Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[C:30]([CH3:32])[CH:31]=2)[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[Cl-].O[NH3+].C([N:40](CC)C(C)C)(C)C.C(O)C>CO>[NH2:40][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:31]=[C:30]([CH3:32])[CH:29]=3)=[CH:19][N:18]2[N:23]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(C)cc(NC(=O)c3cc(C)nn3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-5-methylphenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (2.65 g, 4.76 mmol), hydroxylammonium chloride (2.96 g, 42.5 mmol), N,N-diisopropylethylamine (5.00 mL, 28.7 mmol), ethanol (100 mL) and methanol (100 mL) was stirred at 80° C. for 14 hr. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and washed with ethanol-ethyl acetate to give the title compound (1.29 g, 72%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].Cl[C:13]([C:15]1[C:16]([Cl:26])=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([O:20][CH3:21])=[O:19])=[O:14]>ClCCl>[Cl:26][C:16]1[C:15]([C:13]([NH:11][O:10][CH3:9])=[O:14])=[C:24]([Cl:25])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
20 4.60 g (0.045 mol) of triethylamine and 3.75 g (0.045 mol) of methoxyamine hydrochloride were added to a solution of 5.35 g (0.02 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate and in 100 ml of dichloromethane. After the reaction solution had been stirred for 12 hours at room temperature, it was washed with dilute phosphoric acid, dried and concentrated. The resulting residue was extracted by stirring with diethyl ether. This gave 4.80 g of methyl 2,4-dichloro-3-(N-methoxy)aminocarbonylbenzoate.
Reaction SMILES: C[O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].CON(C1C=CC=CC=1)[C@H](C(O)=O)C.N[C@H](C(O)=O)C.[I-].[Na+]>Cl.Br>[NH2:5][C@H:4]([C:3]([OH:14])=[O:2])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Br
Agent: CON(c1ccccc1)[C@@H](C)C(=O)O
Agent: C[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 105 °C
Reaction time: 12 h

Procedure:
The synthesis was carried out with reference to the disclosure of Reference Article (8). There was dissolved 1.02 g (3.8 mmol) of the tyrosine methyl ester (25) in 50 ml of a 1N HCl solution, and then the resulting solution was stirred at 105° C. for 12 hours. After cooling, the resulting mixture was concentrated and then ion-exchanged using Dowex-50w-X8 to thus give 775 mg (3.77 mmol) of methoxyphenyl alanine. This alanine and 623 mg (4.15 mmol) of sodium iodide were dissolved in 45 ml of a 48% hydrobromic acid solution, the container was closed with a septum and firmly tightened with a wire and the content thereof was stirred at 92° C. for 4 hours. After cooling down to room temperature, the resulting mixture was concentrated and then ion-exchanged using Dowex-50w-X8 to thus give the title compound: tyrosine (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:15]#[N:16])[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[BH4-].[Na+].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ClC1C=CC(CC(CO)C#N)=CC=1.N1C=CN=C1>CC(O)C.CN(C=O)C>[Si:19]([O:12][CH2:10][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:15]#[N:16])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Cl)cc1
Agent: N#CC(CO)Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCC(C#N)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of ethyl 3-(4-chlorophenyl)-2-cyanoacrylate (6.2 g, 26 mmol) in 2-propanol (80 mL) was added dropwise to a stirred suspension of NaBH4 (2.8 g, 74 mmol) in 2-propanol (20 mL). The mixture was stirred at room temperature overnight. Excess NaBH4 was destroyed with saturated NH4Cl, and most of the 2-propanol was removed in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The crude 2-(4-chlorobenzyl)-3-hydroxypropanenitrile was used without purification. TBS-Cl (2.77 g, 18.4 mmol) in dry DMF (15 mL) was added to a solution of the crude 2-(4-chlorobenzyl)-3-hydroxypropanenitrile (3.00 g, 15.3 mmol) and imidazole (4.18 g, 61.3 mmol) in DMF (25 mL) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ether and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column (hexanes:EtOAc, 30:1) to give 3-(tert-butyldimethylsilyloxy)-2-(4-chlorobenzyl)propanenitrile (3.70 g, 78%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:5][CH:4]([N:6]2[C:10]3[N:11]=[C:12](S(C)=O)[N:13]=[C:14]([C:15]4[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=4)[C:9]=3[CH2:8][CH2:7]2)[CH2:3]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[CH2:32][OH:33].[F-].[Cs+]>C(#N)C>[NH2:21][C:18]1[N:17]=[CH:16][C:15]([C:14]2[C:9]3[CH2:8][CH2:7][N:6]([CH:4]4[CH2:5][C:2]([F:25])([F:1])[CH2:3]4)[C:10]=3[N:11]=[C:12]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@H:27]3[CH2:32][OH:33])[N:13]=2)=[CH:20][N:19]=1
Reactant: OC[C@@H]1COCCN1
Reactant: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: Nc1ncc(-c2nc(N3CCOC[C@H]3CO)nc3c2CCN3C2CC(F)(F)C2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-[7-(3,3-difluorocyclobutyl)-2-(methylsulfinyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine (35 mg, 0.096 mmol) in acetonitrile (0.3 mL) was added (3R)-morpholin-3-ylmethanol (68 mg, 0.576 mmol) and CsF (56 mg, 0.288 mmol), and the reaction mixture was sealed and heated at 120° C. for 96 h.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=C(C3C=CC(C(F)(F)F)=CC=3)C=CC=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7]>CCOC(C)=O>[CH3:35][N:2]([CH3:1])[C:3](=[O:34])[C@H:4]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C[C@H](C(=O)N(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](C(=O)N(C)C)c1ccc(O)cc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Dimethylamide 22.1 (2.1 g, 4.23 mmol) was dissolved in 50 mL of EtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 g of palladium on carbon (5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (100 mL) and hexane (50 mL). The ACN layer was washed with hexane (4×50 mL). The ACN layer was concentrated under reduced pressure to afford (S)-methyl 4-(dimethylamino)-3-(4-hydroxyphenyl)-4-oxobutanoate 22.2 (1.0 g, 3.98 mmol) as a colorless oil. MS ESI (pos.) m/e: 252.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8]([CH3:24])=[C:9]2[C:13](=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]=1[CH3:16])[NH:12][CH2:11][CH2:10]2)=[O:5])[CH3:2].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:12]1[C:13]2[C:9](=[C:8]([CH3:24])[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]([CH3:16])[C:14]=2[NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:10][CH2:11]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCI
Reactant: CCOC(=O)Cc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CCc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
N-(5-Ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in DMF (15 ml), and 1-iodooctane (5.0 g) and K2CO3 (2.9 g) were added, which was followed by stirring under a nitrogen atmosphere at 50° C. for 2 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0 -50/1) to give 3.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:32]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:37]=1>>[CH2:32]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:20][CH:21]=1)[CH3:37]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1

Procedure:
4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=463.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.Br[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccncc4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (49.8 mg) was dissolved in DMF (2 mL). Diisopropylethylamine (79 μL) and 4-bromopyridine hydrochloride (43.2 mg) were added, and the mixture left heating overnight at 100° C. After 17 h added more diisopropylethylamine (79 μL) and 4-bromopyridine hydrochloride (40.2 mg) and continued heating at 100° C. for another 24 h. The volatiles were removed in vacuo and the residue purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 5.0 mg of impure product that was purified by HPLC (Zorbax Rx-SIL, 60:40 hexanes:ethanol) to yield 3.0 mg of the title compound. Mass spectrum (ESI) 408.4 (M+1).
Reaction SMILES: C(=O)=O.[ClH:4].[NH+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)CO.[F:17][C:18]([F:29])([F:28])[C:19]([O:21]C(=O)C(F)(F)F)=[O:20].FC(F)(F)C(OCC(F)(F)F)=O>>[F:17][C:18]([F:29])([F:28])[C:19]([O-:21])=[O:20].[NH+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C(OCC(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: OCC(F)(F)F
Product: O=C([O-])C(F)(F)F

Procedure:
A 250 ml three-neck flask fitted with KPG stirrer, dry-ice condenser and dropping funnel was charged with 23.11 g (0.2 mole) of pyridinium hydrochloride and 20.0 g (0.2 mole) of 2,2,2-trifluoroethanol. Subsequently, at an internal reaction temperature from 52° to 55° C., 42.01 g (0.2 mole) of trifluoroacetic anhydride were added dropwise over a period 3 hours. The yield of trifluoroethyl trifluoroacetate was 98% (GC). The resulting reaction solution was either used as catalyst mixture for experiments as described in Example 1, or 2,2,2-trifluoroethanol was distilled off. During the course of the distillation the trifluoroacetic acid, which initially formed in the reaction, reacted in the distillation flask with the pyridinium hydrochloride to form pyridinium trifluoroacetate and HCl.
Reaction SMILES: [N:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=2[F:18])[CH2:8][CH2:7][C:6]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[Cl-].[NH4+]>CCOCC>[F:18][C:11]1[CH:12]=[C:13]([F:17])[C:14]([F:16])=[CH:15][C:10]=1[C@H:9]1[C@H:4]([NH2:1])[CH:5]=[C:6]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])[CH2:7][CH2:8]1
Reactant: CC(C)[Si](OC1=CC(N=[N+]=[N-])C(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)[Si](OC1=C[C@@H](N)[C@H](c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of {[3-azido-4-(2,4,5-trifluorophenyl)cyclohex-1-en-1-yl]oxy}(triisopropyl)silane (48.2 g) in ether (280 mL) at 0° C. in a three-neck flask (1 L) was added lithium aluminum hydride (1M in ether, 85 mL) while maintaining the temperature below 5° C. The reaction mixture was allowed to warm up to room temperature after completion of addition of the hydride. The mixture was transferred to ice with some saturated aqueous ammonium chloride solution and filtered. The residue was washed with ethyl acetate (1 L), and the organic layer separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed (silica gel, gradient 10-35% ethyl acetate in heptane) to yield the faster eluting cis- and the slower-eluting trans 6-(2,4,5-trifluorophenyl)-3-[(triisopropylsilyl)oxy]cyclohex-2-en-1-amine.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:24]1
Reactant: CC1CCCNC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 3-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from isopropyl ether, 3-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]piperidine (1 g), melting at 116° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](N)([CH3:23])([CH3:22])[CH3:21].Cl>[Cu](Cl)Cl.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[C:16]([C:21]1[C:15]([OH:19])=[CH:14][CH:13]=[C:23]3[C:20]=1[CH:22]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:10]=[CH:11]3)[C:15]([OH:19])=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ccc(OCc3ccccc3)cc2c1
Reactant: CC(C)(C)N
Agent: Cl[Cu]Cl
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccc(OCc3ccccc3)cc2c1-c1c(O)ccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
To a mixture of 55.8 g (0.223 mol) of 7-benzyloxy-naphthalene-2-ol, 60.0 g (0.446 mol) of copper chloride (II), and 1.5 L of methanol was added a methanol (500 mL) solution of 130.5 g (1.78 mol) of t-butylamine, followed by 20 hours of stirring at room temperature. The reaction liquid was cooled on an ice bath and after addition of 500 mL of 6N hydrochloric acid, methanol was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate (1.5 L) and the resulting solution was washed with saturated brine. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 47.3 g of the title compound. Yield 85%.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH3:12])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:17]>[Cu](Br)Br>[Br:17][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH3:12])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: CC1OC(=O)c2cc(N)ccc21
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: CC1OC(=O)c2cc(Br)ccc21
Reaction time: 2 h

Procedure:
58.25 g of 6-amino-3-methylphtalide (3-4) was dissolved in 1.5 l of 4.7% hydrobromic acid and 405.60 g of copper (II) bromide was added thereto, and under cooling with ice, 400 ml of aqueous solution of 41.92 g of sodium nitrite was dropped thereto. The resulting mixture was stirred at the same temperature for 2 hours and then stirred at a room temperature for 15 hours, and thereafter, extracted with chloroform. The resulting organic layer was washed with saturated sodium bicarbonate solution and saturated salt water in order, and dried over anhydrous magnesium sulfate, and thereafter, the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to obtain 71.56 g of 6-bromo-3-methylphtalide (3-5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9]C(=O)C(C)(C)C)=[N:6][C:7]=1[Cl:8].Cl.O.CCO>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccc(Cl)c(Cl)n1
Temperature: 87.5 °C
Yield: 93.1 %

Procedure:
A mixture of N-(5,6-dichloropyridin-2-yl)pivalamide (790 mg, 3.20 mmol), hydrochloric acid, 37% (1.25 mL), water (1.25 mL), and EtOH (3 mL) was heated for 4 hrs in an oil bath at 85-90° C. LCMS showed nearly complete conversion to product. The reaction was cooled to room temperature and the reaction mixture was evaporated down to a small volume, then transferred to a separatory funnel where it was partitioned between aqueous sodium carbonate and ethyl acetate. The layers were separated, the aqueous phase was washed again with ethyl acetate, and the combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated to give a white solid. The material was subjected to a Biotage column in 20% ethyl acetate/hexane, collecting the main component. 5,6-Dichloropyridin-2-amine (0.49 g, 2.98 mmol, 93%) was obtained as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.44 (d, J=8.55 Hz, 1H), 6.36 (d, J=8.24 Hz, 1H), 4.58 (s, 2H). MS (LC/MS) R.T.=1.28; [M+H]+=164.8.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]([CH2:18][CH2:19][C:20]#[N:21])[C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCOCC1>[C:20]([CH:19]1[CH2:18][N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:11]([CH3:17])([CH3:16])[C:12]1=[O:14])#[N:21]
Reactant: COC(=O)C(C)(C)N(CCC#N)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(C#N)C(=O)C1(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
NaH (60%, 3 g; 73.2 mmol) was added to a solution of methyl 2-[(tert-butoxycarbonyl)(2-cyanoethyl)amino]-2-methylpropanoate (16.5 g, 61.0 mmol) in 1,4-dioxane (300 mL) and the reaction mixture was stirred at 100° C. for 4 hours then concentrated in vacuo. The residue was taken up in water (200 mL) and the pH adjusted to 3.5 with citric acid. The solution was extracted with EA (2×). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (11.5 g, 79%) as an off-white solid. 1H NMR (DMSO-d6) δ 12.24 (s, 1H), 4.02-3.98 (m, 2H), 1.46-1.39 (m, 15H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][CH3:18])=[O:16].NC1[CH:25]=[N:24][CH:23]=[C:22]([Cl:26])[N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:26][C:22]1[N:21]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:25]=[N:24][CH:23]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CNC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from 4-hydroxy-2-methyl-N-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[C:13]([CH3:26])[CH:12]=2)=[C:5]2[CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH2:31][C:4]=12)[CH3:2].[NH3:34]>CO>[NH2:34][CH2:20][CH2:19][CH2:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][C:5]=23)=[O:27])=[CH:12][C:13]=1[CH3:26]
Reactant: N
Reactant: CCc1sc(C(=O)CCc2cc(C)c(CCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Solvent: CO
Product: CCc1sc(C(=O)CCc2cc(C)c(CCCN)c(C)c2)c2c1CC(C)(C)CC2

Procedure:
A solution of methanesulfonic acid 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propyl ester (160 mg, 0.326 mmol) in 7 N NH3 in methanol is stirred at 70° C. for 16 h in a sealed vial. The solvent is removed and the residue is purified by CC on silica gel eluting with DCM containing 7% of methanol to give 3-[4-(3-amino-propyl)-3,5-dimethyl-phenyl]-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (101 mg) as a pale yellow resin; LC-MS: tR=0.95 min, [M+1]+=412.36; 1H NMR (CDCl3): δ 6.87 (s, 2H), 3.09-3.00 (m, 4H), 2.97-2.88 (m, 4H), 2.76-2.60 (m, 6H), 2.30 (s, 2H), 2.28 (s, 6H), 1.80-1.70 (m, 2H), 1.54 (t, J=7.0 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H), 0.96 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O.CCOCC>[C:15]1(=[O:25])[N:19]([CH2:2][CH:3]([OH:14])[CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1cccc(OCC(O)CCl)c1
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(O)CN2C(=O)c3ccccc3C2=O)c1

Procedure:
The distilled product from Example 1 (21.1 g, 0.098 mol) and potassium phthalimide (37 g, 0.20 mol) are dissolved in 100 ml of N,N-dimethylformamide and the mixture is heated 22 hours on a steam bath under N2. The mixture is cooled, diluted with 200 ml of ether and filtered. The filtrate is concentrated to remove ether and diluted to 500 ml with water to give the crystalline title product, 30.8 g, mp 122°-126°.