Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH:22]=[CH:23][C:24]=2[F:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(N(CC)CC)C.[C:42]([O:45][CH2:46]C(Cl)=O)(=[O:44])[CH3:43].[Cl-].[NH4+]>O1CCCC1>[C:42]([O:45][CH2:46][C:27]([NH:26][C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:34])[CH:20]=1)=[O:33])(=[O:44])[CH3:43]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(NC(=O)OC(C)(C)C)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2 h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.56 (1F), −115.99 (1F), −129.48 (1F) ppm. LC/MS, tr=5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 540 (M+H). Step 2 Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorophenyl}-2-hydroxyacetamide
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:6][CH2:5][C:4]([CH:15]=[O:16])=[CH:3]1.C(O)C.[BH4-].[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C@@H:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:6][CH2:5][C:4]([CH2:15][OH:16])=[CH:3]1
Reactant: CC1(C)C=C(C=O)CC[C@@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)C=C(CO)CC[C@@H]1OC1CCCCO1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
(4S)-3,3-dimethyl-4-tetrahydropyranyloxycyclohexene-1-carbaldehyde (8) (0.71 g, 2.98 mmoles) was dissolved in tetrahydrofuran (7 ml), and a 95% ethanol solution of sodium borohydride (0.38 g, 10 mmoles) was added dropwise over an ice bath. After the addition, the mixture was stirred for 2 hours at a temperature below 10° C. The solvent was evaporated under reduced pressure. The residue was diluted with water, and extracted twice with diethyl ether. The ethereal layer was dried over magnesium sulfate, filtered, concentrated, and purified by column chromatography (30 g of silica gel; n-hexane/ethyl acetate) to give 0.65 g (yield 91.3%) of a compound (9).
Reaction SMILES: [C:1]([C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)(=[O:4])[CH:2]=[CH2:3].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[CH:16]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C.C(Cl)(Cl)Cl>[CH:16]1([S:22][CH2:3][CH2:2][C:1]([C-:5]2[CH:9]=[CH:8][CH:7]=[CH:6]2)=[O:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: C=CC(=O)[c-]1cccc1
Reactant: SC1CCCCC1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(CCSC1CCCCC1)[c-]1cccc1

Procedure:
A solution of acryloyl ferrocene (2.16g) and cyclohexylmercaptan (1.16g) in ethanol (50 ml) was set aside at ambient temperature for 24 hours. Evaporation of the ethanol gave an oil which was dissolved in chloroform (100 ml). The chloroform solution was washed successively with aqueous sodium hydroxide and water, dried over sodium sulphate and evaporated affording crude product. This was chromatographed through a silica-gel column (66g) using initially 1% ethyl acetate/petroleum ether (60°-80°) then 3% ethyl acetate/petroleum ether as eluent. This afforded an oil which crystallised on cooling and trituration with petroleum ether. The solid was filtered off, washed well with petroleum ether and dried giving the title compound, m.p. 46.5°-48.5°to C.
Reaction SMILES: C(C#N)(=[O:5])C(C)C.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]#[N:15])=[O:13]>>[Cl:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:14]([NH2:15])=[O:5]
Reactant: CC(C)C(=O)C#N
Reactant: N#CC(=O)CCCCl
Product: NC(=O)C(=O)CCCCl
Yield: 87 %

Procedure:
The procedure was the same as that described in Example 1 except that instead of isobutyryl cyanide there were employed 131.5 grams (1.0 mole) of 4-chlorobutyryl cyanide. After recrystallization from water there were isolated 130 grams (87% of theory) of 5-chloro-2-oxovaleramide having a melting point of 87° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[O:17]1CCOCC1.CO>[OH-].[K+].Cl.O>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([OH:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol) in p-dioxane/methanol (1:1, 120 mL) and 6N aqueous KOH (20 mL) is stirred at room temperature for 2 h. After acidification with concentrated HCl, the mixture is diluted with water and extracted into EtOAc. Workup gives 2,4-dinitro-5-hydroxybenzamide (4.91 g, 98%) as yellow cubes. 1H NMR (DMSO) δ8.64 (1H, s), 8.16 (1H, brs), 7.81 (1H, brs), 7.13 (1H, s), 5.80 (1H, brs).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7](Br)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>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.[Cu]I.O>[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Nc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccnc1C#C[Si](C)(C)C
Temperature: 100 °C

Procedure:
A mixture of (2-bromo-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-2 (395 mg, 1.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), triethylamine (0.25 mL, 1.8 mmol), copper(I)iodide (10 mg, 0.05 mmol) and trimethylsilylacetylene (0.131 mL, 2.4 mmol) was placed in a sealed tube, and heated at 100° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the title compound (0.42 g, 1.6 mmol, quantitatively) was obtained.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccsc2)CCN(C)C1
Yield: 6.5 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (165 mg, 0.736 mmol), 3-bromothiophene (100 mg, 0.613 mmol), TBAF.3H2O (580 mg, 1.84 mmol), and dichlorobis(triphenylphosphine)palladium (II) (13 mg, 0.018 mmol) were heated by microwave at 80° C. for 5 min. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product obtained was purified by HPLC to yield 12.2 mg of 2,8-dimethyl-5-thiophen-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.50 (s, 1H), 7.40 (d, 1H), 7.38 (d, 1H), 7.20 (m, 2H), 7.10 (d, 1H), 3.68 (s, 2H), 2.98 (t, 2H), 2.90 (t, 2H), 2.58 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9]/[CH:10]=[CH:11]/S(C)(=O)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[I-:16].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][I:16])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C/C=C/S(C)(=O)=O)CCOCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC1(/C=C/CI)CCOCC1
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a 0° C. solution in acetone of 4-methoxy-4-(3-methanesulfonyl-trans-prop-2-enyl)tetrahydropyran (505 mg, 2.02 mmol), prepared as in step 5 was added sodium iodide (605 mg, 4.03 mmol), and the reaction was stirred for 15 min. The reaction was partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 4-methoxy-4-(3-iodo-trans-propenyl)tetrahydropyran (550 mg, 97%) as a dark yellow oil. The iodide was of sufficient purity to use without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:23]3[C:24]4[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=4[CH:20]=[CH:21][C:22]=3[F:25])[CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CN(C)C=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]2[N:18]=[CH:17][C:16](=[O:26])[N:15]3[CH2:14][C:13]([CH2:12][N:28]4[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]4)([OH:27])[C:23]=1[C:24]=23
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)cnc4ccc(F)c2c43)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 50 °C

Procedure:
A mixture of (7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl 4-methylbenzenesulfonate (3.64 g, 9.3 mmol) (for a preparation, see Example 9(f)), 1,1-dimethylethyl 4-piperidinylcarbamate (2.0 g, 10.2 mmol) and sodium carbonate (2.9 g, 27.9 mmol) in ethanol (110 mL) and dimethylformamide (10 mL) was heated at 50° C. for 6 h. The mixture was evaporated to remove ethanol and the residue was partitioned between dichloromethane and half-saturated brine (200 mL each).
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[C:22]1[C:23](=[O:37])[O:24][C:25]2[C:30]([C:31]=1[CH3:32])=[CH:29][CH:28]=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=2.[CH:38](OC1C=CC=CC=1)=[O:39]>C1COCC1>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[C:22]1[C:23](=[O:37])[O:24][C:25]2[C:30]([C:31]=1[CH2:32][CH:38]=[O:39])=[CH:29][CH:28]=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=2
Reactant: COCOc1ccc(-c2c(C)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Reactant: O=COc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCOc1ccc(-c2c(CC=O)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a clean dry 200 ml flask purged with nitrogen was added diisopropylamine (2.7 ml, 19.5 mmol, 3 eq), dry THF (50 mL) and 3-(2,4-Bis-methoxymethoxy-phenyl)-7-methoxymethoxy-4-methyl-chromen-2-one (8.1 mL, 16.25 mmol, 2.5 eq.) at −78° C. After 30 minutes, to this solution was added drop-wise, a solution of 3-(2,4-bis-methoxymethoxy-phenyl)-7-methoxymethoxy-4-methyl-chromen-2-one (2.7 g, 6.5 mmol, 1 eq.) in dry THF (13 mL). The solution was warmed to −10° C. and stirred at this temperature for 30 minutes. Phenyl formate (3.6 ml, 33 mmol, 5 eq) was then added slowly into the reaction mixture. The reaction mixture was then stirred for 30 mins, quenched with saturated aqueous NH4Cl, extracted with ethyl acetate and then concentrated to yield th title product as a crude solid which was purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title product as a solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6](F)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>O.C(#N)CC.CN(C)C1C=CN=CC=1>[Cl:4][C:5]1[C:6]([C:1]#[N:2])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: O
Solvent: CCC#N
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
A reactor was charged with a solution of sodium cyanide (73.5 g) in water (150 ml), propionitrile (500 ml), 4-dimethylaminopyridine (16 g), and 3-chloro-2-fluoro-5-trifluoromethylpyridine (149.3 g) added over 30 minutes. After stirring for 5 hours at 20° C., the upper organic phase was separated off and washed with water. The lower aqueous layer was extracted with propionitrile, the two organic layers combined and solvent distilled off under vacuum at 45° C. to give an 83% yield of 3-chloro-2-cyano-5-trifluoromethylpyridine.
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[C:27]([O:26][CH:22]([C:11]1[C:10]([CH3:31])=[CH:9][C:8]2[C:13](=[CH:14][C:5]([C:4]#[C:3][C:2]([NH:1][C:35]([O:37][CH3:38])=[O:36])([CH3:33])[CH3:32])=[CH:6][CH:7]=2)[C:12]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Reactant: COC(=O)Cl
Product: COC(=O)NC(C)(C)C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (97) was prepared by the method of Example 94 from 2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid using methyl chloroformate. 1H-NMR: 400 MHz, (CD3OD) δ: 7.72 (d, J=8 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.26 (s, 1H), 5.16 (s, 1H), 3.60 (s, 3H), 2.60 (s, 3H), 1.58 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33ClNO5: 522.2. found: 522.1.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.COCCOC>O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]21[C:17]1[C:5](=[CH:4][CH:3]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:18]=1)[CH2:6][CH2:7]2
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncnc1
Solvent: O
Solvent: COCCOC
Product: NC1=N[C@@]2(CCc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 19 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with pyrimidin-5-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (19% yield) as an off-white solid. MS (ISP): m/z=317.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>O1CCCC1.CCOCC>[CH3:11][C:10]1[C:3]2[CH:2]=[C:6]([C:20](=[O:23])[CH2:21][CH3:22])[S:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)N(C)OC
Reactant: Cc1cccc2scc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1cc2c(C)cccc2s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A solution of 3-bromo-4-methylbenzo[b]thiophene (1.69 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 3.87 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of N-methoxy-N-methylpropionamide (1.31 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, the mixture was stirred at −70° C. for 3 hours, then it was allowed to warm to ambient temperature and quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), and dried (MgSO4). The solvents were removed in vacuao to give 1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.53 g) as an orange solid which was used without further purification.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([OH:16])=O)[CH2:3][CH3:4].C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH2:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([Cl:1])=[O:16])[CH2:3][CH3:4]
Reactant: CCCC1=C(C(=O)O)SC2=NCCCN21
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Yield: 203.8 %

Procedure:
In 35 ml of thionyl chloride was suspended 5.3 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained Example 12, followed by reflux under heating for 40 minutes. The reaction mixture was cooled with ice, and poured into dry diethyl ether. The precipitated crystals were collected by filtration to yield 5.78 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl chloride hydrochloride as colorless powder. This powder was suspended in the mixture of 200 ml of pyridine and 20 ml of dimethylformamide. To the mixture were added 3.38 g of 3.5-dichloroaniline and 250 mg of 3,5-dimethyl-aminopyridine, followed by stirring at 60° C. for 18 hours. The reaction mixture was concentrated and to the mixture was added water. The precipitated crystals were collected by filtration, washed successively with water and cold methanol and suspended in ethanol. To the mixture was added saturated hydrogenchloride diethylether. The formed crystals were collected by filtration and recrystallized from ethanol to obtain 3.65 g of the titled compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]C(O)=O)([O-:18])=[O:17].N1CCCCC1>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)C)c1O
Yield: 86.8 %

Procedure:
To a solution of 3,5-diisopropyl-4-hydroxybenzaldehyde (0.95 g, 4.6 mmol) and 2-nitrophenyl acetic acid (1.1 g, 6.2 mmol) in xylene (10 ml) was added piperidine (0.05 ml) and the mixture was heated under reflux for 8 hrs while removing water producing with the progress of reaction. After distilling off the solvent followed by purification of the residue by a silica gel column chromatography, recrystallization from hexane gave 2,6-diisopropyl-4-(2-nitrostyryl)phenol (1.3 g, 87%) as crystals.
Reaction SMILES: [Cl-].CO[NH3+].[CH3:5][O:6][N:7](C)[C:8]([C:10]1[N:11]=[C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[S:13][CH:14]=1)=O.O.[CH2:30](O)[CH3:31]>>[CH:30]1([CH2:31][C:8]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:13][CH:14]=2)=[N:7][O:6][CH3:5])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1
Reactant: CON(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CCO
Agent: CO[NH3+]
Agent: [Cl-]
Solvent: O
Product: CON=C(CC1CCCCC1)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
At room temperature, methoxyammonium chloride (171 mg) was added to a solution of tert-butyl 4-{4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (403 mg) in ethanol (2 ml). The reaction mixture was stirred at 50° C. for 24 hours, and water was then added. The aqueous phase was separated off and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically. This gave tert-butyl 4-[4-(2-cyclohexyl-N-methoxyethanimidoyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (361 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][C:18]1[C:19]([OH:31])=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[OH:31][C:19]1[C:18]([NH:17]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:23][CH:22]=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[N:20]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCN(c2ccc(N)c(O)n2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(O)n2)CC1
Temperature: 100 °C

Procedure:
(4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.12 g, 0.35 mmol), 3-amino-6-(4-methyl-piperazin-1-yl)-pyridin-2-ol (0.15 g, contaminated with triethylammonium trifluoroacetate) were coupled in N,N-dimethylformamide (3 mL) with triethylamine (0.27 mL). The mixture is heated in a 100° C. oil bath for three hours. The reaction mixture is purified by reverse phase HPLC to give (4Z)-4-({[2-hydroxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione.2 trifluoroacetic acid salt (18 mg, 7.0%).
Reaction SMILES: N1C=CC=CC=1CC(=O)C.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:25]1[CH:26]=[C:27]([C@@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[O:17]([C:25]1[CH:26]=[C:27]([C@@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: Oc1ccccc1
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C[C@H](N)c1cccc(Oc2ccccc2)c1
Temperature: 90 °C
Yield: 50.5 %

Procedure:
Into a 20 ml microwave vial was weighted 1-(pyridin-2-yl)propan-2-one ligand (90 mg, 0.665 mmol), phenol (407 mg, 4.32 mmol), CuBr (47.7 mg, 0.332 mmol) and Cs2CO3 (2166 mg, 6.65 mmol). To the mixture was added DMSO (5 ml) and (S)-1-(3-bromophenyl)ethanamine (0.5 ml, 3.32 mmol). The tube was flushed with N2, capped, and the black mixture heated in the oil bath at 90° C. for 18 hours. The heterogenous mixture was diluted with EtOAc and filtered through a glass-fritted funnel, eluting with EtOAc and another 5 mls of DMSO. The volatiles were then removed in vacuo and the crude brown liquid was filtered through 1 um PTFE filter and purified by reverse phase HPLC. The combined product fractions were desalted by addition of equal amount of EtOAc and about 250 mg Na2CO3 in a separatory funnel. The phases were separated and the organic washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-1-(3-phenoxyphenyl)ethanamine (361.5 mg, 1.678 mmol, 50.5% yield) as an amber oil. LCMS m/z 214.1 (M+H)+, Rt 0.61 min.