Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:13]1=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[ClH:10].[O:1]([CH2:8][CH2:9][N:17]1[CH2:18][CH2:19][C:14]2([C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]([CH3:11])[C:13]2=[O:26])[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCOc1ccccc1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C2(CCN(CCOc3ccccc3)CC2)c2ccccc21
Product: Cl
Reaction time: 5 h

Procedure:
A mixture of 1.63 g of phenoxyethylchloride, 1.5 g of 1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, 1.44 g of anhydrous potassium carbonate, 0.1 g of potassium iodide and 30 ml of dimethylformamide was stirred at 90°-100° C. for 5 hours. The resulting mixture was poured into water and was extracted with diethylether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thus obtained oil was treated with hydrochloric acid to give 1'-(2-phenoxyethyl)-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine hydrochloride
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[C:21](O)(=[O:25])[C:22]#[C:23][CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:21]([N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])=[CH:12][CH:13]=2)[CH2:18]1)(=[O:25])[C:22]#[C:23][CH3:24]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: CC#CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC#CC(=O)N1CCc2ccc(C(=O)NOC3CCCCO3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 67 mg butynoic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated and the residue is purified by silica gel flash chromatography. 130 mg of a colorless foam are obtained after drying.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]=O)[C:5]#[N:6].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH2:25][CH2:26]1)[C:5]#[N:6]
Reactant: Cc1cc(C#N)ccc1CC=O
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C#N)ccc1/C=C/N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 3-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (188 mg, 0.8 mmol) and NaBH(OAc)3 in 25 mL of dry methanol were stirred at room temperature over night. The solid was filtered to get 160 mg of 3-methyl-4-((E)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}vinyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.31˜7.40 (m, 5H), 6.72 (d, J=13.5 Hz, 1H), 5.35 (d, J=13.9 Hz, 1H), 3.20 (s, 4H), 2.95 (s, 2H), 2.57˜2.75 (m, 6H), 2.26 (s, 3H). MS m/z: 377 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].O.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 85.2 %

Procedure:
To a solution of ethyl 4-{[4-chloro-3-(trifluoromethyl)phenoxy]methyl}benzoate (Preparation 17, 350 mg, 0.98 mmol) in methanol (8.0 mL) was added water (2 mL) followed by sodium hydroxide (400 mg, 9.8 mmol). The reaction mixture was heated to 55° C. for 3 hours, then cooled and diluted with EtOAc (50 mL) and 2M HCl (50 mL). The aqueous layer was separated and washed with EtOAc (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (276 mg, 86%).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.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>[F:1][C:2]1[C:7]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][N:18]=2)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1ccc(B(O)O)c(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)n1

Procedure:
1,1-Dimethylethyl 4-{[(2′-fluoro-6′-methyl-2,3′-bipyridin-5-yl)oxy]methyl}-1-piperidinecarboxylate (0.21 g, 72%) was prepared as an off-white solid from 2-fluoro-6-picoline-3-boronic acid (0.14 g, 0.87 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 76, Step 1, 0.27 g, 0.72 mmol), 2M Na2CO3 (2.5 mL) and PdCl2(PPh3)2 (26 mg, 0.04 mmol) DME (8 mL) in a manner similar to Example 21, Step 3. The crude material was purified by chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 to give 1,1-dimethylethyl 4-{[(2′-fluoro-6′-methyl-2,3′-bipyridin-5-yl)oxy]methyl}-1-piperidine carboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.45-8.35 (m, 2H), 7.81 (d, 1H, J=8.0 Hz), 7.30-7.25 (m, 1H), 7.15-7.10 (m, 1H), 4.16 (bs, 2H), 3.88 (d, 2H, J=6.4 Hz), 2.80-2.65 (m, 2H), 2.53 (s, 3H), 2.10-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 402 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.CS(C)=O.F[C:21]1[C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:23]([CH3:38])[C:24]([C:36]#[N:37])=[C:25]2[C:29]=1[O:28][C:27]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[N:26]2>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:21]2[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:23]([CH3:38])[C:24]([C:36]#[N:37])=[C:25]3[C:29]=2[O:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:26]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCOCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCOCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (55 μl, 0.435 mmol) and triethylamine (70 μl, 0.502 mmol) were added to a dimethyl sulfoxide (3 ml) solution of 7-fluoro-5-methyl-2-morpholin-4-yl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-283) (113 mg, 0.335 mmol), followed by stirring in an oil bath at 150° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was recrystallized from hot ethanol to obtain the entitled compound (33.0 mg, 22%) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][CH:11]([OH:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:11](=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
For example, a solution of (3R,5R)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methylenecyclohexanol (compound 9) in toluene is made to react with aluminum isopropoxide and cyclohexanone to produce (3R,5R)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methylenecyclohexanone (compound 10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:43])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH2:25][C:26]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)(CCC)[C:27]([C:30](=[O:32])[CH3:31])=[CH:28][CH:29]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+].[CH3:50][C:51]([CH3:53])=O>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:43])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:25]=1[CH2:50][CH2:51][CH3:53])[CH3:17]
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Reactant: CC(C)=O
Reactant: CCCC1(OCCCCCBr)CC(OCCCC(=O)OCC)=CC=C1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCCCC(=O)OCC)c1CCC
Yield: 38 %

Procedure:
A mixture of 0.990 g (0.0043 mole) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.980 g (0.0043 mole) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-3-propylphenoxy]butanoic acid ethyl ester and 1.2 g (0.0087 mole) of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 22 hours. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC using 25% ethyl acetate-hexane to give 1.008 g (38% yield) of 4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10]CC.[C:19]1([C:25]#[C:26][C:27]([O:29]CC)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O.[C:41]1(C)C=CC=C[CH:42]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:27](=[O:29])[C:26]([CH2:41][CH3:42])=[C:25]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: Cc1ccccc1
Reactant: CCCC(=Nc1ccccc1Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=O

Procedure:
To 300 of toluene were added 10.3 g (0.040 mole) of N-(2-chlorophenyl)-1-phenylbutaneimine, 5.2 g (0.030 mole) of ethyl phenylpropiolate and 5.3 g (0.040 mole) of aluminum chloride. After heating the reaction mixture under reflux for 20 hours under a nitrogen atmosphere, the reaction mixture was poured into 500 ml of 2N sulfuric acid which had been ice-cooled, followed by extraction with chloroform. After washing the organic layer with 50 ml of a 10% aqueous solution of sodium hydroxide and then with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) so that 2.0 g of 1-(2-chlorophenyl)-3-ethyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 165°-166° C. was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:33])([F:21])[F:34])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OC(F)(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(trifluoromethoxy)picolinic acid [J. D. Scott et al. WO2011044181 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=481.4 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:11]([CH3:10])[CH:12]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)c1ccc([N+](=O)[O-])c(C)c1
Yield: 87.8 %

Procedure:
The same operation as in Example (102a) was performed using serine methyl ester hydrochloride (5.24 g, 33.7 mmol), 3-methyl-4-nitrobenzoic acid (6.1 g, 33.7 mmol), WSC hydrochloride (6.71 g, 35 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (4.52 g, 35 mmol) and dichloromethane (100 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 2/1, 1/0) to obtain 8.35 g of the title compound as a light yellow solid (88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].I[CH2:13][CH3:14]>>[CH2:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[CH3:14]
Reactant: CCI
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Product: CCOC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (1.5 g), in dimethylfomylamide (30 mL), 60% sodium hydride (0.50 g) was added portion-wise at 0° C. then warmed to ambient temperature. Iodoethane (3.5 mL) was added to the mixture at 0° C. then stirred for 16 h at room temperature. The reaction mixture was filtered then the filtrate was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O (×2) then brine and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/Et2O (1:1) as eluent to give the subtitle compound as clear, colourless oil. Yield: 1 g
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:52]([NH2:56])[CH:53]([CH3:55])[CH3:54]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:56][CH2:52][CH:53]([CH3:55])[CH3:54])=[O:20])[CH:17]=2)[NH:12][N:11]=1
Reactant: CC(C)CN
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)CNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 19 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo [d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (200 mg, 0.55 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (231 mg, 0.61 mmol) and isobutylamine (60 μL, 0.61 mmol); (71 mg, 19% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7–8.8 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.3–7.5 (m, 2H), 3.2 (m, 2H), 2.0 (m, 1H), 1.0 (d, 6H), ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH3:31])[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Reaction time: 6 h
Yield: 4.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added o-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.0 mg, 5%).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.Cl[N:39]1[CH2:44][CH2:43][O:42][CH2:41][C:40]1=C=O.CN(C)[CH:49]=[O:50]>CCOC(C)=O>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:49]([N:39]6[CH2:40][CH2:41][O:42][CH2:43][CH2:44]6)=[O:50])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: CN(C)C=O
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C=C1COCCN1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (200 mg, 0.44 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.5 mL, 3 mmol). The reaction mixture was stirred at 0° C. for 5 min prior to the addition of 4-chloro-carbonylmorpholine (65 mg, 0.44 mmol) in DMF (0.5 mL). The resulting mixture was stirred at 0° C. for 1 h, diluted with EtOAc (30 mL), washed with water (2×15 mL), brine (15 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to 5 mL, and the resulting off-white solid was collected by filtration to give the title compound. LC-MS (ES, Pos.): 462 [MH+], and 1H NMR (DMSO-d6, 400 MHz): δ=2.53 (m, 2H), 3.17 (m, 4H), 3.43 (m, 2H), 3.60 (m, 4H), 3.96 (m, 2H), 6.42 (s, 1H), 6.82 (d, J=1.2 Hz, 1H), 7.88 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.23 (s, 1H), 9.60 (s, 1H), 12.0 (s, 1H).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[S:34](=[O:36])(=[O:35])[N:33]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:32](=[O:41])[CH2:31]2)=[CH:26][CH:25]=1>O1CCCC1>[C:37]([N:33]1[C:32](=[O:41])[CH2:31][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:7](=[O:8])[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:29][CH:28]=2)[S:34]1(=[O:36])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CBr)cc2)S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)CC(c2ccc(CC(C(=O)c3ccccc3)c3ccccc3)cc2)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
A solution of deoxybenzoin (62.6 mg, 0.32 mmol) in tetrahydrofuran (1.3 mL) was cooled to −78° C. and potassium tert-butoxide (0.15 mL, 0.15 mmol, 1.0 M in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and 4.19-A of Step 1 (115 mg, 0.32 mmol) in tetrahydrofuran (1.5 mL) was added dropwise. The reaction mixture was warmed to 25° C. and quenched with saturated ammonium chloride (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried with sodium sulfate, filtered, and concentrated to a crude yellow oil which was purified by flash column chromatography to yield the desired product (75 mg, 50%). LCMS found for C28H29NO4SNa (M+Na)+: m/z=498.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]#[C:21][CH2:22][OH:23])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C1C[O:35]CC1>>[OH:23][CH2:22][C:21]#[C:20][C:3]1[C:2]([NH:1][C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[O:35])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:6](=[O:11])[NH:7]2
Reactant: ClCc1ccncc1
Reactant: C1CCOC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#CCO)c21
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)c3ccncc3)c(C#CCO)c21

Procedure:
Using Method M above, (Z)-5-amino-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (20 mg, 0.065 mmol) (from Example 32 above) was acylated with isonicotinyl chloride (23 mg, 0.13 mmol) (Aldrich) in THF (2 mL) at room temperature for 10 days to give (Z)-N-[2,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-5-yl]-4-pyridinecarboxamide. (Yield 10 mg, 37%).
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)(C)(C)C.[C:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1.[CH:40]([O:43][C:44]1[CH:45]=[C:46]([CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=1)[C:47]([NH:49][C@H:50]([C@@H:58]1[CH2:62][C@@H:61]([CH3:63])[C:60](=[O:64])[O:59]1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])([CH3:42])[CH3:41]>>[CH2:51]([C@H:50]([NH:49][C:47](=[O:48])[C:46]1[CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=[C:44]([O:43][CH:40]([CH3:42])[CH3:41])[CH:45]=1)[C@@H:58]([OH:59])[CH2:62][C@H:61]([C:60](=[O:64])[NH:39][CH2:38][CH2:37][C:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1)[CH3:63])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Reactant: NCCC1=CCCCC1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC2=CCCCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from 2-(1-cyclohexenyl)ethylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).