Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]1=[O:16].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]1=[O:16]
Reactant: COC(=O)c1cc2cccnc2n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cccnc2n(CBr)c1=O
Reaction time: 4 h
Yield: 72.5 %

Procedure:
10.71 g (49.0 mmol) of methyl 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in carbon tetrachloride (200 mL), and 8.64 g (49.0 mmol) of N-bromosuccinimide and 0.1 g of 1,2-azobis(2-methylpropionitrile) were added thereto. While the mixture was irradiated with light, the mixture was stirred for 4 hours. 3.0 g (17.0 mmol) of N-bromosuccinimide was further added to the mixture, and the resulting mixture was stirred for 3 hours while the mixture was irradiated with light. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:chloroform=1:19), and thus 10.56 g (yield: 73%) of the title compound was obtained as colorless crystals.
Reaction SMILES: C[Li].[CH3:3]COCC.[CH3:8][C:9]1[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[CH:14]=1.[Cl-].[NH4+]>[Cu]I.CCOC(C)=O>[CH3:8][C:9]1([CH3:3])[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][CH:10]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOCC
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(=O)CC1(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Methyllithium (170 mL of a 1.6 M solution with Et2O, 260 mmol) was added to a stirring mixture of copper (I) iodide (25 g, 130 mmol) and Et2O (130 mL), at −40° C. under a nitrogen atmosphere. After stirring for 10 min at −40° C., ethyl 2-methyl-4-oxo-2-cyclohexene-1-carboxylate (12 g, 66 mmol) was added. After stirring for 30 min at −40° C., the reaction mixture was allowed to warm to −20° C. After stirring for 90 min at −20° C., saturated aqueous ammonium chloride and EtOAc were added sequentially, the mixture was partitioned between more saturated aqueous ammonium chloride and EtOAc, the layers were separated, the organic material washed sequentially with saturated aqueous ammonium chloride (2×) and brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was dissolved with DCM, silica gel (39 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (gradient elution; 19:1 to 9:1 hexane-EtOAc) to give ethyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (8.9 g, 68% yield; racemic mixture) as a clear yellow oil.
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[O:37]1[CH2:42][CH2:41][CH:40]=[C:39]([CH:43]=O)[CH2:38]1>O1CCCC1>[C:3]1([CH2:2][O:9][CH2:10][CH2:11][CH:12]=[CH:43][C:39]2[CH2:38][O:37][CH2:42][CH2:41][CH:40]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1=CCCOC1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=CC1=CCCOC1)CCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a suspension of (3-benzyloxypropyl)triphenylphosphonium bromide (9.90 g) in dry tetrahydrofuran (30.5 ml) at −15° C. was added butyllithium (8.06 ml, 2.5M in hexanes) dropwise to give a dark orange solution. The reaction temperature was increased to 0° C. and stirring was continued for 30 minutes. A solution of 5,6-dihydro-2H-pyran-3-carbaldehyde (2.26 g) in dry tetrahydrofuran (3 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered through celite and washed with diethyl ether. The filtrate was concentrated in vacuo to give an orange oil. The product was purified by silica chromatography using a gradient elution of 0-25% ethyl acetate/cyclohexane to afford the title compound as a colourless oil (2.04 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C.[Fe]>[C:14]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
150 g (0.83 mole) of 4-nitrophenylacetic acid are heated to 95° C. in 1.5 liters of glacial acetic acid. With vigorous stirring, 160 g (2.86 moles) of iron powder are added in portions in such a manner that the internal temperature does not rise above 105° C. Towards the end of the reaction, the reaction mixture clears up. 200 ml of acetic anhydride are added, and stirring is afterwards continued for a further 30 minutes at 100° C. Cooling to room temperature is allowed to take place; this is followed by suction filtration from formed iron salts, concentration to half the volume, and dilution with 1.5 liters of water. Extraction is effected three times with, in each case, one liter of ethyl acetate. This is followed by washing the organic phase with water and then concentrating it to dryness to obtain 133 g (83.1% of theory) of 4-acetamidophenylacetic acid (m.p. 168° to 170° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Na].[NH3:15].[Cl-].[NH4+]>C(OCC)C>[NH2:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: N
Reactant: Clc1ccc(-c2ccccc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOCC
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 36 %

Procedure:
A solution of 2-chloro-5-phenylpyridine (4.0 g., 0.021 mole) in dry diethyl ether (160 ml.) was added dropwise to a solution of sodium (3.39 g., 0.15 g-atom) in liquid ammonia (160 ml.) containing ferrous nitrate hexahydrate (0.095 g.). The resulting suspension was allowed to reflux for 4 hours. Ammonium chloride was added and the ammonia allowed to evaporate. The residue was treated with 5% aqueous sodium hydroxide (5 ml.). The mixture was filtered. The aqueous layer was extracted with ether (2×100 ml.). The combined ethereal layers were washed with brine and dried over sodium sulfate. The solution was concentrated and the residue recrystallized from methylcyclohexane. The product was triturated with chloroform (100 ml.). The mixture was filtered and the filtrate evaporated to give 2-amino-5-phenylpyridine (1.3 g., 36%), m.p. 133°-135° (lit. m.p. 133° in Chem. Ber., 91, 247 (1958).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)/C=C\C(=O)O)c1

Procedure:
A stirred solution of 1.0 g. of the N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide from Preparation 27 in 25 ml. of toluene was heated on a steam bath, and then 0.32 g. of maleic anhydride was added in one portion. After a few minutes the reaction mixture was cooled and the toluene was removed by evaporation in vacuo. The residue was recrystallized from acetonitrile to give 0.70 g. of the title compound as a white solid, m.p. 79°-78° C. (dec.). The IR spectrum (KBr disc) showed absorptions at 3448, 3279, 2941, 1724, 1639, 1587 and 1563 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.9 (m, 3H), 1.09 (m, 3H), 1.26 (s, 16H), 2.47 (m, 3H, under DMSO-d6), 3.8 (m, 1H), 6.26 (m, 3H), 7.62 (m, 6H) and 10.44 (s, 1H) ppm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[NH:10][C:7]2=[N:8][CH:9]=1.I[CH3:27].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:10]([CH3:27])[C:7]2=[N:8][CH:9]=1
Reactant: CI
Reactant: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ncc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)n(C)c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 15 mg, 0.38 mmol) was added to a stirred, cooled (0° C.) solution of methyl 5-chloro-2-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-propanoate (Description 4, 82 mg, 0.23 mmol) in dimethylformamide (5 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (24 μL, 54 mg, 0.38 mmol) was added and the mixture was stirred at room temperature for 5 min. Water (15 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (82 mg, 96%). 1H NMR (360 MHz, CDCl3) δ 8.27 (1H, d, J 2.2 Hz), 7.87 (1H, d, J 2.2 Hz), 7.50 (2H, m), 7.34 (2H, m), 3.64 (3H, s), 3.60 (3H, s), 2.98 (2H, t, J 7.8 Hz), and 2.51 (2H, t, J 7.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([OH:36])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC1CNC1
Product: O=C1N=C(N2CC(O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-azetidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidin-3-ol following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.C[N:13](C)[CH2:14][CH2:15]CN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.C(N)C>O1CCCC1.O.CN(C)C=O>[CH2:14]([NH:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH3:15]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
5-Bromo-pyridine-2-carboxylic acid (34, 0.417 g, 2.06 mmol) was dissolved in 19 mL of tetrahydrofuran. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.633 g, 3.30 mmol), N,N-diisopropylethylamine (1.81 mL, 10.4 mmol), and 1-hydroxybenzotriazole (0.363 g, 2.68 mmol) were added, followed by 2.00 M ethylamine in tetrahydrofuran (35, 1.20 mL, 2.40 mmol). The reaction mixture was stirred overnight at room temperature, after which 1.5 mL of dimethylformamide was added and stirred for another 4 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (36, 163 mg). MS (ESI) [M+H+]+=229.29, 231.3.
Reaction SMILES: [C:1]([C@@H:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[N:2].[CH3:18][C:19]1([CH3:32])[CH:21](/[CH:22]=[C:23](\[Cl:28])/[C:24](=[O:27])[O:25][CH3:26])[CH:20]1[C:29](O)=[O:30]>C1C=CC=CC=1>[CH3:18][C:19]1([CH3:32])[C@@H:21](/[CH:22]=[C:23](\[Cl:28])/[C:24](=[O:27])[O:25][CH3:26])[C@H:20]1[C:29]([O:17][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:30]
Reactant: COC(=O)/C(Cl)=C/C1C(C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R, cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+62.5°±1.5° (c=1% in benzene).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:21]([O:23][C:24](=[O:33])[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH2:32])[CH3:22].C(O)(=O)C.[Na]>CCCCCC.C(OCC)(=O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)=[O:33])[CH3:22]
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Reactant: CCOC(=O)c1cc(F)ccc1N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc(F)ccc1N[C@H]1CC[C@H]2CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]2C1
Yield: 21.1 %

Procedure:
Following the procedures from Example 1A, and using ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg, 1.9 mmol), 2-amino-5-fluoro-benzoic acid ethyl ester (183 mg, 1.0 mmol), glacial acetic acid (0.36 mL, 6.0 mmol), and sodium triacethoxyborohydride (590 mg, 2.8 mmol), flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 95 mg (22% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[CH:30])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCN(CC)CC.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>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][C:29]#[C:30][C:17]1[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[CH:18]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Oc1cc(C#CCNC(=O)OC(C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 29.2 %

Procedure:
To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1 g, 20.0 mmol) in THF (60 mL) and Et3N (60 mL) was added Cul (63 mg, 0.3 mmol) and Pd(PPh3)4 (384 mg, 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction was complete. The mixture was extracted with EtOAc and washed by water. The crude product was purified on a silica gel column eluting with 20–40% EtOAc in hexanes to provide (3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-prop-2-ynyl)-carbamic acid tert-butyl ester (2.2 g, 29% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[H-].[Na+].Cl[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:19]=1.C(O)(=O)C>CN(C=O)C.O>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:20]1[N:19]=[C:18]([O:11][CH2:10][CH2:9][NH:8][C:6]2[N:7]=[C:2]([NH2:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][CH:5]=2)[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=1
Reactant: Nc1nc(NCCO)ccc1[N+](=O)[O-]
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1nc(NCCOc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-[(6-Amino-5-nitropyridin-2-yl)amino]ethanol (Example 48A) is introduced into DMF (3 ml) at 0° C., and sodium hydride (60% oil dispersion, 15 mg, 0.4 mmol) is added. The mixture is stirred at 0° C. for 10 min. 5-Chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) (125 mg, 0.4 mmol) in DMF (1 ml) is added dropwise, and the reaction mixture is stirred at RT for 12 h. Glacial acetic acid (200 μl) is added, and the reaction mixture is poured into water and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is precipitated from acetonitrile, filtered off, washed with acetonitrile and dried. 36 mg (18% of theory) of product are obtained as a solid.
Reaction SMILES: [CH2:1]1[CH2:10][CH:9]2[CH2:11][CH:5]3[CH2:6][CH2:7][CH:8]2[CH:3]([CH2:4]3)[CH2:2]1.C=CCCCC1CCC=CC=1.S(=O)(=O)(O)O>CCCCC>[CH2:6]1[CH:5]2[CH2:4][CH:3]3[CH2:8][CH:9]([CH2:11]2)[CH2:10][CH:1]([CH2:2]3)[CH2:7]1
Reactant: C1CC2CC3CCC2C(C1)C3
Agent: C=CCCCC1=CC=CCC1
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: C1CC2CC3CC1CC(C2)C3
Yield: 20 %

Procedure:
4-Homoisotwistane (II) is a compound disclosed by Krantz et al (Chem., Commun., 1971, 1287 and J. Amer. Chem. Soc., 95, 5662 (1973)) in their report concerning the selectivity of the intermolecular Diels-Alder reaction of 1-penten-5-ylcyclohexadienes. However, the selectivity of 4-homoisotwistane (II) is very low in this reaction and the starting 1-penten-5-ylcyclohexadiene is not readily available or cannot easily be synthesized. Accordingly, from the industrial viewpoint, it is very disadvantageous to synthesize 4-homoisotwistane according to the process of Krantz et al. Majerski et al (Tetrahedron Letters, 4915 (1973)) succeeded in synthesizing 4-homoisotwistane (II) in a yield of about 20 percent by reacting homoadamant-4-ene or homoadamantan-4-ol with concentrated sulfuric acid and n-pentane. This process also is industrially disadvantageous because it is difficult to obtain the starting homoadamantane derivatives.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1.C(N(CC)CC)C.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:38]([CH3:40])[CH3:37])[CH2:14][CH2:13]1)[C:8](=[O:18])[C:7]12[C:22]2=[CH:23][C:24]3[O:28][CH2:27][O:26][C:25]=3[CH:29]=[C:21]2[O:20][CH2:19]1
Reactant: O=C1N(CC2CCNCC2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(F)c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a stirred solution of 7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (120 mg, 0.28 mmol) and triethylamine (3.9 μL, 0.028 mmol) in 5.00 mL dichloromethane was added acetone (4.1 μL, 0.56 mmol) followed with sodium triacetoxyborohydride (124 mg, 0.56 mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight, quenched with water (10.0 mL). The mixture was extracted with dichloromethane (3×30.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (2% methanol in ethyl acetate/hexane) to give 7′-fluoro-1′-[(1-isopropylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (85 mg, 69%) as a white solid, which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 157-160° C.; 1H NMR (300 MHz, CD3OD) δ 7.22-7.05 (m, 2H), 7.05-6.98 (m, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.68 (d, 1H), 3.95-3.77 (m, 2H), 3.55-3.42 (m, 3H), 3.12-2.96 (m, 2H), 2.30-2.10 (m, 1H), 2.10-1.97 (m, 2H), 1.76-1.52 (m, 2H), 1.34 (d, 6H); 13C NMR (75 MHz, CD3OD) δ 179.7, 157.6, 150.6, 150.4, 147.1, 143.9, 136.6, 125.8, 121.2, 120.3, 118.0, 103.9, 103.0, 94.3, 81.8, 60.1, 59.7, 47.6, 35.33, 35.30, 28.6, 28.5, 16.98, 16.96; MS (ES+) m/z 439.27 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[C:20]([C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccccn2)CCNCC1

Procedure:
Prepare by the method of example 30.3 using 1-tert-butoxycarbonyl-4-cyano-4-(pyridin-2-yl)-piperidine (3 mmol) and HCl in dioxane (40 mmol, 4N). Concentrate the solvent in vacuo and dry under high vacuum to give the title compound.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:5][CH2:4][N:3]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(Cl)Cl.O>C1COCC1>[N:3]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:2]=[CH:7][N:6]([C:8]([O:10][CH2:11][CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:9])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C=CN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C

Procedure:
In a round bottom flask charged with stirring bar, 1-tert-butyl 4-(9H-fluoren-9-ylmethyl) 2-hydroxypiperazine-1,4-dicarboxylate (4.34 g, 10.2 mmol) was dissolved in THF (100 mL) and was cooled down to 0° C. under N2. Then TFAA (1.589 mL, 11.25 mmol) was added. After stirring at 0° C. for 20 minutes, reaction was quenched by adding saturated aq. NaHCO3 and warmed up to room temperature. Then reaction was diluted by adding 200 mL of DCM and 100 mL of water. Layers were separated and aqueous layer was extracted with 100 mL of DCM. Organic phases were combined and dried over anhydrous Na2SO4. Removing solvent gave crude product that was purified by ISCO (120 gram silica gel column, 0-50% EtOAc/Hexane gradient). Concentration gave the title compound. 1H NMR (ppm) (500 MHz, CDCl3): δ 7.81 (2H, d, J=7.59 Hz), 7.61 (2H, dd, J=13.92, 7.51 Hz), 7.44 (2H, t, J=7.49 Hz), 7.35 (2H, t, J=7.47 Hz), 6.27-6.14 (2H, m), 4.52 (2H, dd, J=19.02, 6.70 Hz), 4.31 (1H, t, J=6.89 Hz), 3.81-3.68 (4H, m), 1.54 (9H, s); LC/MS (M+23)+=429.13;