Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]([NH:32][NH2:33])=O)[CH:27]=[CH:26][C:25]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>C(#N)C>[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]2[N:3]3[CH2:4][CH2:5][CH2:6][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]3=[N:33][N:32]=2)[CH:27]=[CH:26][C:25]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
To a mixture of ethyl 2-oxopiperidine-3-carboxylate (3.5 g) in acetonitrile (100 mL) was added trimethyloxonium tetrafluoroborate (3.0 g) at room temperature, and the mixture was stirred at room temperature for 2 hr. 6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbohydrazide (5.0 g) was added to the reaction mixture at room temperature, and the solvent was evaporated under reduced pressure. Methanol (100 mL) was added to the residue at room temperature, and the mixture was stirred for 2 hr under reflux. The solvent in the reaction mixture was evaporated under reduced pressure, acetonitrile (100 mL) was added to the residue at room temperature, and the mixture was stirred at 80° C. overnight. The solvent in the reaction mixture was evaporated under reduced pressure, the residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue of another lot synthesized similarly was combined, and the mixture was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.1 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCCO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a stirring solution of 4-(4-hydroxy-butyl)-benzoic acid methyl ester (2.24 g, 0.01 mol) in THF (100 mL) was added dropwise a solution of lithium aluminum hydride (8.0 mL, 1M in THF). After completion of addition the reaction mixture continued to stir at room temperature. After 6 hours, the reaction mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield 4-(4-hydroxymethyl-phenyl)-butan-1-ol as a yellow oil (1.90 g, 0.01 mol, 98% yield). 1H (CDCl3, 600 MHz): δ 7.29 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz), 4.60 (2H, s), 3.60 (2H, t, J=7.5 Hz), 2.62 (2H, t, J=7.5 Hz), 1.67 (2H, m), 1.56 (2H, m); 13C (CDCl3, 150 MHz): δ 141.7, 138.5, 128.5, 127.0, 65.0, 62.5, 35.2, 32.1, 27.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH:21][C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([NH:21][C:22](=[CH:27][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:17])[CH:11]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(C)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere a mixture of 40.0 g (137 mmol) 2-benzyloxy-5-bromo-1,3-dimethylbenzene and 24.1 g (165 mmol) methyl 2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrile was combined with 3.5 g (11.2 mmol) tri-o-tolyl-phosphane and 2.5 g (11.1 mmol) Pd(OAc)2 and the mixture was stirred for 18 h at 80° C. The precipitate was suction filtered, the filtrate was evaporated down i. vac. and combined with 800 mL DCM and 800 mL water. The organic phase was separated off, suction filtered through Na2SO4, the solvent was removed i.vac., the residue was stirred with EtOAc, suction filtered and dried i. vac.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[N:18]#[C:19][NH2:20].FC(F)(F)S(O)(=O)=O>C1COCC1>[C:19](=[NH:18])([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[NH2:20]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a solution of 2-{4-[(4-fluorophenyl)oxy]phenyl}ethanol (750 mg, 3.23 mmol) and cyanamide (149 mg, 3.55 mmol) in THF (15 mL) was added trifluoromethanesulfonic acid (0.344 mL, 3.88 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via reverse phase flash chromatography then afforded the title compound (290 mg, 1.057 mmol, 32.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]
Reactant: CCOC(COc1ccc(N)cc1Cl)OCC
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: CCOC(COc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.495 g (0.028 mol) of CDl was added to a solution of 6.365 g (0.025 mol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product 2b) in 100 mL abs. THF and the mixture was stirred for 30 minutes at 50° C. 6.494 g (0.025 mol) of 3-chloro-4-(2,2-diethoxy-ethoxy)-phenylamine was added and the mixture was stirred for 16 hours at RT. The reaction mixture was poured into ice water and stirred for 1 hour. The precipitate formed was filtered off, washed with water and dried at 50° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2>>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 73 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d as starting materials to give 2-(Z)-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-[(S)-2-hydroxy-3-morpholin-4-yl-propyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 7 (49 mg, yield 73%) as a red solid.
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[CH:47]([O:50][C:51](=[O:55])[O:52][CH2:53]Cl)([CH3:49])[CH3:48].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:53][O:52][C:51]([O:50][CH:47]([CH3:49])[CH3:48])=[O:55])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1
Reactant: CC(C)OC(=O)OCCl
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester (Example 45, 75 mg), carbonic acid chloromethyl ester isopropyl ester [CAS No. 35180-01-9] (44.3 mg), potassium carbonate (33.3 mg) and N,N-dimethylformamide (3 mL) was stirred at 85° C. for 60 minutes. After cooling the reaction mixture to room temperature, ethyl acetate and water were added thereto. The organic layer was collected, the aqueous layer was reextracted with ethyl acetate, and all the organic layers were combined. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (28.9 mg) as a solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[CH2:1]([C:5]1[O:6][C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[NH:35][N:34]=[N:33][N:28]=2)[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC#N)ccc3c2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)o1
Temperature: 100 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (504 mg, 1.19 mmol), prepared in the previous step, sodium azide (230 mg, 3.54 mmol) and ammonium chloride (191 mg, 3.56 mmol) in 15 mL of DMF was stirred at 100° C. for 5 h. By TLC starting material remained. Additional sodium azide (230 mg, 3.54 mmol) and ammonium chloride (189 mg, 3.52 mmol) were added and the reaction stirred at 100° C. for two hours. Again by TLC starting material remained. Additional sodium azide (232 mg, 3.54 mmol) and ammonium chloride (191 mg, 3.55 mmol) were added and the reaction stirred at 100° C. for two hours. The reaction was diluted with water, made basic by the addition of 1N NaOH and extracted three times ethyl acetate The aqueous layer was acidified with 1N HCl. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (308 mg, 56%) as a white solid, mp 238-240° C. Elemental Analysis for C27H23N5O3 Calc'd: C, 69.66; H, 4.98; N, 15.04. Found: C, 69.51; H, 4.99; N, 15.1
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CO.CCO.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1>O>[ClH:32].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)cc2)nc(N)n1

Procedure:
To solution of amine E5 (267 mg, 0.720 mmol) in ˜1:1:1 MeOH:EtOH:H2O were sequentially added 4-chloroquinoline (1.06 g, 6.48 mmol) and 3 drops of CHCl, and the resulting mixture was refluxed for ˜24 h. After this time, solvent was removed under reduced pressure, and the resulting residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH/EtOAc, and then further purified by preparative HPLC, to afford Cpd. E as an amorphous yellow solid (16 mg, 4%). 1H NMR [(CD3)2SO]: 1.91 [s, 3H, ArCH3], 6.11 [s, 1H, ArH], 7.02 [d, J=6.77 Hz, 1H, ArH], 7.65 [d, J=8.55 Hz, 2H, ArH], 7.71 [br s, 2H, ArNH2], 7.84 [m, 4H, ArH], 8.04 [m, 2H, ArH], 8.15 [d, J=8.55 Hz, 2H, ArH], 8.63 [d, J=6.77 Hz, 1H, ArH], 8.70 [d, J=8.50 Hz, 1H, ArH], 10.38 [s, 2H, ArNHAr & ArH], 10.77 [br s, 1H, ArNHAr], 13.10 [v v br s, 2H, ArC(O)NHAr & quinoline-N+H]. LCMS (APCl+): 463 (100%). HPLC: 95.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C@@H:7]([CH3:19])[CH2:6]1.C(O)(=O)C.[CH:40](=O)[CH2:41][CH2:42][CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.O>[CH3:1][O:2][C:3](=[O:35])[N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:22]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:40][CH2:41][CH2:42][CH3:43])[C@@H:7]([CH3:19])[CH2:6]1
Reactant: CCCC=O
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCN1c2cc(OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 84.9 %

Procedure:
A solution of cis-(3,5-bis-trifluoromethyl-benzyl)-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (Example 67) (34 mg, 0.067 mmol), acetic acid (4 μL, 0.067 mmol), butyraldehyde (17 μL, 0.34 mmol), and sodium triacetoxyborohydride (71 μL, 0.34 mmol) in anhydrous dichloroethane (1 mL) were stirred at room temperature overnight. Water (5 mL) was added, the aqueous phase made basic with potassium carbonate, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-15% ethyl acetate/hexanes as eluent afforded 32 mg of the title compound (82%): MS m/z 563 (M++1); 1H NMR (CDCl3) δ6.31 (C8, s, 1H), 3.64 (CO2Me, s, 3H), 1.20 (C2-Me, d, 3H, J=6.3 Hz). The hydrochloride salt was prepared by treating an ethereal solution of the free base with an ethereal solution of HCl. Hydrochloride salt: 1H NMR (CDCl3) δ3.83 (CO2Me, s, 3H), 1.20 (C2-Me, d, 3H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1N.Cl.N([O-])=O.[Na+].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Reactant: N#C[Cu]C#N
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Product: N#Cc1ccc(OC(F)(F)F)cc1Cl
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
An aqueous solution of 2-chloro-4-(trifluoromethoxy)phenylamine (9.0 g) was cooled at 0° C., and concentrated hydrochloric acid (75 mL) was dropped slowly to its solution. The reaction mixture was stirred for 30 minutes, and sodium nitrite (3.73 g) was added to the reaction mixture. The reaction mixture was stirred for 40 minutes. An aqueous mixture solution of copper cyanide (4.65 g) and sodium cyanide (7.08 g) which been cooled off in 0° C. was added to the reaction mixture, and the reaction mixture stirred at room temperature for an hour. The reaction mixture was poured into 5N aqueous solution of sodium hydroxide which been cooled with ice, and extracted twice with ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (high flash-SI, size 4 L (made in Yamazen corporation), n-hexane→ethyl acetate/n-hexane=1/8) to obtain a title compound (7.36 g) having the following physical data.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[CH:9][N:8]=1.[Br:17]Br>C(O)(=O)C>[Br:17][C:12]1[C:7]([OH:6])=[N:8][CH:9]=[N:10][C:11]=1[C:13]([F:16])([F:14])[F:15]
Reactant: BrBr
Reactant: Oc1cc(C(F)(F)F)ncn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncnc(C(F)(F)F)c1Br
Reaction time: 3 h
Yield: 53.4 %

Procedure:
77.5 g (945.0 mmoles) of anhydrous sodium acetate was added, at room temperature, to a solution of 49.2 g (300.0 mmoles) of 4-hydroxy-6-trifluoromethylpyrimidine dissolved in 600 ml of acetic acid. Thereto was gradually added 50.3 g (315 mmoles) of bromine at 45° C. The resulting mixture was stirred at the same temperature for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 38.9 g (yield: 53.4%) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([CH:19]=1)[C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:3])=[O:2].[OH-:21].[Na+].Cl>C(O)C.OO>[C:1]([C:4]1[CH:19]=[C:8]2[C:7](=[CH:6][CH:5]=1)[O:20][C:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:10]([OH:21])[C:9]2=[O:18])([OH:3])=[O:2]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(O)c(C(=O)C=Cc2ccccc2)c1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
5'-Carboxy-2'-hydroxychalcone (30 mmol) and sodium hydroxide (5.2 g, 130 mmol) were dissolved in 200 ml of ethanol, to which 11.4 ml (100 mmol) of a 30% aqueous solution of hydrogen peroxide were added under ice cooling. The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 16 hours. 2 N hydrochloric acid was added to the reaction mixture to acidify the same. The resulting precipitate was collected by filtration, washed with water, dried in air, and then recrystallized from THF-EtOH, whereby the title compound represented by the following formula was obtained (yield: 83%). ##STR58##
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([O:20]C)[CH:11]=1>C(O)(=O)C.Br>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:11]=[C:12]([OH:20])[C:13]([OH:19])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: COc1cc(-c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3[nH]2)cc(O)c1O

Procedure:
A suspension of 860.1 mg of 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol in 10 ml of glacial acetic acid and 10 ml of 48 percent hydrobromic acid is heated to boiling under reflux for 72 hours. The mixture is then evaporated and the residue is treated four times with 50 ml of toluene each time, which is again distilled each time. There is obtained 5-(2-benzimidazolyl)-3-nitropyrocatechol of m.p. >300° (from an acetone/water).
Reaction SMILES: [CH2:1]([CH:21](CCC(CCCC(CCCC(CCCC(C)C)C)C)C)[OH:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].Cl.CN(C)CCCC(O)=O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([CH2:21][OH:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCC(O)CCC(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: CN(C)CCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCO
Yield: 87.3 %

Procedure:
To a solution of diphytanyl methanol (6.4 g, 10.3 mmol) and 4-(dimethylamino)butyric acid hydrochloride (2.25 g, 13.4 mmol) in anhydrous dichloromethane (60 mL) under nitrogen at room temperature was added EDC (2.77 g, 18.0 mmol), diisopropylethylamine (5.4 mL, 31.0 mmol), and 4-dimethylaminopyridine (45 mg, 0.37 mmol). After 16 hours the reaction mixture was diluted with dichloromethane (75 mL). The organic layer was washed with saturated NaHCO3, water, and brine, and then dried on MgSO4, filtered, and concentrated. The resulting yellow oil was purified by column chromatography (column 10″L×2″W; eluted with a gradient of 100% hexanes→10%→50% ethyl acetate in hexanes) to afford the product as a pale yellow oil (3.53 g, 49%) with recovery of some phytanyl methanol (2.81 g, 44%).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=O)#[N:2].[H][H]>C(O)C.[Ni]>[CH3:15][O:14][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[CH:4]([CH2:3][CH2:1][N:2]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCC(CC#N)C2=O
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CCN=C21

Procedure:
The solution of 50 g of 2-cyanomethyl-6-methoxy-1-tetralone in 1000 ml of ethanol is hydrogenated in the presence of 15 g of Raney nickel at atmospheric pressure and room temperature until 2 mole equivalents of hydrogen are consumed. The mixture is filtered, the filtrate evaporated and the crude product dissolved in 500 ml of N hydrochloric acid. The solution is washed with diethyl ether, treated with charcoal, filtered and the filtrate is basified with 3 N aqueous sodium hydroxide. It is extracted with methylene chloride, the extract dried, evaporated, the residue crystallized from petroleum ether and recrystallized from hexane, to yield the 7-methoxy-3,3a,4,5-tetrahydro-2H-benz[g]indole melting at 102°-104°.