Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C@H:13]([C:22]([OH:24])=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][O:26][NH:25][C:22]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][N:14]1[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[O:24])=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Reaction time: 3 h
Yield: 83.5 %

Procedure:
(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid (0.879 g, 2.54 mmol) described in Example 98 and tert-butyl 2-(aminooxy)ethylcarbamate (0.559 g) of Reference Example 9 were dissolved in N,N-dimethylformamide (11 mL), and to which was added 1-hydroxybenzotriazole.monohydrate (0.489 g), followed by ice-cooling. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.613 g), and the temperature was elevated to room temperature, followed by reacting for 3 h. Water was added to the reacted mixture, and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 1.07 g of the title compound (yield 84%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=1[NH2:26].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[NH:19][C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[NH2:26])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cn1c(N)c(NC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-tert-butoxycarbonylamino-phenyl)-acetic acid (0.825 mmol) and crude 5,6-diamino-1,3-dimethyl-1H-pyrimidine-2,4-dione (0.75 mmol) in N,N-dimethylformamide (3 mL) under argon at 25° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.825 mmol) and 4-dimethylaminopyridine (0.15 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was triturated with water and the resulting solid collected by filtration, washed well with water and dried in vacuo to afford crude {4-[(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-methyl]-phenyl}-carbamic acid tert-butyl ester as a light beige solid which was of sufficient purity for subsequent use without additional purification (87%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[F:22][C:23]1[C:24]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[C:23]=3[F:22])=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2F)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCOCC5)c4F)cc32)c1Cl
Yield: 35 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 4-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholine as in General Procedure 4A to give the title compound as a tan foam (35% yield). M.p. (foam), LCMS: m/z=476.02 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (t, J=4.8 Hz, 2H), 3.48 (t, J=4.8 Hz, 4H), 3.52-3.65 (m, 2H), 3.87 (t, J=4.6 Hz, 4H), 4.50 (s, 2H), 5.38 (bs, 1H), 6.82-6.86 (m, 1H), 6.97-7.04 (m, 1H), 7.08 (s, 1H), 7.04-7.15 (m, 1H), 7.70 (s, 1H), 8.00 (d, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[F:34][C:20]([F:19])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([C:2]([Cl:1])=[O:4])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A mixture of triphosgene (3.2 g, 10.85 mmol) in tetrahydrofuran (10 mL) was slowly treated with pyridine (1.72 g, 21.72 mmol) via syringe. The resulting white suspension was then treated portionwise with 1-[3-(trifluoromethyl)phenyl]piperazine (500 mg, 2.17 mmol). The reaction mixture was allowed to stir at 25° C. for 18 h. At this time, the reaction was slowly quenched by the addition of water. The aqueous layer was extracted with methylene chloride. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-(3-trifluoromethyl-phenyl)piperazine-1-carbonyl chloride (500 mg, 79%). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(C(C)(C)C)(C)C.Cl>CO.O.C(OCC)C>[OH:8][CH2:9][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1CO
Reaction time: 0.17 h

Procedure:
To a solution of 15.021 g (39.368 mM) of N-[2-(tert-butyldimethylsilyloxymethyl)benzyl]phthalimide in 50 ml of methanol was added 5 ml of concentrated hydrochloric acid at room temperature and the mixture was stirred at the prevailing temperature for 10 minutes. This reaction mixture was poured in water-diethyl ether and the resulting precipitate was recovered, rinsed serially with water and diethyl ether, and dried to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([CH3:32])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:12][CH:13]=2)[CH:8]=1)C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]2[C:14]3[C:9](=[N:10][C:11]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][CH:13]=3)[CH:8]=[C:7]2[CH2:6][C:5]([CH3:33])([CH3:32])[C:4]([OH:34])=[O:3])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1cc2nc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 60 °C

Procedure:
3-[1-(4-Chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (0.024 g, 0.05 mmol) was dissolved in THF (0.1 mL), MeOH (0.1 mL), and H2O (0.1 mL). LiOH (0.008 g, 0.20 mmol) was added and the reaction was heated to 60° C. for 2 hours. Once no starting material was seen by LCMS, the reaction was cooled to room temperature and diluted with EtOAc and water. The mixture was neutralized with solid citric acid to ˜pH 5, the aqueous layer was extracted three times with EtOAc, the combined organics were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated to give the desired acid. LCMS (ESI) M+H 450.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:19][O:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol), 1-hydroxybenzotriazole (97.0 mg, 0.72 mmol), 4-chlorobenzoic acid (94.0 mg, 0.60 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (8 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 67/33) to give 4-chloro-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)benzamide (172 mg, 62%) as a white solid: LCMS: 463 [M+1]+. 1H NMR (DMSO-d6) δ: 1.70 (m, 2H), 1.90 (m, 2H), 3.01 (m, 2H), 3.13 (m, 2H), 3.98 (d, 1H), 7.51 (d, 2H), 7.68 (m, 2H), 7.95 (m, 2H), 8.11 (m, 2H), 11.6 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]([OH:2])[CH:12]=[CH:11]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3c(-c4ccccc4)c(OC)ccc3c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3c(-c4ccccc4)c(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)-1-phenylnaphthalene (0.36 g, 1.06 mmol) in CH2Cl2 (25 mL) at 0° C. was slowly added boron tribromide (3.2 mL of 1 N in CH2Cl2). The mixture was allowed to warm slowly to room temperature and was stirred overnight. The resulting solution was poured into water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporation of thesolvent, and purification by silica column chromatography (25% ethyl acetate-hexanes) followed by preparative reverse-phase HPLC and drying under vacuum at 105° C. yielded 0.14 g (42%) of the title compound as a white solid: mp 142-146° C.; 1H NMR (DMSO-d6): δ 6.86 (2H, d, J=8.50 Hz), 7.26-7.42 (5H, m), 7.48-7.61 (5H, m), 7.84 (1H, d, J=8.96 Hz), 8.02 (1H, d, J=1.46 Hz), 9.52 (2H, s); MS (ESI) m/z 311 (M−H)−.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]2[N:5]([CH:10]=[CH:11][N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1.[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Br:2][C:3]1[C:4]2[N:5]([C:10]([F:14])=[CH:11][N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1cc(Br)c2nccn2n1
Agent: Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Fc1cnc2c(Br)cc(Cl)nn12
Reaction time: 6 h
Yield: 24.2 %

Procedure:
In a 20 ml reaction vial was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride salt (0.33 g, 1.4 mmol) from Example I(1), step 1b, CH3CN (7.0 ml) and selectflor (0.5 g, 1.4 mmol). The reaction was stirred at 50 C for 6 hrs, then concentrated to dryness. Purification was done by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to give 0.085 g of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:12](=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.Br[CH2:25][CH2:26][CH2:27][Cl:28]>CN(C)C=O>[Cl:28][CH2:27][CH2:26][CH2:25][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:23])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:4]1=[O:3]
Reactant: COc1ccc(Cn2c(=O)[nH]c3ccccc3c2=O)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3ccccc3n(CCCCl)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.34 g) in N,N-dimethylformamide (30 ml), 2,4-dioxo-3-(4-methoxybenzyl)-1,2,3,4-tetrahydroquinazoline (2.0 g) obtained in Reference Example 26 was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, 1-bromo-3-chloropropane (1.05 ml) was added and the mixture was stirred for further 13.5 hours. The solvent was distilled off under reduced pressure, and the residue was combined with iN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4), and the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the title compound (1.58 g, 62%). Recrystallization from ethyl acetate-isopropyl ether yielded a colorless crystal having a melting point of 124 to 125° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)=[C:20]([CH:23]=1)[C:21]#[N:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:3]=2)[CH2:9][C@H:10]1[CH3:13]
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(C(F)(F)F)c1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)/[CH:7]=[CH:8]/[CH3:9])[OH:3]>O.C(O)C>[OH:3][C:2]1[CH:4]=[CH:5][C:6]([C:7]2[O:3][C:2]3[C:1]([O:11][CH3:12])=[CH:10][C:6](/[CH:7]=[CH:8]/[CH3:9])=[CH:5][C:4]=3[C:8]=2[CH3:9])=[CH:10][C:1]=1[O:11][CH3:12]
Reactant: C/C=C/c1ccc(O)c(OC)c1
Solvent: CCO
Solvent: O
Product: C/C=C/c1cc(OC)c2oc(-c3ccc(O)c(OC)c3)c(C)c2c1
Reaction time: 24 h

Procedure:
150 g ferric chloride in 400 ml water are added to a solution of 100 g (E)-isoeugenol in 1.3 liter 75 percent ethanol and allowed to stand for 24 hours at 0° C. The resulting sediment is filtered off and recrystallized from ethanol, resulting in 53 g trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl-7-methoxy3-methyl-5-(E)-propenylbenzofuran ("dehydrodiisoeugenol") as colorless crystals; melting point 132°-133° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21](I)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1.C(COC)OC>[Br:18][C:19]1[CH:24]=[C:23]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Reaction time: 4 h
Yield: 74 %

Procedure:
Under an argon gas atmosphere, 31.4 g (141 mmol) of 9-phenanthreneboronic acid, 40.0 g (141 mmol) of 3-bromoiodobenzene, 3.30 g (2.83 mmol) of tetrakis(triphenylphosphine) palladium(0), 200 mL of toluene, 50 mL of dimethoxyethane and 212 mL of 2M sodium carbonate solution were mixed, and stirred for four hours while being refluxed. After the reaction, the reaction mixture was further added with toluene, and cleansed by water. After organic phase thereof was dried with magnesium sulfate, the toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 34.7 g of 9-(3-bromophenyl)phenanthrene was obtained with an yield of 74%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].CCN(CC)CC.C1(C)C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CN(C=O)C.O>[CH3:1][N:2]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:3][CH2:4][OH:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCO
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)OCc1ccccc1
Yield: 54.1 %

Procedure:
To a stirred and cooled (0° C.) solution of N-methyl ethanolamine (3.10 g, 41.27 mmol), Et3N (11.80 mL, 84.66 mmol) in DMF—H2O (3:1, v/v, 40 mL) was added dropwise 30% toluene solution of benzyl chloroformate (25.40 g, 49.13 mmol) for over 15 min. The resulting mixture was stirred for 1 day at room temp. The mixture was extracted with EtOAc. The extract was washed with sat. NaHCO3, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with n-hexane:EtOAc (3:1, v/v) then CHCl3 as eluent to give 4.67 g (54%) N-methyl-N-(benzyloxy carbonyl)ethanolamine as a colorless oil. 1H-NMR (CDCl3) d 1.82 (bs, 1 H), 3.00 (s, 3 H), 3.46 (bs, 2 H), 3.77 (bs, 2 H), 5,13 (s, 2 H), 7.29-736 (m, 5 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]([CH2:23][C:24]4[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=4[F:32])[N:12]=[C:13]4[C:18]=3[CH:17]=[CH:16][CH:15]=[C:14]4[C:19]([F:22])([F:21])[F:20])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br>CN(C=O)C>[Cl:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[CH2:38][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]([CH2:23][C:24]4[C:25]([F:32])=[CH:26][C:27]([F:31])=[CH:28][C:29]=4[F:30])[N:12]=[C:13]4[C:18]=3[CH:17]=[CH:16][CH:15]=[C:14]4[C:19]([F:22])([F:21])[F:20])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc3[nH]ccc3c2)c(F)c1
Reactant: Clc1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc3c(ccn3Cc3ccc(Cl)cc3Cl)c2)c(F)c1
Reaction time: 8 h

Procedure:
A solution of 3-(1H-indol-5-yl)-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.025 g, 0.056 mmol) and sodium hydride (60% in oil, 0.003 g, 0.07 mmol) in 1 mL DMF was stirred at ambient temperature under nitrogen for 20 minutes. 2,4-dichlorobenzyl bromide (0.081 g, 0.42 mmol) was added to the reaction mixture, which was stirred overnight and then partitioned between EtOAc and H2O. The organic phase was concentrated and purified by normal phase HPLC (silica, hexane-EtOAc, 4:1) to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:19]=[O:20]>C(O)C.Cl.C(OCC)(=O)C.O>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: COCCCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Potassium carbonate (14.7 g, 106 mmol) and benzyl chloride (12.2 mL, 106 mmol) were added to a solution of 3-hydroxy-4-(3-methoxypropoxy)benzaldehyde described in Production Example 32-1 (17.2 g, 81.7 mmol) in ethanol (200 mL) under nitrogen atmosphere at room temperature, and the mixture was stirred under a thermal condition of 90° C. for 2 hours. The reaction liquid was cooled to 0° C., and the mixture was diluted with 2 M hydrochloric acid, ethyl acetate, and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-3:7) to obtain the title compound (19.8 g, 81%).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[CH:20]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([S:26]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: O
Product: O=S(=O)(NC1CCN(CCc2c[nH]c3ccccc23)CC1)C1CCCCC1

Procedure:
Using an analogous procedure to Example 1 3-[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with cyclohexanesulphonyl chloride to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1.C(O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Br:8][C:6]1[CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]2[O:12][CH2:13][C:14]([CH3:16])([CH3:15])[C:2]=2[CH:7]=1
Reactant: C=C(C)COc1c(Br)cc(Br)cc1C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)cc2c1OCC2(C)C

Procedure:
Following general procedure C and using 1,5-dibromo-3-isopropyl-2-(2-methyl-allyloxy)-benzene (Compound 6, 28.45 g, 82 mmol), palladium(II)acetate (0.808 g, 3.5 mmol), triphenyl phosphine (1.02 g, 3.5 mmol), 7.7 mL of piperidine and 21 mL of 98% formic acid in a total volume of 1L of anhydrous N,N-dimethylformamide, the title compound was obtained as a colorless oil (1.6 g, 7.3%). 1H NMR (300 MHz, CDCl3): δ 7.12 (d, 1H, J=2.2 Hz), 7.03 (d, 1H, J=2.2 Hz), 4.21 (s, 2H), 3.06 (heptet, 1H, J=6.9 Hz), 1.32 (s, 6H), 1.22 (d, 6H, J=6.9 Hz).