Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[OH-].[Li+].[CH2:16]1[CH2:20]OC[CH2:17]1>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:16]([CH3:20])[CH3:17])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 2 h

Procedure:
To a solution of 3 (0.376 mol) in THF (200 mL) and water (100 mL) was added lithium hydroxide (31.6 g, 0.752 mol) and the mixture stirred for 2 hours. The reaction mixture was filtered through a silica gel plug (the pH of the filtrate was about 7) and concentrated. The residue was dried under vacuum to give 4 (0.376 mol).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][C:8]2([S:11]([O-])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1.[Na+].P(Cl)(Cl)([Cl:19])=O>>[CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][C:8]2([S:11]([Cl:19])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](CC2(S(=O)(=O)[O-])CC2)O1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Product: CC1(C)OC[C@H](CC2(S(=O)(=O)Cl)CC2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium (S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate (1 eq) and phosphoryl trichloride (POCl3, 0.7 mL/mmol) is heated at 80° C. for 1 hour. The reaction mixture is cooled to room temperature, poured onto ice, stirred for 30 minutes and extracted with chloroform (2×). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: C#CCNC
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and CuI (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1N
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(Br)c3)c2c1N
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
To a solution of ethyl 4-amino-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 46) (6.309 g, 16.12 mmol) in DCM (100 mL) was added N-bromosuccinimide (3.44 g, 19.35 mmol) at RT. The mixture was stirred for 3.5 h. The solvent was removed in vacuo. The crude residue was then purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (5.13 g). LCMS (A) m/z: 471 [M+1]+, Rt 1.52 min (acidic).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[Br:18]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:18])=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCc2ccc(O)cc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(Br)c(O)cc21
Temperature: 12.5 °C
Reaction time: 0.75 h
Yield: 73.6 %

Procedure:
A stirred suspension of finely powdered 1-acetyl-6-hydroxyindoline (D63, 2.4 g, 0.013 mole) in a mixture of DMF (25 ml) and glacial acetic acid (125 ml) at 15° C. was treated portionwise over 5 minutes with N-bromosuccinimide (2.65 g, 0.015 mole). The reaction mixture changed from yellow to grey-green in colour. The mixture was stirred at 1 5-20° C. for 45 minutes, then cooled to 5° C. and the solid filtered off, washed with acetic acid and dried to give the title compound as a grey solid (2.45 g, 71%).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[CH2:23]([CH2:25][NH2:26])[OH:24]>C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[OH:24][CH2:23][CH2:25][NH:26][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NCCO)s1
Yield: 81.1 %

Procedure:
To a stirred solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (Example 93c, 1.0 g, 3.12 mmol) in toluene (7 mL) was added ethanolamine (229 mg, 3.75 mmol) and TBD (261 mg, 1.88 mmol). After 22 h the reaction mixture was diluted with Seignette's salt and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated in vacuo, then purified by chromatography (silica, 0 to 10% methanol in dichloromethane) then on a 5×50 cm Chiralpak AD column at room temperature using an isopropanol:heptane (2:8) mobile phase with UV detection at 220 nM to give the less polar component 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (884 mg, 81%) as a pale yellow solid then the most polar component 2-[(Z)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (80 mg, 7%) as a pale yellow solid. MS: m/e=350.4 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(N(CC)CC)C>[C:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCCCC
Reactant: O=Cc1ccc(Br)s1
Solvent: CCN(CC)CC
Product: CCCCCCC#Cc1ccc(C=O)s1
Temperature: 105 °C
Yield: 78.1 %

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (8.5 g, 0.05 mole) was combined with 1-octyne (11.0 g, 0.1 mole) and triethylamine (200 ml). The mixture was degassed under argon and cuprous iodide (950 mg, 10 mole %) and tetrakis (triphenylphosphine) palladium (1.75 g, 5 mole %) were added. The mixture was heated at 105° C. for twenty hours under argon and cooled. The triethylamine was evaporated and the residue purified by chromatography on silica eluting with hexane/chloroform (3:1) to yield the title compound 8.6 g (83.7%) as a yellow oil. mp 130° C., νmax (film) 3320, 2225, 1675, 1050, 805, 780, 675; δ(CDCl3) 0.87(3H, t, J=6 Hz), 1.33(8H, m), 2.33(2H, t, J=6 Hz), 7.13(1H, d, J=6 Hz), 7.65(1H, d, J=6 Hz), 9.87(1H, s).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([NH:22][CH3:23])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)=O)(C)(C)C.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([NH:22][CH3:23])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1
Reactant: CCOC(=O)c1nc(NCCNC(=O)OC(C)(C)C)sc1NC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nc(NCCN)sc1NC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 2-[2-(tert-butoxycarbonylamino)ethylamino]-5-methylamino-thiazole-4-carboxylate (184 mg, 0.534 mmol) in a mixture of diethyletehr (15 ml) and anhydrous ethanol (15 ml) was added hydrochloric acid (4N in dioxane, 5 ml, 20 mmol) and the mixture was stirred at room temperature for two days. The solids were collected by filtration, washed with diethylether and dried under reduced pressure to yield 145 mg (0.457 mmol, 86%). MS(ESI) m/z=245.1 [M+1]+.
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]1([N:7]2[CH2:11][CH2:12][O:13][C:22](=[O:24])[O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCN(CCO)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN(c2ccccc2)CCO1
Yield: 55.3 %

Procedure:
The procedure of Example 1 was followed using N-phenyldiethanolamine (15.2 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a clear oil containing a mixture of products. The product was purified using a column chromatography EtOAc:Hexanes (3:1) yielding 3.3 g (19%) of a clear oil which turned brown over time.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:7]=2[CH:24]=1)#[CH:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[C:7]2[CH:24]=[C:3]([C:1]#[C:2][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:4]=[CH:5][C:6]=2[N:12]2[C:13]([CH3:16])=[N:14][N:15]=[C:11]2[CH2:10][N:9]=1
Reactant: Brc1cncnc1
Reactant: C#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C)n1-2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccc(C#Cc3cncnc3)cc1C(c1ccccc1F)=NC2
Reaction time: 24 h

Procedure:
A mixture of 316 mg (1 mmol) of 8-ethynyl-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 200 mg (1.25 mmol) of 5-bromopyrimidine, 45 mq of triphenylphosphine, 10 mg of cuprous iodide, 0.5 ml of triethylamine and 10 ml of dimethylformamide was stirred and degassed for 10 minutes by a slow stream of argon. Palladium acetate, 15 mg, was then added and stirring under argon was continued for 24 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and methylene chloride. The organic layer was washed with water, dried and evaporated, at the end azeotropically with xylene. The residue was chromatographed over 20 g of silica gel (Merck 70-230 mesh) using 5% of ethanol in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give off-white crystals of the title compound with m.p. 143°-146° C.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)(C)C.[BH4-].[Na+].C(OCC)(=O)C.[H-].[Na+].[CH3:39][OH:40]>>[O:40]=[C:39]1[N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)c2ccccc2)C1
Reactant: CO
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Bis(1,1-dimethylethyl)2-benzoyl-1,4-piperazinedicarboxylate (0.10 g, 0.26 mmol) was dissolved in methanol (2 mL), sodium borohydride (19 mg, 0.51 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL), 60% sodium hydride (12 mg, 0.30 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with ethyl acetate, washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to obtain the title compound (47 mg, yield 57%) as a diastereomer mixture. Diastereomer ratio (α:β=1:5).
Reaction SMILES: [OH:1][C:2]1([CH3:11])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][C:9]#[CH:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1([CH3:11])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][C:9]#[CH:10])(=[O:14])[CH3:13]
Reactant: C#CCC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Product: C#CCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, 3-hydroxy-2-propargyl-3-methyl-4-cyclopentenone (30 g) and acetic anhydride (70 g) were charged, and the resultant mixture was stirred at 100° to 120° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 11, followed by purification to give 36.4 g of dl-3-acetoxy-2-propargyl-3-methyl-4-cyclopentenone. Yield, 95%. B.P., 82°-86° C./0.2-0.3 mmHg.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=[O:18].Cl>CN(C)C=O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:11][C:2]2[CH:3]=[N:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[N:1]=2)[C:16]=1[CH:17]=[O:18]
Reactant: Oc1cnc2c(n1)CCCC2
Reactant: O=Cc1c(F)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cccc1Oc1cnc2c(n1)CCCC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
0.3 g of 5,6,7,8-tetrahydroquinoxalin-2-ol were dissolved in 5 ml of dimethylformamide. 0.1 g of sodium hydride were added thereto. 0.35 g of 2-chloro-6-fluoro-benzaldehyde were added to the reaction solution followed by stirring for 3 hours at 100° C. 1 N hydrochloric acid was then added to the reaction solution. Subsequently, the reaction solution was extracted with ethyl acetate and the organic layer was concentrated followed by purifying by silica gel column chromatography to obtain 0.26 g of 2-chloro-6-(5,6,7,8-tetrahydro-quinoxalin-2-yloxy)-benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[OH:19])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:44]=[C:45]([C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1)[CH3:46]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:44]=[C:45](/[C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)\[CH3:46])[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[OH:19])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: OC(CCCN1CCc2[nH]c3ccc(Cl)cc3c2C1)c1ccc(F)cc1
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(CCCC(O)c1ccc(F)cc1)CC2)c1ccncc1
Temperature: 85 °C

Procedure:
4-(8-Chloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)-1-(4-fluorophenyl)butan-1-ol (200 mg, 0.538 mmol) was dissolved in DMF (5 mL). potassium phosphate (457 mg, 2.15 mmol), copper (I) iodide (10.22 mg, 0.054 mmol) and L-proline (12.4 mg, 0.108 mmol) were added, followed by addition of 4-(1-bromoprop-1-en-2-yl)pyridine (158.1 mg, 0.806 mmol). Nitrogen gas was purged for 2 min and the reaction mixture was heated at 85° C. overnight (prolonged heating required in some cases). DMF was evaporated, water (20 mL) added and the compound extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL) and the desired compound purified through silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. It was further purified through reverse phase HPLC. Yield: 5.4 mg (di HCL salt). 1H NMR (CD3OD, Di-HCl salt) δ (ppm): 8.85 (d, 2H), 8.38 (d, 2H), 7.82 (s, 1H), 7.62 (s, 1H), 7.42 (t, 2H), 7.30 (s, 2H), 7.10 (t, 2H), 4.78 (m, 3H), 4.40 (m, 1H), 3.95 (m, 1H), 3.60 (m, 1H), 3.45 (t, 2H), 3.20 (m, 1H), 2.18 (s, 3H), 2.10-1.85 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]1[C:16](=[O:17])[C:15](=[O:20])[C:14]=1[NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: COc1ncccc1N
Solvent: CCO
Product: CCOc1c(Nc2cccnc2OC)c(=O)c1=O

Procedure:
A solution of 3-amino-2-methoxypyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 62A to provide the title compound.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[C:68]([C:69]([F:72])([F:71])[F:70])=[CH:67][CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[F:59][C:60]1[C:68]([C:69]([F:70])([F:71])[F:72])=[CH:67][CH:66]=[CH:65][C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4F)cc3)cc2C1=O
Yield: 32 %

Procedure:
The compound of example 193 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-fluoro-3-trifluoromethyl benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14](CC2C=CC(OC)=CC=2)[C:13](=[O:27])[N:12]=[C:11]3[CH:28]2[CH2:30][CH2:29]2)[CH:5]=[CH:6][CH:7]=1.[O-]S([C:35](F)(F)F)(=O)=O.[Mg+2].[O-]S(C(F)(F)F)(=O)=O.C[Mg]Br>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:27])[NH:12][C:11]3([CH:28]2[CH2:29][CH2:30]2)[CH3:35])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(-c4cccc(Cl)c4)ccc32)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: C[Mg]Br
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C2CC2)NC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To a solution of 6-(3-chlorophenyl)-4-cyclopropyl-1-(4-methoxybenzyl)-1H-quinazolin-2-one (0.25 g, 0.6 mmol) in anhydrous ether was added, at ambient temperature under nitrogen, magnesium triflate (0.78 g, 2.4 mmol). The mixture was stirred for 30 minutes and treated with a solution of methylmagnesium bromide in ether (3.0 M, 1.0 mL, 3.0 mmol). The reaction mixture was kept at room temperature under nitrogen for 3 hours and quenched with a mixture of a saturated aqueous ammonium chloride solution (10 mL) and 1N aqueous HCl solution (5 mL). The mixture was stirred at room temperature for 20 minutes and ethyl acetate (40 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed and a half portion of the residue was dissolved in TFA (3 mL) and was stirred under nitrogen at room temperature for 72 hours. The solution was poured onto ice-water and the white precipitate obtained was collected on a filter. The solid was washed with water and then purified by a flash chromatography (methylene chloride:methanol/25:1, silica gel) to give 6-(3-chlorophenyl)-4-cyclopropyl-4-methyl-3,4-dihydro-1H-quinazolin-2-one as off-white solid (40 mg, 43%): mp 125-127° C.; 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 7.71 (s, 1H), 7.61 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=1.6 Hz), 7.47 (dd, 1H, J=8.3, 1.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.36 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=8.2 Hz), 6.79 (s, 1H), 1.54 (s, 3H), 1.11 (m, 1H), 0.42 (m, 1H), 0.15-0.20 (i, 3H); MS (ESI) m/z 313([M+H]+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:44]1[C:52]2[C:51]([NH2:53])=[N:50][CH:49]=[N:48][C:47]=2[N:46]([CH3:54])[CH:45]=1.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOCC.O1CCOCC1>[CH3:54][N:46]1[C:47]2[N:48]=[CH:49][N:50]=[C:51]([NH2:53])[C:52]=2[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]3)=[CH:45]1
Reactant: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Reactant: Cn1cc(Br)c2c(N)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2ccccc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To a mixture of 5-bromo-1-(phenylacetyl)-2,3-dihydro-1H-indole (139 mg, 0.440 mmol), bis(pinacolato)diboron (117 mg, 0.462 mmol), and potassium acetate (130 mg, 1.321 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (19.08 mg, 0.023 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 C into a sealed vessel. The reaction was cooled down to room temperature. 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.440 mmol) and sat. aq. NaHCO3 (2 mL) were added, and N2 gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (17.98 mg, 0.022 mmol) was added, the vessel was sealed, and the reaction mixture was stirred for 3 days at 100 C). The mixture was allowed to cool to room temperature and poured onto water (˜150 mL). The resulting mixture was filtered. The solid in the filter was mixed with a 80:20 mixture of CHCl3:CH3OH (˜7 mL), and the resulting mixture was filtered. The filtrate was injected into a 90 g SiO2 columns. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90:10:1 CHCl3:CH3OH:NH4OH) provided the product. Trituration with Et2O afforded the title compound 7-methyl-5-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (22 mg) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 3.21 (t, J=8.21 Hz, 2H), 3.73 (s, 3H), 3.87 (s, 2H), 4.21 (t, J=8.46 Hz, 2H), 7.15-7.42 (m, 8H), 8.11-8.15 (m, 2H)
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:15][CH2:16][CH3:17])[CH2:9][CH2:8][CH:7]([C:10](OCC)=[O:11])[CH2:6][CH2:5]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:16]([O:15][C:4]1([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH:7]([CH2:10][OH:11])[CH2:8][CH2:9]1)[CH3:17]
Reactant: CCOC(=O)C1CCC(OCC)(OCC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC1(OCC)CCC(CO)CC1

Procedure:
Ethyl 4,4-diethoxycyclohexanecarboxylate (6.67 g) synthesized according to a literature procedure (European Journal of Organic Chemistry, 2008, 5, 895) in tetrahydrofuran (60 mL) was treated with 2 M lithium aluminum hydride in tetrahydrofuran (14.5 mL) at 0° C. for 1 hour. Water (3 mL) was slowly added to quench the reaction. The precipitates were filtered off and washed with ethyl acetate. The filtrate was dried over Na2SO4, filtered, and concentrated to provide the title compound.