Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(C#CCCC)=CC1.[CH3:29][C:30]1([CH3:58])[C:39]2[CH:38]=[CH:37][C:36]([C:40]#[C:41][C:42]3[CH:52]=[CH:51][C:45]([C:46]([O:48]CC)=[O:47])=[CH:44][CH:43]=3)=[CH:35][C:34]=2[C:33]([C:53]2[O:54][CH:55]=[CH:56][CH:57]=2)=[CH:32][CH2:31]1>>[CH3:29][C:30]1([CH3:58])[C:39]2[CH:38]=[CH:37][C:36]([C:40]#[C:41][C:42]3[CH:43]=[CH:44][C:45]([C:46]([OH:48])=[O:47])=[CH:51][CH:52]=3)=[CH:35][C:34]=2[C:33]([C:53]2[O:54][CH:55]=[CH:56][CH:57]=2)=[CH:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1
Agent: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(c2ccco2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoic acid (Compound 84), 60.3 mg (0.15 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-furyl)naphth-3-yl)ethynyl]benzoate (Compound 122) was converted into the title compound (colorless solid) using 16.0 mg (0.38 mmol) of LiOH in H2O.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cn1cncc1CC(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cncc1CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethanone (1.3 g.), sodium borohydride (0.25 g.) and methanol (50 ml.) was stirred at ambient temperature for 2 hours under an inert atmosphere. The methanol was evaporated away and water (30 ml.) added to the residue. The mixture was filtered and the solid washed with more water and dried to give 1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethanol (1.18 g.).
Reaction SMILES: Br[C:2]1[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:11][C:12]([CH3:15])=[N:13][N:14]=3)=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=2[CH:20]=1.[F:27][C:28]1[C:29]2[CH:30]=[C:31]3[C:40]4[N:41]=[C:42]([Sn](C)(C)C)[CH:43]=[CH:44][C:39]=4[O:38][CH2:37][N:32]3[C:33]=2[CH:34]=[CH:35][CH:36]=1.[Li+].[Cl-]>CC(O)C>[F:27][C:28]1[C:29]2[CH:30]=[C:31]3[C:40]4[N:41]=[C:42]([C:2]5[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]6[O:9][C:8]([C:10]7[O:11][C:12]([CH3:15])=[N:13][N:14]=7)=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=6[CH:20]=5)[CH:43]=[CH:44][C:39]=4[O:38][CH2:37][N:32]3[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: CNC(=O)c1c(-c2nnc(C)o2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)O
Product: CNC(=O)c1c(-c2nnc(C)o2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a mixture of compound 5-bromo-N-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.16 mmol), 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (95 mg, 0.24 mmol) and LiCl (20 mg, 0.47 mmol) in IPA (2 mL), chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) (50 mg) was added under N2 protection. After stirring at 100° C. overnight, the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=100:1) to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 21%). 1H-NMR (CDCl3, 400 MHz) δ 9.81 (br s, 1H), 8.81 (s, 1H), 7.77 (s, 1H), 7.55˜7.46 (m, 2H), 7.25˜7.18 (m, 2H), 7.13 (s, 1H), 6.89˜6.80 (m, 1H), 6.01 (s, 2H), 3.41 (s, 3H), 3.09 (d, J=4.4 Hz, 3H), 2.76 (s, 3H), 2.68 (s, 3H). MS (M+H)+: 603.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].Cl[C:21]1[CH:26]=[C:25](Cl)[CH:24]=[C:23](Cl)[C:22]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.ClCCl.CO>[C:21]1([O:4][C:3](=[O:5])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCC(Br)C(=O)Oc1ccccc1
Reaction time: 0.25 h

Procedure:
2-Bromohexadecanoic acid (1 g) was dissolved in dry chloroform (20 ml). After addition of 2,4,6 trichlorophenol (0.558 g), the reaction mixture was placed in an ice bath. Dicyclohexylcarbodiimide (0.736 g) dissolved in dry chloroform (2 ml) was added to the solution. After stirring the solution for 15 minutes in an ice bath, the temperature was adjusted to 20° C. Formation of the product was ascertained by thin layer chromatography on silicic-acid plates with dichloromethane/methanol (10:0.1 v/v) mixture as solvent. The solution was stirred for 24 h at 20° C. and the precipitated urea removed by filtration. The filtrate was washed twice with sodium bicarbonate (0.05M) solution and water. The crude reaction product was purified by liquid chromatography on silica gel using the same solvent system as eluent.
Reaction SMILES: B#B.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[NH:9][CH2:8][CH2:7]2.O>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7]2
Reactant: O=C1NCCc2cc(F)ccc21
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c(c1)CCNC2
Temperature: 25 °C

Procedure:
Diborane (1 M, THF, 24 mL) was added at 0° C. to a solution of 6-fluoro-3,4-dihydro isoquinolin-1(2H)-one (1.14 g, 6.9 mmol) in THF (8 mL). The mixture was stirred at reflux for 18 h. It was cooled to room temperature and water was added. The mixture was extracted with dichloromethane, and the organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (hexanes:ethyl acetate 1:1) afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16].Cl>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:15]([OH:16])([CH3:17])[CH3:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1nc(Br)ccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (25 g, 142 mmol) in diethylether (600 ml) was slowly added n-butyllithium (2.5 M in hexane, 56.8 ml, 142 mmol) at −78° C. under a nitrogen atmosphere. The resulting yellow reaction mixture was stirred at −78° C. for 2 hours and dry acetone (11.47 ml, 156 mmol) was added over 30 minutes. Stirring was continued at −78° C. for 1 hour. HCl (2N, 50 ml) was added and the reaction mixture was warmed to 0° C. The pH of the mixture was adjusted to ˜7 with 2N HCl solution. The reaction mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (29.36 g) was chromatographed over silica gel (cyclohexane:ethyl acetate 9:1): 22.3 g (67.1% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.33; LCMS RtH5=0.89 min (ES+ 234, 236). 1H-NMR (360 MHz, DMSO-d6): 7.72-7.62 (m, 2H), 5.27 (s, 1H, OH), 1.50 (s, 6H, 2×CH3).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>N1C=CC=CC=1>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1)=[O:33])[CH3:30]
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)cn3c2)c1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cn2cc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (301 mg, 0.800 mmol), ethyl isocyanate (100 μL, 1.27 mmol) and pyridine (10 mL) was stirred at 50° C. for 18 hr. The mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→0/100) and recrystallized from ethyl acetate-hexane to give the title compound (78.0 mg, 22%) as a pale-yellow solid.
Reaction SMILES: [ClH:1].[CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)([CH3:4])[CH3:3]>CCOC(C)=O>[ClH:1].[CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccccc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Excess HCl in EtOAc was added dropwise to a solution of intermediate 33 (172 mg, 0.51 mmol) in EtOAc and the reaction mixture was stirred at rt for 1.5 h. Filtration gave 1-(2-isopropoxyphenyl)-1,4-diazepane hydrochloride (intermediate 34) (175 mg, 100%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:16][C@H:17]([C:29](O)=[O:30])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:9]([NH:16][C@H:17]([C:29]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCc1ccccc1
Yield: 93.6 %

Procedure:
In substantially the same manner as Working Example 2, benzylamine (0.93 g) was condensed with Boc-3-(2-naphthyl)-L-alanine (2.50 g) to give N-(Boc-3-(2-naphthyl)-L-alanyl)benzylamine (3.0 g) as white crystals (yield 94%). The Boc group of the product was deprotected by using 4N hydrochloric acid/ethyl acetate solution, and 1.82 g of thus-obtained compound was condensed, in substantially the same manner as Working Example 2, with Compound 1 (1.47 g) to give the above-titled compound (Compound 109; 0.85 g) as white crystals (yield 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[NH3:14]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CO
Product: NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Bromobenzenesulfonyl chloride (1.0 g, 3.9 mmol), methanol/ammonia solution (5 mL, excess), and methanol (5 mL) were mixed together in a 25 mL-single neck flask and stirred overnight under a nitrogen atmosphere. In the morning, the reaction was concentrated under reduced vacuum to yield intermediate title compound (1.13 g, 100%) as a white solid. This material was used without further purification. Ion spray M.S. 235.9 (M*).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:8]
Reactant: COc1ccc(OC)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 3 l-volume three-necked flask were charged 372 g of m-nitrobenzoyl chloride and 280 g of p-dimethoxybenzene, and 1.6 l of methylene chloride were added thereto to form a solution. To the solution were added dropwise 300 g of aluminum chloride over about 1 hour while stirring at room temperature. The reaction mixture slightly generated heat, and the methylene chloride began to reflux. After stirring was continued for about 2 hours, the reaction mixture was allowed to stand overnight.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: O=C1CCC(CO)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (0.3 g) and 2,2-dimethoxypropane (2 ml) in dichloromethane was refluxed in the presence of a crystal (ca. 10 mg.) of p-toluenesulfonic acid for 20 hours. Aqueous extractive work up followed by solvent evaporation produced 0.18 g of (R)-tetrahydro-3,3-dimethyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one as an oil (TLC showed a single spot at Rf =0.6 (ethyl acetate)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]2[CH3:26].[S:27](Cl)(=[O:30])(=[O:29])[NH2:28].O>CC(N(C)C)=O>[S:27](=[O:30])(=[O:29])([O:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([N:6]2[C@@H:5]([CH3:26])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:18])=[O:17])=[CH:24][CH:23]=1)[NH2:28]
Reactant: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OS(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a stirred solution of 4-{[(6S)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol (1.11 g, 3.0 mmol) in dimethyacetamide (10 mL), cooled to 0° C., was added sulfamoyl chloride (1.39 g, 12.0 mmol). The mixture was allowed to warm to room temperature and stirring continued for 16 hours. Water (100 mL) was added and a white precipitate deposited on the inside of the reaction vessel. The water was removed and the flask was washed with additional water. The white solid was dissolved in dichloromethane and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane, to afford the title compound (1.16 g, 87%) as a white solid, m.p. 166.5-167° C.;
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]1([C:11]23[CH2:22][CH:15]4[CH2:16][C:17]([C:19](=[O:21])C)([CH2:18]2)[CH:13]([CH2:14]4)[CH2:12]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[O:24]C(C)(C)C>O.O1CCOCC1>[C:5]1([C:11]23[CH2:22][CH:15]4[CH2:16][C:17]([C:19]([OH:24])=[O:21])([CH2:18]2)[CH:13]([CH2:14]4)[CH2:12]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(C)(C)C
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C

Procedure:
Dioxane (1.81) was added to a solution, cooled to −22° C., of sodium hydroxide (724 g) in water (4.8 l). Bromine (578 g) was metered into this solution such that a temperature of −15° C. was not exceeded. A solution of 1-(2-phenylhexahydro-2,5-methanopentalen-3a-yl)ethanone (290 g) in dioxane (600 ml) was metered into this solution, and the reaction was allowed to warm up gradually to room temperature. tert-Butyl methyl ether was added. Subsequently, water was metered in (2.5 l). After phase separation, the aqueous phase was washed with tert-butyl methyl ether. Subsequently, after addition of tert-butyl methyl ether (5 l), hydrochloric acid (32%) was used to establish a pH of pH 1.5. After phase separation, the organic phase was washed repeatedly with water and clarified with activated carbon. The solvent was changed by distillation under reduced pressure with addition of diisopropyl ether. After extractive stirring with diisopropyl ether at reflux, 2-phenylhexahydro-2,5-methanopentalene-3a-carboxylic acid (292 g) was obtained as a solid with 95% purity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18]C)=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(C(C)C)c2cc(C#N)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a 50 ml round bottom was added methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (230 mg, 0.897 mmol), followed by methanol (1 mL) and THF (1 mL). To the solution was added 3 M NaOH (0.449 mL, 2.69 mmol). The reaction stirred at rt for 20 h. The reaction was evaporated and treated with acidic water to pH 5. A brown solid crashed out and was collected by filtration. The solid was an impurity. The pH of the liquid was adjusted to 3 and the liquid was evaporated leaving a residue. Trituration of the residue with water, followed by filtration yielded 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (155 mg, 0.576 mmol, 64.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-δ6) δ ppm 13.16 (br. s., 1H) 8.33 (s, 1H) 7.78 (s, 1H) 7.66 (s, 1H) 4.81-4.98 (m, 1H) 2.33 (s, 4H) 1.45 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 243.3.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A mixture of 5-(azidomethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (139 mg, INTERMEDIATE 2) and triphenylphosphine (226 mg) was heated to 65° C. for 8 h in 66 ml of tetrahydrofuran and 9 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (5 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (5 column volumes), to provide the title compound (122 mg, 94%). Mass spectrum (ESI) 228.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]([NH2:26])=[O:25])=[CH:14][CH:13]=2)(C)(C)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[NH2:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]([NH2:26])=[O:25])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.23 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the precipitated crystals were crystallized from methanol-diethyl ether to give 3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxamide hydrochloride (0.18 g, 94.7%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2OC2C=CC=CC=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:25].Cl.[CH2:27]([NH:31][CH2:32][CH2:33][NH2:34])[CH:28]([CH3:30])[CH3:29]>C1(O)C=CC=CC=1>[ClH:25].[ClH:25].[N+:1]([C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2[NH:34][CH2:33][CH2:32][NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)CNCCN
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Oc3ccccc3)c12
Agent: Cl
Solvent: Oc1ccccc1
Product: CC(C)CNCCNc1c2ccccc2nc2cccc([N+](=O)[O-])c12
Temperature: 90 °C

Procedure:
1-Nitro-9-phenoxyacridine (1.58 g) is dissolved in about 5 g of phenol, and then 0.95 g of 2-isobutylaminoethylamine dihydrochloride is added and is heated at a temperature of 90° C. for 1.2 hour. It is isolated in a similar manner, as in Example VII. There is obtained 1-nitro-9-isobutylaminoethylaminoacridine dihydrochloride with a melting point of 230° C. (with decomposition).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:5]2[S:6][C:2]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:28]#[N:29])[CH2:26][CH2:27]4)=[CH:21][CH:20]=3)([CH3:1])[C:3](=[O:17])[N:4]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: CC1SC(N[C@@H](C)c2ccc(F)cc2)=NC1=O
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C3(C#N)CC3)cc2)S1)c1ccc(F)cc1

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(4-fluorophenyl)ethylamino)thiazol-4(5H)-one with 1-(4-bromophenyl) cyclopropane carbonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 394 (M+1).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].C([O-])([O-])=O.[K+].[K+]>Cl[Cu].CN1C(=O)CCC1>[NH:6]1[C:10]2[C:3](=[CH:2][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3.2 mg (0.03 mmol) CuCl and 3.2 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 100° C. and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4 hours, full conversion of (S)-2-bromophenylalanine was found. The yield (measured in solution) of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was 95.9%, ee>98.6%.