Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]OS(C)(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:14][C:13](=[CH:12][CH2:11][CH2:10][C@H:2]([CH3:1])[CH2:3][CH3:4])[CH3:15]
Reactant: CC(C)=CCC[C@H](C)CCOS(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To alkene 108 (60 g, 0.256 mol) in THF (1 L) at 0° C. was added lithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours, a further 3.8 g of lithium aluminum hydride was added and the solution warmed to room temperature. After 18 hours, a further 3.8 g of lithium aluminum hydride was added. After a further 21 hours, the reaction was carefully quenched with 1N citric acid and the solution diluted further with brine. The resultant two phases were separated and the organic phase was dried (MgSO4) and concentrated to afford an oil which was used without further purification. MS, m/z (relative intensity): 139 [M−H, 100%].
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>>[CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Nc1ccc(Cc2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
4-benzyl-2-bromo-aniline and 3-nitrobenzene boronic acid were combined to form 4-benzyl-2-(3-nitrophenyl)aniline,
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[C:14]=2[CH:21]=1)(=O)=O.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:23][O:22][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:33]2[CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:14]2[C:15]([CH3:20])=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2oc(=O)cc(C)c2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2oc(=O)cc(C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 77 %

Procedure:
Method B (26 h at 50° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (example 74) and 4-phenylpiperidine; yield 77%; fusion point 141°-143° C. (from isopropanol and ethanol). Fumarate: method E; yield 89%; fusion point 221°-223° C. (from ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([C@@H:14]([NH:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([C:24]([NH2:26])=[O:25])[CH:18]=1)[CH3:15])(=[O:13])[NH2:12].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[C:11]([C@@H:14]([NH:16][C:17]1[N:22]=[C:21]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[N:20]=[C:19]([C:24]([NH2:26])=[O:25])[CH:18]=1)[CH3:15])(=[O:13])[NH2:12]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(O)cc2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A 100 mL round-bottom flask was charged with 4-hydroxyphenyl boronic acid (1 g, 7.25 mmol), 6-((S)-1-carbamoyl-ethylamino)-2-chloro-pyrimidine-4-carboxylic acid amide (7.25 mmol, 1.76 g), PdCl2(PPh3)2 (Aldrich, 0.5 mmol, 0.3562 g), Na2CO3 (7.25 mL, 2M aqueous solution), and dioxane (5 mL). The flask was purged with nitrogen and heated to 100° C. for 16 h at which time the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was suspended in 50% MeOH in DCM, filtered by vacuum, and the filter cake was discarded. The filtrate was concentrated under reduced pressure and was suspended in DCM, stirred for one hour, and filtered by vacuum filtration to provide the title compound as a light brown powder (2 g, 91%). 1H NMR (CD3OD) 8.25-8.09 (m, 2H), 7.09-6.92 (m, 1H), 6.82-6.70 (m, 2H), 4.62-4.40 (m, 1H), 1.49-1.31 (m, 3H). LC/MS: m/z 301[M+H]+.
Reaction SMILES: Cl.[SH:2][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[CH3:10]OC(OC)N(C)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:10])[N:8]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccnc(S)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(C)n1

Procedure:
2-Mercapto-4-methylpyrimidine hydrochloride (100 g, 617 mmol), dimethylformamide dimethylacetal (100 mL, 754 mmol), diisopropylethylamine (161 mL, 926 mmol) and toluene (200 mL) were combined under argon. The resulting solution was heated to reflux for 4 h. The solvent was removed in vacuo and water and sodium bisulfate were added. The resulting mixture was extracted with ether (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford an oil. Vacuum distillation gave Compound 2 as a liquid: 70.5 g, (504 mmol, 82%)
Reaction SMILES: C1(C[N:8]2[CH:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:10](=[O:20])[CH2:9]2)C=CC=CC=1.[CH3:21][S:22]([OH:25])(=[O:24])=[O:23]>C1COCC1.[Pd]>[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[C:14]1([CH2:13][CH:12]2[NH:8][CH2:9][C:10](=[O:20])[CH2:11]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CC(Cc2ccccc2)N(Cc2ccccc2)C1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: O=C1CNC(Cc2ccccc2)C1

Procedure:
A mixture of intermediate 22 (0.027 mol) and CH3SO3H (0.03 mol) in THF (200 ml) was hydrogenated with palladium on activated carbon (10%, 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off, yielding (±)-5-(phenylmethyl)-3-pyrrolidinone methanesulfonate (1:1) (intermediate 23).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[F:33]C(F)(F)C([O-])=O.[Na+].FF>FC(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@@:11]3([F:33])[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1
Reactant: O=C([O-])C(F)(F)F
Agent: FF
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: FC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@@]4(F)[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1

Procedure:
3β-Acetoxy-5α,6β-dichloropregnan-20-one (1.4g) was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml) containing sodium trifluoroacetate (ca. 2g) and sodium fluoride (ca. 2g). The resulting solution was cooled to -78° and vigourously stirred, whereupon fluorine from four 750 cc bottles (10% v/v fluorine in nitrogen) was bubbled through the solution over a period of 8 hours. The reaction solution was then poured into aqueous sodium thiosulphate and the organic layer was separated, washed with water, dried over potassium carbonate and evaporated to dryness to yield crude 3β-acetoxy-5α,6β-dichloro-14α-fluoropregnan-20-one.
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36](Cl)=[C:37]([NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)[N:38]=2)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[F:2])[CH2:11][CH2:10]3)=[C:37]([NH:42][CH:43]3[CH2:44][CH2:45][CH2:46]3)[N:38]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:19]([OH:20])([C:21]([F:24])([F:23])[F:22])=[O:18]
Reactant: COc1ccc(OC2CCNCC2)c(F)c1
Reactant: Clc1nc2c(nc1NC1CCC1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (56.7 mg, 0.217 mmol), 6-benzyl-3-chloro-N-cyclobutyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (80 mg, 0.181 mmol), sodium tert-butoxide (52.1 mg, 0.542 mmol), BINAP (16.9 mg, 0.027 mmol) and Pd2(dba)3 (24.8 mg, 0.027 mmol) in toluene (602 μL) was heated at 90° C. in a sealed tube for 16 h. The mixture was purified by HPLC Method A to afford 6-benzyl-N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as its TFA salt (85.2 mg, 74.7%) as a yellow foam. ESI-MS m/z [M+H]+ 518.4.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1)=[O:5])C.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:4]([C:6]2[S:10][C:9]([Cl:11])=[N:8][CH:7]=2)=[O:5])[CH2:14][CH2:15]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc(Cl)s1
Product: O=C(NC1CCOCC1)c1cnc(Cl)s1
Yield: 73 %

Procedure:
As described for example 135a, 2-chloro-thiazole-5-carboxylic acid ethyl ester (500 mg, 2.6 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (471 mg, 73%) which was obtained as a white solid after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=247.3 [M+H]+.
Reaction SMILES: C([CH:8]([CH2:22]CCCN)[CH:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)O)(OC(C)(C)C)=O.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28].[CH2:34](Cl)Cl>>[OH:33][C:27]([C:29]([F:32])([F:31])[F:30])=[O:28].[N:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([CH:9]([CH3:34])[CH2:8][CH2:22][CH2:29][CH2:27][OH:33])=[N:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)C(CCCCN)C(O)c1nnc(-c2ccncc2)o1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CCCCO)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
2-(2-Boc-amino-1-hydroxyhexyl)-5-(4-pyridyl)-1,3,4-oxadiazole (950 mg, 2.62 mmol) and MeCl2 (5 ml) were mixed and TFA (1 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 2-amino-1-(5-(4-pyridyl-[1,3,4]oxadiazol-2-yl)-1-hexanol TFA salt (1 g); MS: 263.0 (M+1).
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Cl)([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccccc1/N=C/c1ccccc1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1NC(c1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To (E)-N-benzylidene-2-methoxyaniline (5.00 g, 23.7 mmol, 1.00 equiv) in anhydrous THF (106 mL) at 0° C. was added isopropylmagnesium chloride (13.0 mL, 2.0 M in Et2O, 26.0 mmol, 1.10 equiv) and the reaction mixture was stirred at 0° C. for 1 h. A saturated aqueous solution of NH4Cl (50 mL) was added and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on SiO2, eluting with 2% v/v EtOAc/hexanes, to give 2-methoxy-N-(2-methyl-1-phenylpropyl)aniline as a colorless oil (1.72 g, 28% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][NH:33]2)=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][CH:28]=[C:27]([Cl:26])[CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Clc1ccc2cn[nH]c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(Cl)cc43)nc12
Temperature: 125 °C
Yield: 68.5 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) and 6-chloro-1H-indazole 64.3 mg, 421 μmoll) in dioxane (5.25 mL) was added sodium tert-butoxide (74.2 mg, 772 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.9 mg, 35.1 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(6-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 69%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH:16](OC)=[O:17].[Na].Cl>C(OCC)C>[OH:17][CH:16]=[C:9]([C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:8]=[CH:7][CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC=O
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)C(=CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(aa) 26.2 g of methyl 3-trifluoromethylphenylacetate were dissolved in 100 ml of diethyl ether and, after the addition of 8.2 ml of methyl formate, treated with 2.76 g of sodium. The mixture was stirred at room temperature until the reaction was completed and treated with 1N hydrochloric acid while cooling. The organic phase was separated and the aqueous phase was extracted twice with ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Distillation yielded methyl 3-hydroxy-2-(α,α,α-trifluoro-m-tolyl)acrylate as a colorless oil of b.p. 59°-62°/0.2 mm.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[F:16])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>C(OC(=O)C)C>[F:16][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[CH2:7][CH2:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NCCc1cc(OC)ccc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(F)c2c1C(=O)NCC2
Temperature: 100 °C
Yield: 25.6 %

Procedure:
[2-(2-Fluoro-5-methoxy-phenyl)-ethyl]carbamic acid ethyl ester (I-44c: 1.6 g, 0.006 mol) was reacted with P2O5 (1.87 g, 0.013 mol) and POCl3 (16 mL) and the resulting mixture was refluxed for 4 hrs at 100° C. The reaction was monitored by TLC (100% ethylacetate). The reaction mass was cooled to room temperature and concentrated under reduced pressure. The concentrate was quenched with ice-water and basified with 2N Na2CO3 solution to pH 8. The resulting solution was partitioned between ethyl acetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 0.3 g of the product (23.25% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:24])=[CH:12][C:13](=[O:23])[N:14]3[CH2:17][CH:18]3OCC[O:19]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:24])=[CH:12][C:13](=[O:23])[N:14]3[CH2:17][CH:18]=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(C3CCCCC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2cc(C3CCCCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.31 g of 7-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one, 10 mL of a 80% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 2 hours and then stood still at room temperature for 15 hours. Thereto were added ethyl acetate and water, and the reaction mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.11 g of a colorless oily substance, (7-cyclohexyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][OH:36])=[CH:4][N:3]=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C.CC1C=CN=C(N)C=1C>ClCCl>[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([O:36][CH2:35][CH2:34]/[CH:33]=[CH:32]/[C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2csc3c(/C=C/CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2csc3c(/C=C/CCOS(=O)(=O)c4ccc(C)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
A solution of N-(4-{4-amino-7-[(1E)-4-hydroxybut-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.20 g, 0.40 mmol) in dichloromethane (10 mL) was treated with p-toluene sulfonyl chloride (0.100 g, 0.521 mmol), triethyl amine (0.08 g, 0.80 mmol), and dimethyl amino pyridine (0.003 g, 0.02 mmol). The reaction mixture was stirred at room temperature for 24 hours. No workup was used. The compound was purified by flash chromatography on silica gel using 1:1 ethyl acetate:heptane then 100% ethyl acetate to give 0.075 g (29%) the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.70 (m, 1H), 8.60 (d, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.30 (m, 2H), 7.21 (m, 2H), 7.19 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.60–6.50 (d, 2H), 6.15–6.10 (m, 1H), 4.95 (s, 2H), 4.20 (t, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 2.70 (q, 2H), 2.39 (s, 3H); LCMS (conditions a) Rt 4.28 min (95%), M+ 653.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:18])[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A solution of 2.67 g of N-benzyloxycarbonyl-4(R)-thiazolidinecarboxylic acid in 42 ml of dry tetrahydrofuran was stirred and cooled to -15° C. in an ice/salt bath while there were added 1.15 g of N-ethylmorpholine followed after 2 minutes by 1.87 g of isobutyl chloroformate. After a further 3 minutes 0.73 g of tert.butylamine was added dropwise and the mixture was then allowed to warm to room temperature and was stirred overnight. Tetrahydrofuran was removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed in sequence with water, 10% citric acid solution, water, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulphate, filtered and evaporated to give 2.85 g of 3-(benzyloxycarbonyl)-N-tert.butyl-4(R)-thiazolidinecarboxamide as a solid which melted at 96°-98° C. after recrystallization from diethyl ether/n-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16]C)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([C:10]2=[O:18])[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([C:10]2=[O:18])[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2=O
Temperature: 0 °C

Procedure:
A mixture of 5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3,9-dione (2.67 g) and pyridine hydrochloride (35 g) was heated at 175°-180° C. in an inert atmosphere for 3/4 hour, poured into ice water and extracted with a mixture of ether and tetrahydrofuran. The organic extracts were washed with water, dried over MgSO4 and evaporated in vacuo to give 5,6-dichloro-7-hydroxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3,9-dione which was used in Step E without further purification.
Reaction SMILES: [C:1]([Cu])#N.C[Li].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]2[N:18]([CH2:19][C:20]#[CH:21])[C:17](=[O:22])[C:16]([CH2:23][CH3:24])=[C:15]([CH3:1])[N:14]=2)[CH:10]=[C:9]([Cl:33])[N:8]=1
Reactant: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(OS(=O)(=O)C(F)(F)F)c(CC)c1=O
Reactant: N#C[Cu]
Agent: [Li]C
Solvent: C1CCOC1
Product: C#CCn1c(-c2cc(Cl)nc(Cl)c2)nc(C)c(CC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a stirred, cold (-78° C.) solution of CuCN (1.91 g, 20 mmol) in 100 mL of THE was added methyllithium (30 mL, 42 mmol, 2.1 equiv, 1.4M in diethyl ether) over 10 min. After stirring for 15 min, this solution was added over 10 min via a canula to a cold (-78° C.) solution of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-3-propargyl-6 -trifluoromethanesulfonyloxy-4(3H)-pyrimidinone in 20 mL of THF. The reaction mixture was stirred for 30 min, quenched with 15 mL of 10% concentrated NH4OH/saturated NH4Cl, diluted with 200 mL of ethyl acetate and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a semi oil. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane, 2/8) to afford 2.29 g (71%) of 2-(2,6-dichloro-4-pyridyl)-5-ethyl-6-methyl-3-propargyl-4(3H)-pyrimidinone as a white solid: mp 143°-144° C.; IR (KBr) 3220, 2125, 1668, 1584, 1541, 1515, 1367 cm-1 ; 1H NMR (270 MHz, CDCl3) δ 1.16 (t, J=7.6 Hz, 3H), 2.35 (s, 3H), 2.43 (t, J=2.6 Hz, 1H), 2.62 (q, J=14.8 Hz, 2H), 4.56 (d, J=2.6 Hz, 2H), 7.60 (s, 2H).