Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)/[CH2:12][OH:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(OCC)(=O)C>C(Cl)Cl>[C:37](=[O:38])([O:13][CH2:12]/[C:11](/[CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[CH:10]/[C:7]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)[O:39][CH2:40][CH3:41]
Reactant: CCCCc1ncc(/C=C(/CO)Cc2ccc(C)o2)n1Cc1ccccc1Cl
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1ncc(/C=C(/COC(=O)OCC)Cc2ccc(C)o2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl }-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenol (6.86 mmol) in methylene chloride (20 mL) and triethylamine (12.4 mmol) cooled to 0° C. under argon is added dropwise ethyl chloroformate (1.34 g, 1.18 ml, 12 mmol). The reaction is then stirred at ambient temperature overnight. Ethyl acetate is added, the precipitate filtered and the concentrated filtrate is flash chromatographed over silica gel with 3:7 hexane/ethyl acetate to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:13])[CH:3]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:5])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:13])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Product: CCCCn1c2c(c(C)cc1=O)C(=O)CCC2

Procedure:
Prepared analogously to Example 5(b) from 4-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and n-butylamine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)(=[O:10])[CH3:9]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccccc2C(C)=O)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
2′-Fluoroacetophenone (10.6 g), methyl 4-hydroxybenzoate (11.7 g) and potassium carbonate (11.2 g) were suspended in dimethylacetamide (70 ml), and the mixture was stirred at 140° C. for one day. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (8.62 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15])=[O:4].[OH-].[K+]>CS(C)=O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:15][C:7]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A mixture of 8 (22 g) and powdered KOH (6.9 g) in DMSO (100 ml) was stirred at 95° C. for 30 min. and poured onto crushed ice (400 g). The resulting precipitate was collected and washed with H2O to give 9 (15.7 g, 85%): mp 230°-232° C.; MS m/e 194 (M+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>C(#N)C>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[N:22]([C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:21]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Solvent: CC#N
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3ccccc3n2)n1
Temperature: 130 °C
Yield: 48.5 %

Procedure:
(2-Chloro-quinazolin-4-yl)-phenyl amine (250 mg, 0.98 mmol) was dissolved in acetonitrile (4 mL) and 3,5-dimethylpyrazole (140 mg, 1.47 mmol) was added. The mixture was heated in a sealed tube at 130° C. for 12 hours. The mixture was concentrated and the residue basified with sodium hydrogencarbonate, extracted with chloroform dried over anhydrous sodium sulfate filtrated and evaporated. The crude product was purified by column chromatography (ethylacetate/hexane) to give [2-(3,5-dimethyl-pyrazol-1-yl)-quinazolin-4-yl]-phenyl-amine (150 mg, 49%). Mp. 262.4-265.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[O:12]1[C:16]2[CH:17]=[C:18]([C:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:30][CH:29]([NH2:31])[CH2:28]4)[CH2:23][CH:22]=3)[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13]1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38]>>[O:12]1[C:16]2[CH:17]=[C:18]([CH:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:30][CH:29]([NH:31][C:41]([CH2:40][NH:39][C:37](=[O:38])[C:36]5[CH:44]=[CH:45][CH:46]=[C:34]([C:33]([F:48])([F:32])[F:47])[CH:35]=5)=[O:42])[CH2:28]4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13]1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC1CN(C2CC=C(c3ccc4c(c3)OCC4)CC2)C1
Agent: CCN=C=NCCCN(C)C
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4c(c3)OCC4)CC2)C1

Procedure:
The title compounds were prepared as white solids from the EDCI coupling between the amine (from step D) and (3-trifluoromethyl-benzoylamino)-acetic acid followed by H-Cube hydrogenation using the procedures described in Steps E and F of Example 1.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:30][CH2:31]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:22])=[O:21])=[O:18])=[C:15]([F:32])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: BrB(Br)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)CCO)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide (0.30 g, 0.64 mmol) in methylene chloride (6 mL) was added a solution of boron tribromide (0.12 mL, 1.29 mmol) and 2,6-lutidine (0.15 mL, 1.29 mmol) in methylene chloride (1 mL) dropwise. The reaction mixture was stirred at 0° C. for 2 h and at ambient temperature for 1 h, then cooled to 0° C. and quenched with saturated sodium bicarbonate solution (15 mL). The mixture was diluted with methylene chloride (15 mL), layers were separated, and the aqueous layer was extracted with methylene chloride (2×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 75% gradient of ethyl acetate in hexanes to afford the title compound as colorless solid (0.07 g, 25%): 1H NMR (300 MHz, CDCl3) δ 8.71 (br. s, 1H), 7.64-7.52 (m, 1H), 6.64-6.50 (m, 1H), 4.22-4.07 (m, 2H), 3.86-3.74 (m, 2H), 3.56 (s, 2H), 2.57 (s, 1H), 2.09-1.99 (m, 4H), 1.84-1.63 (m, 12H), 1.00-0.89 (m, 2H), 0.69-0.59 (m, 2H); MS (ES+) m/z 452.3 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][N:15]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:11]([CH3:24])[CH:10]=2)C=CC=CC=1>CO.[Pd]>[CH3:24][C:11]1[CH:10]=[C:9]([NH2:8])[CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: Cc1cc(N=C(c2ccccc2)c2ccccc2)cc2c1cnn2C1CCCCO1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A mixture of N-(diphenylmethylene)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine (0.80 g, 2.0 mmol, prepared using B from Preparation #AB.1 with diphenylmethanimine [Alfa Aesar]) and Pd/C (0.080 g, 0.752 mmol, 10 wt %) in MeOH (10 mL) were stirred at rt for about 16 h under a H2 atmosphere. The mixture was filtered through Celite® and the filter cake was washed with MeOH. The filtrate was concentrated to provide 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine (0.45 g, 74%): LC/MS (Table 2, Method h) Rt=1.76 min; MS m/z: 232 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC([N:19]1[C:24](=[O:25])[CH:23]2[CH:21]([CH:22]2[C:26]([O-:28])=[O:27])[CH:20]1[C:29]([O-:31])=[O:30])=O)(C)(C)C.O>C(Cl)Cl>[C:26]([CH:22]1[CH:23]([C:24]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:25])[CH:21]1[CH:20]([C:29]([OH:31])=[O:30])[NH2:19])([OH:28])=[O:27]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of AlCl3 (53.8 mg, 0.40 mmol) in dry CH2Cl2 (1 mL) at 0° C., aniline (70 μl, 0.77 mmol) in CH2Cl2 (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 10 min, and then ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0)hexane-2,6-dicarboxylate (106 mg 0.31 mmol) in dry CH2Cl2 (0.5 mL) was added. After stirring at room temperature for 4 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2 (X3). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 1/1) to give 67.5 mg of the desired compound (50% yield).
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:38]1[O:39][CH:40]=[CH:41][N:42]=1)CCC>C1(C)C=CC=CC=1.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>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9]([CH:38]3[NH:42][CH2:41][CH2:40][O:39]3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3NCCO3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Yield: 31.1 %

Procedure:
A solution of 49 mg of 13d, 50 mg of 2-tributylstannyl oxazole and 10 mg of Pd(PPh3)4 in 3 ml of degassed toluene was heated under N2 at 100° C. for 48 hr. The reaction mixture was cooled and applied to a silica gel column and eluted with a gradient of toluene/ethyl acetate. The product obtained was triturated with diethyl ether to provide 15 mg of 13f as white crystalline material; Mp 218-220° C. Rf 0.20 (toluene/ethyl acetate 1/1). MS-ESI: [M+1] 482.23.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1COCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1COCCN1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
Morpholine-3-carboxylic acid (10 g, 76 mmol) was dissolved in water (50 ml) and cooled to 5° C. A solution of 50% sodium hydroxide (6.10 g, 76 mmol) was added and the reaction mixture was cooled back to 5° C. An additional portion of 50% sodium hydroxide (7.93 g, 99 mmol) was then diluted to 22 mL with water and added to an addition funnel. Benzyl chloroformate (65.3 ml, 458 mmol) was added to a separate addition funnel and the two reagents were simultaneously added dropwise over about 30 minutes while maintaining the reaction temperature below 10° C. The pH of the mixture was about 6 when the addition was completed. Additional 50% NaOH (1.13 g, 14.3 mmol) was added to adjust pH to 9. The reaction was stirred at 10-15° C. for 2 hours. The reaction mixture was extracted with hexanes (2×30 ml) to remove excess benzyl chloroformate. EtOAc (50 ml) was added into the aqueous phase. The mixture was acidified to pH of about 0 with concentrated HCl (10 g). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic solution was concentrated to afford an oil. The product was further dried under high vacuum overnight to afford 21.2 g of crude 4-(benzyloxycarbonyl)morpholine-3-carboxylic acid which was used in the next step without further purification. [M−H] calculated for C13H15NO5, 264. found, 264
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])[N:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])[N:3]=1
Reactant: COCCN(C)c1nc(Cl)ccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COCCN(C)c1nc(Cl)ccc1C#N
Temperature: 55 °C
Yield: 88.6 %

Procedure:
To a solution of 6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide (3) (14 g, 58 mmol) in acetonitrile (anhydrous, 360 mL) were added pyridine (37.5 mL, 463.8 mmol) and POCl3 (21.2 mL, 232 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. The solution was extracted with EtOAc (3×200 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-30% EtOAc/hexanes gradient, to afford 11.6 g (90% yield) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=7.4 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 3.87 (t, J=5.3 Hz, 2H), 3.64 (t, J=5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H).
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:16][C:17]1[C:18]([C:14]#[C:13][C@@H:12]2[CH2:11][C@H:10]([OH:15])[CH2:9][NH:8]2)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3C[C@H](O)CN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (3S,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (132 mg, 0.62 mmol) (Example 103A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated, and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 4 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4S)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 58%).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>C(#N)C(C)C>[CH2:7]([O:14][C@H:6]1[C@H:2]([OH:1])[CH2:3][O:4][CH2:5]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1OCC2OC12
Reactant: OCc1ccccc1
Agent: CC(C)C#N
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O[C@@H]1COC[C@H]1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a flask fitted with a condenser and nitrogen inlet was added 3,4-epoxytetrahydrofuran (20 g, 0.23 mol), isobutyronitrile (100 ml, 5 vol), benzyl alcohol (124 g, 1.15 mol, 5 eq.) and finally magnesium perchlorate (10.3 g, 0.046 mol, 0.2 eq). The solution was heated at 100° C. for 24 hours. After cooling to room temperature, the reaction was quenched with water (1000 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×400 mL). After drying the organic phases over MgSO4, filtering and concentrating in vacuo, the trans-3-benzyloxy-4-hydroxytetrahydrofuran was isolated by column chromatography to give 29 g (66% yield) of a clear colorless liquid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>CCN(CC)CC.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>[CH3:9][O:8][C:6]1[N:5]=[CH:4][C:3]([NH2:10])=[C:2]([C:14]#[C:13][CH:12]([CH3:15])[CH3:11])[CH:7]=1
Reactant: C#CC(C)C
Reactant: COc1cc(I)c(N)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C#CC(C)C)c(N)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-iodo-6-methoxypyridin-3-amine (Compound 3, 845 mg, 3.4 mmol) in Et3N (12 ml) in a re-sealable pressure tube was added Pd(PPh3)2Cl2 (24 mg, 0.034 mmol), Cul (7.0 mg, 0.034 mmol), and 3-methyl-1-butyne (0.66 ml, 6.8 mmol). The mixture was stirred at room temperature for 20 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as beige solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH:11][C:12]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=S)=[CH:9][N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C(O)C>[Hg]=O.CN(C)C(=O)C>[CH:1]1([N:4]2[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:11][C:10]3[C:5]2=[N:6][CH:7]=[N:8][CH:9]=3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cncnc2NC2CC2)CC1
Agent: O=[Hg]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cncnc3n2C2CC2)CC1
Yield: 14.1 %

Procedure:
A mixture of 15.7 parts of ethyl 4-[[[[4-(cyclopropylamino)-5-pyrimidinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate, 20 parts of mercury(II) oxide. 40 parts of ethanol and 135 parts of N,N-dimethylacetamide was stirred overnight at 80° C. The reaction mixture was filtered over diatomaceous earth while hot. The filtrate was poured into water and the product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (14.1%) of ethyl 4-[(9-cyclopropyl-9H-purin-8-Yl)amino]-1-piperidinecarboxylate; mp. 177.0° C. (compound 17).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][CH2:16][CH2:21][O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCSC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.