Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+:7].[Na+].[C:9]([NH:13][NH:14][C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])(=[O:12])[CH:10]=[CH2:11]>O>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+:7].[C:9]([NH:13][NH:14][C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])(=[O:12])[CH:10]=[CH2:11].[Na+:7]
Reactant: C=CC(=O)O
Agent: C=CC(=O)NNc1ccc(C(=O)[O-])c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)[O-]
Temperature: 8.5 °C

Procedure:
A mixture of acrylic acid (80.9 g) and deionized water (114 g) in a 500 mL beaker equipped with a magnetic stirrer is cooled to 7-10° C. and a 50% solution of sodium hydroxide in water (92 g) is added dropwise over 30 minutes while maintaining the reaction mixture temperature below 15° C. After the addition of sodium hydroxide, powdered N-acryloyl-4-amino salicylic acid (19 g, prepared as described in Example 11) is added and the mixture is stirred to form a homogenous solution.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:15]1([NH:21][C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1

Procedure:
A solution of 50 g (0.22 mol) of 2-nitro-4-trifluoromethyl-1-chlorobenzene, 22 g (0.22 mol) of cyclohexylamine and 61 g (0.44 mol) of potassium carbonate in 600 ml of ethanol was refluxed for 4 hours. The reaction mixture was concentrated and then the crude product was washed with water and ether. The organic phase was worked up, and the product was purified by column chromatography on silica gel (mobile phase:heptane/ethyl acetate=5/1).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)c1nc(C=O)cs1
Reaction time: 0.5 h

Procedure:
A solution of ethyl 2-isopropylthiazole-4-carboxylate (1 mmol) in 50 ml of dry dichloromethane was cooled to -78° C. under N2 atmosphere and treated dropwise with 1.2 mmol of diisobutylaluminum hydride (1.5M in toluene). The resulting solution was stirred for 0.5 h, quenched with aqueous Rochelle salts, extracted with dichloromethane, dried over Na2SO4, and concentrated in vacuo to provide the crude desired compound.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH2:21][OH:22])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)CC[C@@H](O)C4)[C@@H]1CC=C2.[BH4-].[K+]>C(O)C>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@:20]3([CH2:21][OH:22])[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH2:9][CH:10]2[OH:11]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: C[C@@]12C=CC[C@H]1[C@@H]1CCC3C[C@H](O)CC[C@]3(C)[C@H]1CC2
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2O

Procedure:
Also known as 19-Hydroxytestosterone, this compound is commercially available from Steraloids, Inc. Alternatively, 19-hydroxyandrost-4-en-3,17-dione (11) is treated with potassium borohydride (KBH4, a) in ethanol at -10° to 0° C. Aqueous work up is followed by extraction and purification to yield 19-hydroxytestosterone (12).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Br:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>[Br:20][C:21]1[C:22]([C:12]2[S:11][C:10]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])=[N:14][CH:13]=2)=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1
Reactant: CC(c1ccc(F)cc1)c1nccs1
Reactant: Clc1ncc(Br)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(F)cc1)c1ncc(-c2nc(Cl)ncc2Br)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 2-(1-(4-fluorophenyl)ethyl)thiazole (200 mg, 0.966 mmol) in 5 mL of tetrahydrofuran was cooled to −78° C. and treated with tert-butyllithium (0.622 mL, 1.7 M solution in pentane, 1.06 mmol) added dropwise. 5-Bromo-2-chloropyrimidine (205.5 mg, 1.06 mmol) was added to the reaction mixture and stirred for another 30 min before quenching with 1 mL of acetic acid in 5 mL of methanol. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (468 mg, 2.06 mmol) was added to the reaction after cooling to 0° C., stirred for 20 min, diluted with sodium ascorbate (0.5M, 100 mL) and water (300 mL). The crude product was extracted from the aqueous layer with chloroform (3×75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography with 0-40% ethyl acetate in hexane to afford the title compound as a yellow amorphous solid (177 mg,). MS (M+H)+ 398/400.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (5 g, 26.2 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5 g, 28.6 mmol), K2CO3 (7.24 g, 52.4 mmol) and Pd(PPh3)2Cl2 (368 mg) in THF (20 mL) and H2O (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether (50 mL) and H2O (50 mL). The aqueous layer was extracted with ether (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to afford 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (5.77 g; yield 85%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.42 (t, J=2.0 Hz, 2 H), 7.34 (d, J=2.0 Hz, 1 H), 6.05 (s, 1 H), 5.82 (s, 1 H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:18][CH3:17])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a stirring solution of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (22.9 g, 89.8 mmol) in 1,4-dioxane (300 mL) at RT under argon was added NaOMe (22.4 mL, 25% solution in MeOH, 97.9 mmol) over 10 min by syringe. After 2 h, TLC indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. A saturated solution of NaCl (200 mL) was added and the resulting solution was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried (Na2SO4), concentrated under vacuum and purified by silica gel column chromatography eluting with CH2Cl2 to give the title compound, 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20.3 g, 90%) as a colorless oil. TLC (CH2Cl2, Rf=0.4); MS [M+H]+ 251; HPLC retention time=2.74 min.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([N:5]1[CH2:10][C@H:9]([N:11]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:21]=3)[C:13]3=[C:29]([NH2:33])[N:30]=[CH:31][N:32]=[C:12]23)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:34]([O:37][CH2:38][O:39][C:40](ON1C(=O)CCC1=O)=[O:41])(=[O:36])[CH3:35].C([O-])(O)=O.[Na+].O>C(#N)C>[C:34]([O:37][CH2:38][O:39][C:40](=[O:41])[NH:33][C:29]1[N:30]=[CH:31][N:32]=[C:12]2[N:11]([C@@H:9]3[CH2:8][CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]=[CH2:1])[CH2:10]3)[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)[C:13]=12)(=[O:36])[CH3:35]
Reactant: CC(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(NC(=O)OCOC(C)=O)ncnc32)C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of ibrutinib (15 mg, 1.0 eq), (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq), and NaHCO3 (3.0 eq) in 1:1 water and acetonitrile (0.5 mL) was stirred at 20° C. overnight. The reaction was then purified by reverse-phase (C-18) liquid chromatography using water and acetonitrile as eluents to yield compound (1). MS (ESI): m/z 557.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C(OCC)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: OCCCBr
Reactant: C1COCCN1
Solvent: CCOCC
Product: OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 31.4 ml (360 mmol) of morpholine in 500 ml of diethyl ether were added slowly 10 g (71.94 mmole) of 3-bromopropanol and the mixture was stirred for one hour at room temperature. The reaction mixture was evaporated under vacuum and 300 ml of methylene chloride and 400 ml of a saturated aqueous solution of sodium bicarbonate were added. The mixture was shaken and he organic layer was separated and washed twice with 300-ml portions of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated to yield 10.3 g of 3-morpholinopropanol.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C@@H:30]([CH2:32][OH:33])[CH3:31]>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:29][C@H:30]([CH3:31])[CH2:32][OH:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(C)(=O)=O
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(SCc2ccccc2)n1
Temperature: 80 °C

Procedure:
To a solution of the product of step i) (21.2 g) in NM) (40 ml) was added (R)-alaninol (10 g) and the whole heated at 80° C. for 4 h. The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was collected, dried (MgSO4) and the solvent removed to leave a pale yellow oil. This was purified by silica gel chromatography (60:40 iso-hexane/EtOAc) to afford the subtitle compound as a colourless oil. Yield: 13.9 g.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.Cl.N1CCNCC1>C1(C)C(C)=CC=CC=1>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:32]=[N:31][NH:30][N:24]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:26][CH2:27][CH2:28][CH2:29]2)[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Agent: C1CNCCN1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in xylene (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and extracted with 5% NaOH solution. The pooled alkaline solution was washed with toluene or xylene (15 ml) and the aqueous phase neutralized to pH 6.5 using concentrated HCL. The resulting suspension was stirred for 3 hours at room temperature and filtered obtain irbesartan (3.6 g, 96% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.C1C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1

Procedure:
In a later publication in Tetrahedron Asymmetry 11 (2000), 1729-1732 the inventors of the above mentioned Chinese patent application reported the resolution of omeprazole using (S)-BINOL. An inclusion complex of (S)-BINOL and (S)-omeprazole was obtained as a grey-blue complex with 90.3% e.e. by mixing racemate omeprazole and (S)-(−)-BINOL in the mole ratio 1:1.5, in a solvent mixture of benzene:hexane (v/v=4:1) at 110° C. The inclusion complex obtained was further purified by recrystallization in benzene:hexane (v/v, 1:1) and separated on a silica gel column to yield (S)-(−)-omeprazole with 98.9% e.e. and 84.1% overall yield. The (S)-(−)-omeprazole so obtained was recrystallized in water to obtain as a white powder with 99.2% e.e.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][C:7]([CH2:13][S+:14]([O-:26])[C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[N:23]=2)=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1.C(O)(=O)C>C(O)C>[CH3:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH3:12])[C:7]([CH2:13][S@@:14]([C:15]2[NH:23][C:22]3[CH:21]=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=3[N:16]=2)=[O:26])=[N:6][CH:5]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 4 h

Procedure:
To aqueous sodium hydroxide (2.03 ml, 1.5 M, 3.04 mmol) at ambient temperature was added omeprazole (1 g, 2.90 mmol) in 5 portions over 10 min. On complete dissolution, ethanol (35 ml) and (S)-1,1,2-triphenyl-1,2-ethanediol (1.26 g, 4.34 mmol) were added. To the resulting colourless solution at ambient temperature was added a solution of aqueous acetic acid (3.04 ml, 1 M, 3.04 mmol) dropwise over 1 h and, on complete addition, stirring was continued for 4 h. The solid was filtered, was washed with ethanol (3×15 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] (925 mg, 69%, 96.4% ee) as a white powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(OCC)(=O)C.Cl>C1CCCCC1.C(Cl)Cl.O1CCOCC1.C(OCC)C>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: NC(=O)CBr
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=O)CN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 143, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide. The crude product was subjected flash chromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane). Pure fractions were combined and concentrated diethyl ether. The resultant precipitate in vacuo and the resultant residue dissolved in DCM and treated with 4M HCl in dioxane then was collected by filtration to give 178 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1 H); 8.48-8.43 (m, 1 H); 8.30 (s, 1 H); 8.05 (s, 1 H); 7.85 (td, J=8.75, 5.93 Hz, 1 H); 7.74-7.63 (m, 2 H); 7.41-7.34 (m, 1 H); 7.22 (d, J=2.30 Hz, 1 H); 7.10 (dd, J=8.45, 2.35 Hz, 1 H); 6.97 (d, J=8.39 Hz, 1 H); 4.22 (t, J=5.00 Hz, 2 H); 3.98 (d, J=4.37 Hz, 2 H); 3.60 (t, J=12.26 Hz, 2 H); 3.24-3.13 (m, 2 H); 3.06 (t, J=4.95 Hz, 2 H); 2.69-2.61 (m, 1 H); 1.87 (s, 4 H). LCMS: RT=7.46 min, M+H+=506
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[O:16]C)([CH3:3])[CH3:2].B(Br)(Br)Br.O.C(OCC)C>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: COc1c(-c2ccccc2)cccc1C(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1cccc(-c2ccccc2)c1O
Temperature: -78 °C
Yield: 94 %

Procedure:
1.98 g (8.64 mmol) of 2-bromo-6-isopropylanisol, 2.10 g (17.28 mmol) of phenylboronic acid, 96 mg (0.43 mmol) of palladium acetate, 0.225 g (0.86 mmol) of triphenylphosphine and 11 g (51.84 mmol) of potassium phosphate were placed in a flask, and a mixed solution of 8 ml of water and 32 ml of dimethoxyethane was added thereto. The mixture was refluxed at room temperature for 12 hours. After the refluxed solution was cooled to room temperature, 15 ml of an aqueous ammonium chloride solution and 30 ml of diethyl ether were added thereto. Then, the organic layer was separated and the residue was extracted with diethyl ether. The collected organic layer was dried over magnesium sulfate, and volatile materials were removed therefrom, thus obtaining 2 g of 2-isopropyl-6-phenylanisol as a gray solid. The obtained anisol was dissolved in 15 ml of methylene chloride without a separate purification process, and then 12 ml of boron tribromide (1M methylene chloride) was added dropwise thereto at −78° C., and the mixture was warmed slowly to room temperature and allowed to react for 12 hours. After completion of the reaction, a mixed solution of 15 ml of water and 30 ml of diethyl ether was added thereto. The organic layer was separated and the aqueous layer was extracted with diethyl ether (15 ml×3). The collected organic layer was dried, and volatile components were removed in a vacuum. The residue was purified using a silica gel chromatography column in a mixed solvent of hexane and methylene chloride, thus obtaining 1.72 g of 2-isopropyl-6-phenylphenol as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1.CC(=O)OCC>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]([OH:8])[CH2:9][N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: Brc1cccc(OCC2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCOC(C)=O
Solvent: CO
Product: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1
Yield: 75.9 %

Procedure:
To a solution of 2-((3-bromophenoxy)methyl)oxirane (1.5 g, 6.55 mmol) in MeOH (15 mL) were added 1,2,3,4-tetrahydroisoquinoline (1.0 g, 7.86 mmol) at 8° C. The mixture was refluxed for 16 h. TLC (PE:EA=2:1) showed that the reaction was completed and the mixture was concentrated to yield crude material which was purified using column chromatography on silica gel to give the desired compound (1.8 g, 78.3%) as colorless oil. LCMS (m/z): 362.1/363.1 [M+H]+/[M+2H]+
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Temperature: 75 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
3-Cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (17.0 g, 55.1 mmol) and 10% Pd/C (1.2 g, 0.6 mmol) were added to toluene (170 mL) in an autoclave. The solution was stirred under 40 psi of H2 at 75° C. for 18 hours. The catalyst was removed by filtration through Celite® and the filter cake was rinsed with toluene (34 mL). The filtrate was concentrated to about 35 mL and heptane (85 mL) was added to the filtrate to precipitate the product which was collected by vacuum filtration and dried under vacuum for 18 hours to afford 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (12.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=O)[NH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:24])=O.Cl.O.N>C(#N)C.O1CCOCC1.CCOC(C)=O>[Cl:24][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:12][N:13]=1
Reactant: COc1cc(CCc2c[nH]c(=O)c3ccccc23)ccn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc(CCc2cnc(Cl)c3ccccc23)ccn1
Temperature: 65 °C
Reaction time: 7 h

Procedure:
Under a N2 atmosphere, 160 mg (0.57 mmol) of 4-[2-(2-methoxy-pyridin-4-yl)-ethyl]-2H-isoquinolin-1-one in 3.7 ml of acetonitrile are mixed with 131 μl (1.43 mmol) of phosphorus oxychloride and 0.28 ml of 4 N HCl in dioxane and stirred for 7 h at 65° C. After cooling to RT, water/NH3 conc. 10:1 and EtOAc are added, the water phase is separated and extraction effected twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 1-chloro-4-[2-(2-methoxy-pyridin-4-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ8.30 (d, 1H), 8.27 (d, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.94 (t, 1H), 7.85 (t, 1H), 6.90 (d, 1H), 6.73 (s, 1H), 3.80 (s, H3C), 3.32 (t, H2C), 2.95 (t, H2C).