-2.74 (m, 1H), 1.95-1.85 (m, 2H), 1.84-1.65 (m, 2H), 1.33 (d, J=6.8 Hz, 6H); MS (ESI(+)) m/e 442 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(I)cc3)c2)CC1
Yield: 116.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-iodobenzoyl chloride (61 mg, 0.229 mmol), 60.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28](N)=[O:29].CC(C)=[O:33].CCCCCC>>[CH:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[CH2:27][C:28]([OH:29])=[O:33]
Reactant: NC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
3.0 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide is refluxed in a mixture of 20 ml. of acetic acid and 30 ml. of concentrated hydrochloric acid for 3 hours. The solution is cooled and poured into water. The mixture is extracted with ethyl acetate and the extract is washed, dried and evaporated to yield 90% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1([C:15](=O)[NH2:16])[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1([C:15]#[N:16])[CH2:11][CH:10]1[CH:12]([CH3:13])[CH3:14])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)C1CC1(C#N)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of (1-carbamoyl-2-isopropyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (6.4 g, 24.9 mmol) in dry DMF (100 mL) was added cyanuric chloride (6.4 g, 34.9 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and was poured into cold 0.5N NaOH (200 mL). The aqueous phase was extracted with EtOAc (2×150 mL) and the combined organic layer was washed with water and brine and dried over Na2SO4. Removal of excess of solvent, followed by purification of the residue by flash column chromatography using hexanes/EtOAc (9:1) as eluent gave 4.4 g (74%) of (1-cyano-2-isopropyl-cyclopropylmethyl)-carbamic acid tert-butyl ester as a colorless foam: 1H NMR (300 MHz, CDCl3) δ 0.87 (m, 1H), 1.05 (s, 6H), 1.23-1.33 (m, 3H), 1.45 (s, 9H), 3.29 (dd, J=6.3, 14.5 Hz, 1H), 3.47 (dd, J=6.1, 14.6 Hz, 1H), 5.31 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.6, 16.9, 21.0, 21.3, 27.1, 33.3, 39.3, 78.5, 122.0, 154.6; MS (APCI) m/z 239 [M+H]+.
Reaction SMILES: [CH2:1]([CH:7]([C:12](=[O:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([CH:7]([CH:12]([OH:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC(CC(=O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCC(CC(O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Temperature: -5 °C
Yield: 96.3 %

Procedure:
7.76 g of methyl 2-hexyl-3-oxo-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate (0.017 mol) were dissolved in 500 ml of THF while gassing with argon, treated with 20 ml of MeOH and cooled to -5° C. 5.3 g of sodium borohydride (0.14 mol) were added portionwise while stirring in such a manner that the temperature did not exceed 0° C. After stirring for 3 hours the excess sodium borohydride was filtered off, the reaction mixture was hydrolyzed (to pH 6) with 2N hydrochloric acid in the cold and the solvent was evaporated off. The residue was extracted with ether and the ethereal phase was dried and evaporated. There were obtained 7.71 g of methyl 2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(CNc2c(F)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenol (180 mg, 0.5 mmol, 1.0 eq) in DMF (3 mL) was added Cs2CO3 (246 mg, 0.75 mmol, 1.5 eq). The reaction was stirred for 30 min at room temperature then isopropyl 2-bromoacetate (99 mg, 0.55 mmol, 1.1 eq) was added. The reaction was stirred a further h then diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 1:0 to 25:1) to give the title compound as a colorless oil (100 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[CH3:17]>>[Cl:16][C:12]1[C:11]([CH3:17])=[C:10]([C:9](=[O:18])[CH2:6][C:2]#[N:1])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cl)c1C
Reactant: Nc1cc[nH]n1
Product: Cc1c(Cl)cccc1C(=O)CC#N
Yield: 74 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 3-Chloro-2-methyl-benzoic acid methyl ester (3.1 g, 16.8 mmol, 1.0 eq). The crude product was precipitated form water and used in the following step without further purification (2.4 g, yield: 74%).
Reaction SMILES: Br[C:2]1[N:18]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:19][C:20]1[O:24][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)=[N:22][N:21]=1>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:31][CH:28]3[CH2:29][CH2:30][N:25]([C:23]4[O:24][C:20]([CH3:19])=[N:21][N:22]=4)[CH2:26][CH2:27]3)[N:18]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nnc(N2CCC(N)CC2)o1
Reactant: Clc1cccc(Oc2cccn3nc(Br)nc23)c1
Product: Cc1nnc(N2CCC(Nc3nc4c(Oc5cccc(Cl)c5)cccn4n3)CC2)o1

Procedure:
Prepared in analogy to example 66f employing 2-bromo-8-(3-chlorophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (see example 152a) and 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-ylamine (see example 40b). The title compound was obtained as yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=2[S:5](=[O:14])(=[O:13])[C:4]1([CH3:16])[CH3:15].Br[C:18]1C=CC2C(C)(O)C(C)(C)S(=O)(=O)C=2C=1>>[CH3:1][O:2][C:3]1([CH3:18])[C:7]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=2[S:5](=[O:14])(=[O:13])[C:4]1([CH3:16])[CH3:15]
Reactant: CC1(O)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Reactant: COC1c2ccc(Br)cc2S(=O)(=O)C1(C)C
Product: COC1(C)c2ccc(Br)cc2S(=O)(=O)C1(C)C

Procedure:
Following the general method as outlined in Intermediate 248, starting from 6-bromo-2,2,3-trimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 246), the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1([SiH3])C=CC=CC=1>C1COCC1.C(Cl)Cl.C([Sn](Cl)(Cl)CCCC)CCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 204.8 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-amino-thiophene-2-carboxylic acid methyl ester (1.512 g, 5.97 mmol) and N-tert-butoxycarbonyl-piperidin-4-one (1.189 g, 5.97 mmol) in 2 mL of dry THF is added dibutyltin dichloride (181 mg, 0.60 mmol), and the mixture is stirred for 10 min at room temperature under nitrogen. Then phenylsilane (810 μL, 6.57 mmol) is added, and the mixture is stirred for 24 h at room temperature. Additional 595 mg of N-tert-butoxycarbonyl-piperidin-4-one, 90 mg of dibutyltin dichloride and 405 μL of phenylsilane are added, and the mixture is stirred for another 24 h. Then the mixture is diluted with CH2Cl2, washed with brine, organic fraction is separated, dried over Na2SO4, and concentrated to give 5.142 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-(N-tert-butoxycarbonyl-piperidin-4-yl)amino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1cccnc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1cccnc1
Yield: 81.9 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 3-aminopyridine (60 mg, 0.64 mmol) to give 170 mg of the title compound (80%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 10.58 (s, 1H), 8.31 (d, 1H, J=4.6 Hz), 8.07 (t, 2H, J=8.1 Hz), 7.79 (t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.10 (dd, 1H, J=4.6, 8.1 Hz), 5.17~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.81 (dm, 1H, J=17.1 Hz), 2.76 (dd, 1H, J=13.5, 7.2 Hz), 2.57 (dd, 1H, J=13.5, 5.4 Hz), 2.07 (dm, 1H, J=13.5 Hz), 1.80~1.94 (m, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]2[S:6][C:2]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)=[CH:3][N:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Nc2ncc(Br)s2)cc1
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Temperature: 120 °C

Procedure:
A mixture of (5-bromo-thiazol-2-yl)-(4-methoxy-phenyl)-amine (203 mg, 0.710 mmol), 3-thiophene-boronic acid (268 mg, 2.10 mmol, 6.0 equiv), Pd(PPh3)4 (12 mg, 0.0105 mmol, 0.03 equiv), Na2CO3 (326 mg, 3.08 mmol, 8.8 equiv), and water (305 μL, 16.7 mmol, 24 equiv) in toluene (10 mL) is heated in a sealed tube to 120° C. for 1 h, under an argon atmosphere. The resulting suspension is allowed to cool to RT and filtered through a pad of celite, washing the filter cake with CH2Cl2 and water. The layers are separated. The organic phase is dried (Na2SO4), filtered and concentrated. Purification by MPLC (CH3CN/H2O/TFA) affords the title compound as a light beige solid: ES-MS: 289.0 [M+H]+; single peak at tR=7.43 min (System 1); Rf=0.56 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 66.2 %

Procedure:
MeOH (28 mL) was added to a flask containing 4-(1-benzylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (1.0 g, 3.46 mmol). NaOMe solution (7 mL, 3.46 mmol, 0.5M in MeOH) and N-bromosuccinimide (0.74 g, 4.15 mmol) were added. The resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl (50 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-40% EtOAc/hexanes) to give 0.77 g of the title compound. MS: (+) m/z 357.95, 359.92 (M+Na, 79/81Br).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]>[Pd]>[C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C=Cc1ccccc1CC#N
Agent: [Pd]
Product: CCOC(=O)CCc1ccccc1CC#N

Procedure:
Reagent XV is prepared from ethyl o-bromomethylcinnamate by the following series of reactions. (1) The starting ester is heated with a solution of sodium cyanide in ethanol to yield ethyl o-cyanomethylcinnamate. (2) This ester is hydrogenated over a Pt or Pd catalyst to afford ethyl o-cyanomethylhydrocinnamate. (3) This ester is reduced with sodium bis(2-methoxyethoxy)aluminum hydride in benzene to yield [2-(3-hydroxypropyl)phenyl]acetonitrile. (4) The nitrile is hydrolyzed by being heated with aqueous-ethanolic sodium hydroxide solution, and the acid is esterified (ethanol and mineral acid catalyst) to give ethyl [2-(3-hydroxypropyl)phenyl]acetate. (5) This hydroxy-ester is treated with phosphorus tribromide in ether to afford reagent XV.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CB(O)O>C1(C)C=CC=CC=1.C(OC(=O)C)C.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>[CH3:21][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3c(Br)cc(OC)cc3s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3c(C)cc(OC)cc3s2)cc1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To a solution of 4-bromo-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (1.0 g, 2.86 mmol) in dry toluene (25 mL) was added potassium carbonate (4.2 g, 30.4 mmol), methylboronic acid (0.92 g, 15.3 mmol) and tetrakis(triphenylphosphine)palladium (0.44 g, 0.38 mmol). The mixture was heated to 100° C. for 24 h, then cooled to room temperature. The mixture was diluted with ethylacetate and washed with water, saturated sodium carbonate and brine. After chromatographic purification gave 4-methyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole as a white solid (0.63 g, 77% yield). Mass spec: MH+=286.
Reaction SMILES: C([N:3]1[C:7]2[CH2:8][CH2:9][C:10]3[C:17]4([CH3:20])[CH:18]([CH3:19])[CH:4]1[CH2:5][C:6]=2[C:11]=3[CH:12]=[CH:13][CH2:14][N:15]=[CH:16]4)#N.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:20][C:17]12[CH:18]([CH3:19])[CH:4]3[NH:3][C:7]4=[C:6]([CH2:5]3)[C:11](=[C:10]1[CH2:9][CH2:8]4)[CH:12]=[CH:13][CH2:14][N:15]=[CH:16]2
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2
Temperature: 0 °C
Yield: 69 %

Procedure:
The nitrile (1.12 g) was dissolved in 60 ml of tetrahydrofuran and 0.80 g of lithium aluminium hydride was added, with cooling to 0° C. under nitrogen. The mixture was allowed to warm to room temperature and was then heated at reflux for 2 hr. The mixture was cooled to room temperature and 10% aqueous tetrahydrofuran was added. The mixture was filtered through anhydrous sodium sulfate and then celite. The filter cakes were washed with a mixture of triethylamine/methanol/ethyl acetate, and the filtrate was concentrated. The residue was purified by flash chromatography (alumina, triethyl amine/methanol/ether) to afford 0.70 g (69%) of 6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine.