Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[CH:2][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Reaction time: 15 h
Yield: 57.3 %

Procedure:
To a 0.35M solution of 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.53 mmol) in THF was added pyridine (Aldrich, 0.21 mL, 2.63 mmol) followed by 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 122 mg, 0.58 mmol). The resulting mixture was stirred for 15 hours. A 1M aqueous solution of HCl (20 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 140 mg (58%) of 94 as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[OH:10].[F:11][C:12]1[CH:19]=[C:18](F)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cl-].[NH4+]>[F:11][C:12]1[CH:19]=[C:18]([O:10][C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: COc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(F)cc1Oc1cc(F)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 2-methoxy-5-fluorophenol (226 mg, 1.59 mmol) in dimethylsulfoxide (10 mL) was added 2,4,5-trifluorobenzonitrile (250 mg, 1.59 mmol) and potassium carbonate (220 mg, 1.59 mmol) This suspension was stirred for 18 hours at room temperature. The reaction mixture was poured in saturated aqueous ammonium chloride solution (20 mL), and extracted with dichloromethane (3×40 mL). The combined organic layers were dried over sodium sulphate, and evaporated to afford the title compound as a clear oil (444 mg, 100%). This was used in the next reaction with no further purification.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.[Cl-].Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>CC(O)C.C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][C:21]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]3)[CH2:1]2)=[CH:22][CH:23]=1
Reactant: Clc1cc[nH+]cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(c3ccncc3)C2)CC1

Procedure:
tert-Butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and N-ethyl-diisopropylamine (2.7 ml, 15.724 mmol) were refluxed in 2-propanol (8 ml) for 15 h, saturated NaHCO3 solution (20 ml) and ethyl acetate (8 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate/methanol/ammonia (25 aq.) 100:10:0.25). Yield: 0.67 g (51.4%)
Reaction SMILES: C(OC([N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH3:26])[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]=4[CH:34]=3)[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1)=O)C=C.C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.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>[CH3:26][C:24]1[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:22]2[CH:34]=[C:18]([C:15]3[CH:16]=[CH:17][C:11]4[O:10][CH2:9][CH2:8][NH:7][CH2:13][C:12]=4[CH:14]=3)[CH:19]=[CH:20][C:21]=2[N:25]=1
Reactant: C=CCOC(=O)N1CCOc2ccc(-c3ccc4nc(C)n(C(=O)OC(C)(C)C)c4c3)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OC(C)(C)C
Yield: 106.9 %

Procedure:
7-[1-[(1,1-dimethylethoxy)carbonyl]-2-methyl-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylic acid 2-propenyl ester (110 mg, 0.27 mmol) was taken into THF (1 mL) followed by addition of sodium triacetoxyborohydride (254 mg, 1.2 mmol) then tetrakis(triphenylphosphine)palladium (0) (6.1 mg, 0.005 mmol) and the mixture was stirred for 1 h at room temperature. The mixture was diluted with chloroform and partitioned with dilute aqueous sodium bicarbonate. The aqueous phase was extracted twice with chloroform and the combined organic layers were dried over anhydrous sodium sulfate then filtered and concentrated to give crude 1,1-dimethylethyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazole-1-carboxylate (109.5 mg) as an amorphous residue. MS (EI) for C22H25N3O3: 380 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.[Li+].[Cl-]>O1CCOCC1.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:22])[CH3:21])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.87 g, 6.93 mmol), tributyl(1-ethoxyvinyl)tin (3.00 g, 8.31 mmol), Pd(PPh3)4 (801 mg, 0.693 mmol), and LiCl (734 mg, 17.3 mmol) in 1,4-dioxane (50 ml) was heated to reflux for 7 hours. The mixture was filtered through a pad of Celite with ethyl acetate. The filtrate was washed with water (100 ml) and brine (100 ml), dried over MgSO4, and evaporated in vacuo. To the obtained residue were added 2N HCl (20 ml) and THF (60 ml). The mixture was stirred at room temperature for 1.5 hours. Saturated aqueous NaHCO3 (60 ml) was added and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over MgSO4, and evaporated in vacuo. The resulting residue was chromatographed over silica gel with hexane/ethyl acetate (3:1) to give 1.51 g (94%) of the title compound as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>C[O-].[Na+].CO>[OH:23][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(OC)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A mixture of 7-hydroxy-2-(4-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (76 mg, 0.23 mmol) and glycine (345 mg, 4.59 mmol) in 0.5 M sodium methoxide/methanol (8.7 mL) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) was added and the suspension was adjusted to pH=10 with 1N HCl (3 mL). The mixture was extracted with dichloromethane. And the remaining aqueous layer was acidified to pH=3 with 1N HCl (5 mL). The suspension was extracted with 2-isopropanol/chloroform (1:3, 50 mL). The organic layer was concentrated and dried in vacuo to give the title compound as a yellow solid (25 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.28 (s, 1H), 9.42 (t, 1H), 8.88 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 4.03 (d, J=5.6 Hz, 2H), 3.88 (s, 3H); MS: (+) m/z 359.94 (M+1), (−) m/z 357.92 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][C:3]=1[C:15](OCC)=[O:16].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][C:3]=1[CH2:15][OH:16]
Reactant: CCOC(=O)c1nc2c3c(ccn2c1C)CCCC3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)nc2c3c(ccn12)CCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
To a solution of ethyl 3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinoline-2-carboxylate (210 mg, 0.81 mmol) in 5 mL of THF was added LAH (920 mg, 2.44 mmol) at 0° C. The mixture was stirred for 3 h at room temperature. To the mixture was added sodium sulfate decahydrate (100 mg) and the mixture was stirred for 15 min at room temperature. The solid was removed by filtration and the filtrate was concentrated to give the crude product of (3-methyl-7,8,9,10-tetrahydroimidazo[2,1-a]isoquinolin-2-yl)methanol (200 mg). ESI MS: m/z 217 [M+H]+. This crude product was used in the next step without further purification.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:67])[N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O>CO.O.Cl>[ClH:66].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:67])[N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1nc(Cl)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: Cn1nc(Cl)c2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 36 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-chloro-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.15 mL) and chromatographed on a 2 g C18 cartridge {gradient 30 to 65% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (10 mg, 36%, 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (br s, 3H), 7.82 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.56-7.53 (m, 2H), 7.51-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.31 (d, J=8.2 Hz, 2H), 4.38 (s, 3H), 2.62-2.49 (m, 4H), 2.22-2.12 (m, 1H), 1.86-1.75 (m, 1H). LCMS (Method E): RT=3.51 min, [M+H]+=456/458.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[NH:3]1.[CH2:15]1[O:17][CH2:16]1>C(O)C>[OH:17][CH2:16][CH2:15][N:3]1[C:4]2[CH:9]([CH:8]([CH3:12])[CH:7]=[CH:6][C:5]=2[O:13][CH3:14])[CH2:10][CH2:11][CH:2]1[CH3:1]
Reactant: C1CO1
Reactant: COc1ccc(C)c2c1NC(C)CC2
Solvent: CCO
Product: COC1=C2C(CCC(C)N2CCO)C(C)C=C1
Yield: 97 %

Procedure:
Next 355 parts of 2,5-dimethyl-8-methoxytetrahydroquinoline in 0.4 l ethanol with 86 parts ethylene oxide was reacted under pressure at 175° C. for 10 hours. The solvent was stripped under reduced pressure to an oil which eventually solidifed to give 97% N-(β-hydroxyethyl)-2,5-dimethyl-8-methoxytetrahydroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([CH3:19])=[CH2:18].C(OCC)(=O)C.CCCCCC>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:17]([CH3:19])=[CH2:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C(C)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chlorophenol (10 g, 0.078 mol) and potassium carbonate (32.25 g, 0.233 mol) in 20 ml DMF is stirred for 30 min at 25°. 1.1 Equivalents of 3-chloro-2-methyl-1-propene in 10 ml DMF is added dropwise at 0° and the mixture is allowed to warm to RT. After stirring at RT for 19 hr, the reaction is checked by thin layer chromatography (TLC) developing with 30% ethyl acetate/hexane. As some starting alcohol is still present, another 0.5 equivalent of 3-chloro-2-methyl-1-propene is added (a total of 1.6 equivalents) and the reaction mixture is heated at 50° for 7 hr. The reaction product is worked up with ice water and ether. The organic phase is washed with 5% NaOH, water until neutral, brine, and dried over magnesium sulfate and solvent is removed to give 3-(4-chlorophenoxy)-2-methyl-1-propene.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1.[CH3:16]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH3:16])=[O:12])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(Br)cc1)[C@H]1C[C@H]1C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a solution of cis-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (10.6 g, 36.63 mmol) in MeOH (250 mL) was added 2,2-dimethoxypropane (9.54 g, 91.59 mmol) and HCl (4.0 M in dioxane, 3.50 mL). The resulting solution was stirred at 40° C. for 3 days, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 15 to 25% ethyl acetate in hexanes to afford methyl cis-2-(4-bromobenzoyl)-cyclopropanecarboxylate (10.34 g, 99%). 1H NMR (400 MHz, CD2Cl2) δ 1.39 (m, 1H), 1.82 (m, 1H), 2.34 (m, 1H), 2.77 (m, 1H), 3.54 (s, 3H), 7.65 (m, 2H), 7.89 (m, 2H).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:26]2[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH:31]=2)=[N:13][C:14]=1[C:15]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][N:16]=1>CO>[C:20]1([C:18]2[O:17][N:16]=[C:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=4)[N:13]=3)[N:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc(C2=CCNCC2)nc1-c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.6 %

Procedure:
A solution of HCl in dioxane (505.5 μL of 4 M, 2.022 mmol) was added to a solution of tert-butyl 4-[5-amino-6-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (170 mg, 0.4043 mmol) in methanol (5 mL) at rt and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo to give the title compound (129 mg, 99% yield); MS (ES+) 321.03
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[OH:21])=[O:11])[CH3:8].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[O:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[O:21][CH2:28][C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1oc2ccncc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2ccncc2c1OCc1ccccc1
Reaction time: 0.08 h

Procedure:
K2CO3 (2.34 g, 17.0 mmol) was added to a stirred solution of 3-hydroxyfuro[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.76 g, 8.5 mmol) in DMF (40 mL). After 5 min, BnBr (1.25 mL, 10.6 mmol) was added, then the mixture was stirred for 16 h, before being poured into H2O and extracted with EtOAc (3×). The combined organic extracts were washed with brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc) yielded the title compound: m/z (ES+)=298.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCCCCCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 66.7 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (0.75 g) and 4-octylaniline (1.0 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-octylphenyl)amine (1.1 g) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1(C(OCC)=O)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])C>CC(O)=O.Cl>[O:11]=[C:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)CC1(C(=O)OCC)CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC1CCCC1=O
Yield: 75.1 %

Procedure:
A solution of ethyl 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopentanecarboxylate (50.0 g, 206 mmol) in HOAc (500 mL) and 6 M HCl (250 mL) was heated at 100° C. for 6 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (500 mL) and H2O (200 mL). Aqueous layer was separated and extracted with EtOAc (2×250 mL). The combined organic layers were washed with H2O (300 mL), brine (300 mL), dried over Na2SO4, decanted and concentrated to yield the title compound as a white solid (22 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.59-1.72 (m, 1H), 1.75-1.90 (m, 1H), 2.03-2.10 (m, 1H), 2.20 (dd, J=10.9, 8.9 Hz, 1H), 2.30-2.40 (m, 2H), 2.40-2.50 (m, 2H), 2.80 (dd, J=15.7, 7.2 Hz, 1H), 11.5 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2.[NH2:16][CH:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Br)ccc2nc1Cl
Reactant: NC(Cc1ccc(O)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-2-chloroquinoline-3-carboxylic acid is reacted with DL-tyrosine in DMSO to provide the title compound in good yield.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1)#[CH:2].[OH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=3)=[CH:25][C:24]=2[C:40]([F:43])([F:42])[F:41])[CH2:18][CH2:17]1>>[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[C:2][C:35]2[CH:36]=[C:31]([CH:32]=[CH:33][C:34]=2[CH3:37])[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH2:22][N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][OH:13])[CH2:17][CH2:18]3)=[C:24]([C:40]([F:43])([F:42])[F:41])[CH:25]=2)=[O:39])=[CH:4][N:5]=1
Reactant: C#Cc1cnnc2ccccc12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnnc2ccccc12

Procedure:
The title compound can be synthesized from 4-ethynylcinnoline and N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:24])[C:15]=2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]([CH2:25][CH2:26][CH3:27])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:36])[C:32](Br)([CH3:34])[CH3:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:36])[C:32]([O:24][C:14]1[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:25][CH2:26][CH3:27])[CH:9]=[C:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1cc(Cc2ccccc2)c2c(Cc3ccccc3)c(O)ccc21
Product: CCCn1cc(Cc2ccccc2)c2c(Cc3ccccc3)c(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3,4-dibenzyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:3]1[NH:4][CH2:5][CH2:6][CH2:7]2.[C:15](O)(=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:15]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]2([CH3:1])[CH2:14][C:13]3[C:8]([CH:3]12)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH3:16]
Reactant: CC12CCCNC1c1ccccc1C2
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCN1CCCC2(C)Cc3ccccc3C12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of (4aRS,9bRS)-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (140 mg) in 1,2-dichloroethane (3 ml) were added acetic acid (0.214 ml) and sodium triacetoxyborohydride (1.1 g), followed by heating and stirring at 70° C. for 3 hours. The reaction solution was basified by adding a 1 M aqueous sodium hydroxide solution, extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (4aRS,9bRS)-1-ethyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (105 mg) as an oily substance. This was made into a hydrochloride by a conventional method, washed with ethyl acetate, and collected by filtration to obtain (4aRS,9bRS)-1-ethyl-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine hydrochloride (108 mg) as a colorless powder.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:21])=O>ClCCCl>[Cl:21][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCc2c(sc3ncn(CCO)c(=O)c23)C1
Solvent: ClCCCl
Product: CN1CCc2c(sc3ncn(CCCl)c(=O)c23)C1
Temperature: 0 °C
Yield: 68 %

Procedure:
42.0 g (158 mM) of 3-(2-hydroxyethyl)-7-methyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one in 240 ml of 1,2-dichloroethane were heated to reflux and then 12.7 ml (175 mM) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After refluxing for 2 h, the reaction mixture was allowed to cool and was poured into ice/water. The mixture was partitioned between methylene chloride and water at pH=10, and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried and then concentrated. The crude product (40 g) was recrystallized from 400 ml of isopropanol. 30.5 g (68%) of product with melting point 159-161° C. were isolated.