Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(S(C)(=O)=O)CC3)ccc21
Yield: 121.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (40.7 mg, 0.0991 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 1-(methylsulfonyl)piperazine hydrochloride (80.0 mg, 0.399 mmol), triethylamine (0.110 mL, 0.789 mmol), acetic acid (0.115 mL, 2.01 mmol) and sodium triacetoxyborohydride (77.7 mg, 0.367 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(methylsulfonyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (67.2 mg).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>CO>[C:5]([N:9]=[N:10][C:11]([S:1][C:2]#[N:3])([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: N#C[S-]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC(C)(C)SC#N
Reaction time: 0.25 h

Procedure:
To a stirred solution of 9.72 grams (0.12 moles) of sodium thiocyanate in 50 ml methanol in a 125 ml erlenmeyer flask was slowly added 16.25 grams (0.1 mole) of 2-t-butylazo-2-chloropropane while holding the reaction temperature at 5° C. with an ice bath. After the addition was complete, the reaction was stirred an additional 15 minutes and poured into 300 ml water. The solids which formed were filtered off and pulled semi-dry on the filter funnel. The crystals were dissolved in pentane, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure. The pale yellow solid residue weighed 8.0 grams (43% crude yield) and melted at 29°-31° C. The infrared spectrum of the product contained a sharp weak band at 2160 cm-1. There also was a weak doublet at 2020 and 2070 cm-1 indicating there was a trace of the isothiocyanato isomer present.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH:24]2[O:26][CH:20]([CH2:21][NH:22][CH2:23]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]2[O:26][CH:24]([CH2:23][N:22]([CH2:2][C:3]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=3)[CH2:21]2)[CH2:25]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A suspension of 4-bromomethylbenzonitrile (10 g, 0.054 mol), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.5 g, 0.0439 mol; see WO 01/28992) and dry K2CO3 (21.2 g, 0.153 mol) in 200 μL of dry acetonitrile was stirred at 60° C. overnight under a N2 atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to yield 10 g of the sub-title compound as colourless liquid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Reactant: OCc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (318 mg, 1.01 mmol), [4-(chloromethyl)phenyl]methanol (240 mg, 1.53 mmol), potassium carbonate (276 mg, 2.0 mmol) and N,N-dimethylformamide (10 mL) was stirred at 120° C. for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (220 mg, yield 50%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[N:4][N:3]=1.[NH2:17][C:18]1[CH:32]=[CH:31][C:21]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[N:24][C:20]=2[CH:19]=1>CC(O)C>[C:25]1([N:22]2[C:21]3[CH:31]=[CH:32][C:18]([NH:17][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[N:4][N:3]=4)=[CH:19][C:20]=3[N:24]=[CH:23]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1
Reactant: C#CCOCc1nnc(Cl)c2ccccc12
Solvent: CC(C)O
Product: C#CCOCc1nnc(Nc2ccc3c(c2)ncn3-c2ccccc2)c2ccccc12
Yield: 28.2 %

Procedure:
A solution of 1-chloro-4-(prop-2-ynyloxy)methylphthalazine (3) (20 mg, 0.09 mmol) and 5-amino-1-phenylbenzimidazole (15 mg, 0.07 mmol) in i-PrOH (2 mL) is stirred at 95° C. under argon for 2.5 h. The reaction mixture is concentrated, quenched with sat. NaHCO3 (10 mL), and extracted with CHCl3 (60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (0:1:2 to 1:25:0 methanol/ethyl acetate/hexane) to give 8 mg (27%) of BI-3035 as a light-brown solid, mp 89-91° C. IR 3321, 2927, 1496 cm−1; 1H NMR (CDCl3) δ 2.60 (t, J=2.4 Hz, 1H, CH≡C—CH2O), 4.98 (s, 2H, CH2), 5.36 (d, J=2.4 Hz, CH≡CCH2O), 6.94 (dd, J=8.7, 2.1 Hz, 1H, 6-BenzimidH), 7.27 (d, J=2.1 Hz, 1H, 4-BenzimidH), 7.41 (d, J=8.7 Hz, 1H, 7-BenzimidH), 7.41-7.63 (m, 5H, PhH), 7.90-8.02 (m, 2H, 6,7-PhthH), 8.06 (s, 1H, 2-BenzimidH), 8.14 (m, 1H, 5-PhthH), 8.35 (m, 1H, 8-PhthH).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C@@H:17]([OH:19])[CH3:18])[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:11]=[C:10]([N:12]4[CH2:16][CH2:15][CH:14]([C@@H:17]([OH:19])[CH3:18])[CH2:13]4)[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: C[C@H](O)C1CCN(c2nc(Cl)cc3nccnc23)C1
Product: C[C@H](O)C1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
The title compound was prepared according to the procedure of Compound 1 (B) using (S)-1-(1-(7-chloropyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)ethanol and 4-morpholinophenylboronic acid. MS (m/z): 406 (M+H)+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:9]O>C(O)(=O)C>[CH3:8][C:1]1[C:6](=[O:7])[CH:5]=[CH:4][C:3](=[O:9])[CH:2]=1
Reactant: Cc1ccccc1O
Reactant: OO
Solvent: CC(=O)O
Product: CC1=CC(=O)C=CC1=O
Temperature: 55 °C

Procedure:
A mixture of o-cresol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and 2-methyl-1,4-benzoquinone formed (96%) was separated by chromatographic purification.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[O:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[C:17]4[CH3:23])=[CH:12][N:13]=2)=CC=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:23][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:11]3[O:10][C:9]([NH2:8])=[N:13][CH:12]=3)[CH:15]=2)[NH:19][N:18]=1
Reactant: COc1ccc(CNc2ncc(-c3ccc4[nH]nc(C)c4c3)o2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3cnc(N)o3)cc12
Temperature: 150 °C

Procedure:
A glass microwave reaction vessel was charged with N-(4-methoxybenzyl)-5-(3-methyl-1H-indazol-5-yl)oxazol-2-amine (196 mg, 587 μmol) and TFA (2.00 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 6 minutes. Toluene was added and the solvents were removed in vacuo to give the desired product. The residual material was treated with 2.0 M NH3 in MeOH and 1 N NaOH and the resulting precipitate was filtered to give a yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:37])(=[O:36])=[N:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]4[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[CH:29]=4)=[O:27])[CH:20]=3)[CH:14]=[N:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH2:45]C)[CH2:43]C>O1CCOCC1.CCOC(C)=O>[CH3:43][N:42]([CH3:45])[CH2:41][CH2:40][CH2:39][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:37])(=[O:36])=[N:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]4[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[CH:29]=4)=[O:27])[CH:20]=3)[CH:14]=[N:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(N)cc4)c3)c2)n(C)n1
Reactant: CCN(CC)CCCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(NCCCN(C)C)cc4)c3)c2)n(C)n1
Temperature: 100 °C
Yield: 4 %

Procedure:
N-[(4-{amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide (0.085 g, 0.168 mmol) was dissolved in dioxane (1.7 mL) then treated with (3-Chloro-propyl)-diethyl-amine (0.047 g, 0.252 mmol) and TEA (0.070 mL, 0.504 mmol). The reaction mixture was then heated to 100° C. for 48 h then cooled to room temperature. The cooled mixture was dissolved in EtOAc (5 mL) and then extracted with water (3×5 mL) and with brine (5 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to give the title compound (4 mg, 3.5%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(C(C(C(O)=O)O)O)(O)=O.[NH:43]1[CH2:48][CH2:47][CH2:46][C@@H:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:44]1>C1(C)C=CC=CC=1.CC(CC(C)C)=O.C(OCC)(=O)C.CCCCCCC.O.C(N(CC)CC)C>[CH2:52]([O:51][C:49]([C@@H:45]1[CH2:46][CH2:47][CH2:48][N:43]([CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:44]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: OCCOCCN1Cc2ccccc2Cc2ccccc21
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCOCCN2Cc3ccccc3Cc3ccccc32)C1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
A mixture of the above alcohol (2.1 g, 7.4 mmol), triethylamine (2.6 ml) and toluene (30 ml) placed under an atmosphere of nitrogen was cooled on an ice-bath. A solution of methanesulfonyl chloride (2.1 g, 15 mmol) in toluene (5 ml) was added dropwise. Stirring was continued for 45 minutes on an ice-bath and then the temperature was allowed to reach ambient temperature. Water (20 ml) was added and the mixture was stirred at room temperature for 15 minutes. The phases were separated and the organic phases were washed with a 5% aqueous sodium bicarbonate solution and brine and dried over magnesium sulphate. The solvent was evaporated in vacuo to give an oil which was dissolved in methyl isobutylketone (40 ml). To this solution was added potassium carbonate (3.6 g, 26 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (4.6 g, 15 mmol). The suspension was heated at 40° C. for 24 h and then at reflux temperature for 3 h. The reaction mixture was allowed to cool to ambient temperature and water (50 ml) was added. The phases were separated and from the organic phase the solvent was evaporated in vacuo. This afforded an oily residue which was submitted to column chromatography on silica gel (125 g) using a mixture of ethyl acetate and n-heptane (1:1) as eluent. Collecting the proper fractions afforded 1.0 g of (R)-N-(2-(2-(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.36 (SiO2 ; ethyl acetate).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:18]1(=[O:27])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[S:1][CH2:2][CH2:3][CH2:4]3)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: Oc1cccc2c1SCCC2
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 97.6 %

Procedure:
Under argon and with stirring, 500 mg (3.01 mmol) of 8-thiochromanol and 930 mg (3.31 mmol) of N-(4-bromobutyl) phthalimide are dissolved in 4 cm3 of dimethylformamide (DMF). 1.25 g (9.03 mmol) of K2CO3 are added. The mixture is heated at 60° C. for 6 hours. The DMF is evaporated off. The residue is taken up in H2O. The product is extracted with CH2Cl2 and dried over MgSO4. Purification over a silica column (eluant: CH2Cl2) yields 1.08 g of the title compound (white solid).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH3:21]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:20][CH3:21])=[CH:4][N:3]=1
Reactant: CCI
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 1-chloro-7-fluoroisoquinolin-4-ol (0.5 g, 2.53 mmol) in acetonitrile (10 ml) was added K2CO3 (700 mg, 5.06 mmol) followed by ethyl iodide (475 mg, 3.04 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-7-fluoro-4-ethoxyisoquinoline (400 mg 70%) as off-white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18](OC)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.CO.[BH4-].[Li+].Cl.[OH-].[Na+]>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([CH2:18][OH:19])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1sc(-c2ccc(OCCCCl)cc2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CO
Temperature: 75 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i105 (6.13 mmol, 1 eq, 2 g) in tetrahydrofuran (60 ml) is added methanol (19.6 mmol, 3.2 eq, 0.8 ml) and lithium borohydride (13.49 mmol, 2.2 eq, 0.29 g). The mixture is stirred at 75° C. overnight. 1 N aqueous hydrogen chloride (2 ml) is added and the mixture is then stirred at room temperature for 1 hour. Then, a 2 M aqueous sodium hydroxide solution is added to reach pH 12 and the mixture is stirred for 6 hours, then extracted twice with ethyl acetate. The organic layer is dried over magnesium sulfate and the solvent is removed under reduced pressure to give 1.65 g of {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}methanol i109 as a white solid.
Reaction SMILES: C[O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:21]=[C:22]([C:24]2[NH:25][C:26]([C:29]3[O:30][CH2:31][C@@H:32]([CH3:34])[N:33]=3)=[CH:27][CH:28]=2)[CH:23]=1)[O:10][C:11]1[CH:16]=[N:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=1)[CH3:5].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:34][C@@H:32]1[CH2:31][O:30][C:29]([C:26]2[NH:25][C:24]([C:22]3[CH:23]=[C:7]([CH:8]=[C:9]([O:10][C:11]4[CH:16]=[N:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=4)[CH:21]=3)[O:6][C@@H:4]([CH3:5])[CH2:3][OH:2])=[CH:28][CH:27]=2)=[N:33]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
2-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulfonyl)pyrazine (456 mg, 0.94 mmol) synthesized in Example (107e) was dissolved in methylene chloride (5.0 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 1.50 mL, 1.50 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 3 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=4%-6%) to afford the desired compound (330 mg, yield 74%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(C1C=CC=C(C(C)(C)C)C=1[O-])(C)(C)C.[Na+].CN1CCN(C)C1=O.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>Cl.O1CCCC1>[CH3:42][S:43]([O:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:45])=[O:44]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Agent: Cl
Agent: [H-]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C(C)(C)C)c1OS(C)(=O)=O
Reaction time: 1 h
Yield: 34.4 %

Procedure:
50 mL of a tetrahydrofuran (THF) solution containing 10.00 g (0.049 mol) of 2,6-di-tert-butylphenol were dropped into 100 mL of a THF suspension of 2.03 g (0.051 mol) of 60% oil-dispersed sodium hydride at 0° C. followed by stirring for 1 hour at the same temperature to prepare sodium 2,6-di-tertbutylphenoxide. 5.81 g (0.051 mol) of 1,3-dimethyl-2-imidazolidinone were added to this solution, and after stirring for 30 minutes at 0° C., 5.83 g (0.051 mol) of methanesulfonyl chloride were dropped in followed by stirring for 2 hours at 25° C. The reaction liquid was placed in 30% aqueous hydrochloric acid solution and following separation of the organic layer, the organic layer was washed once with 1 N aqueous NaOH solution and twice with water followed by drying with MgSO4 and concentrating. The resulting crude crystals were purified by crystallization with a 1/1 (volumetric ratio) mixture of n-hexane and isopropanol to obtain 4.8 g (yield: 35%) of 2,6-di-tert-butylphenyl methanesulfonate (white crystals, melting point: 83° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:2]=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[N:5][CH:6]=1)#[N:9]
Reactant: CCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
6.3 G. of 4-chloro-5-cyano-2-(4-n-pentylphenyl)-pyrimidine are reacted in 290 ml. of 50% dioxane with 25.3 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-pentylphenyl)-pyrimidine as colorless crystals having a melting point of 96.0°-96.2° C. and clearing point of 109.0° C. The substance is identical with the compound obtained according to Example
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27]([C:25]2[S:26][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:28])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)s1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 5-chloro-2-thiophenecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.[Br:9]Br>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=1[Br:9]
Reactant: BrBr
Reactant: Nc1cccc(O)n1
Solvent: CC(=O)O
Product: Nc1nc(O)ccc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
Under an argon atmosphere 2-amino-6-hydroxy-pyridine (19.6 g, 178 mmol) was suspended in acetic acid (100%, 390 mL). Br2 (9.2 mL, 178 mmol) was added at 20° C. over 5 min. The green suspension was stirred at RT for 20 min. The mixture was poured onto H2O (400 mL) and filtered. The filtrate was mixed with brine (200 mL) and extracted with EtOAc (10×400 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford 6-Amino-5-bromo-pyridin-2-ol as a yellow solid (23 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:18][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C#N
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available 2-fluoro-6-methylbenzonitrile (Apollo Scientific, 15.0 g, 111 mmol) was dissolved in triflic acid (75 mL) at 0° C. then NBS (20.7 g, 117 mmol) was added. The reaction mixture was stirred at RT for 1 h then poured into ice water and extracted twice with DCM. The organic layer was washed with brine, dried over Na2SO4, then filtered and evaporated to dryness to yield 3-bromo-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=214, 216.