Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Cl:11][C:12]1[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.[CH3:35][O:36][C:37](=[O:46])[CH:38]([P:40]([O:44][CH3:45])([O:42][CH3:43])=[O:41])[NH2:39]>CN(C)C=O>[CH3:35][O:36][C:37](=[O:46])[CH:38]([P:40]([O:42][CH3:43])([O:44][CH3:45])=[O:41])[NH:39][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)=[O:22])=[CH:20][C:12]=1[Cl:11]
Reactant: COCOc1cccc(CNC(=O)c2ccc(C(=O)O)c(Cl)c2)c1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCOc1cccc(CNC(=O)c2ccc(C(=O)NC(C(=O)OC)P(=O)(OC)OC)c(Cl)c2)c1
Reaction time: 12 h
Yield: 45.4 %

Procedure:
N,N-dicyclohexylcarbodiimide (0.216 g, 1.05 mmol) and 1-hydroxybenzotriazole (0.027 g, 0.2 mol) were added to a solution of 2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoic acid (Example 124; 0.34 g, 1.0 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 197 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred for 12 h, then was filtered and diluted with ethyl acetate. The resulting solution was washed with water, dried (Na2SO4), evaporated and the residual material was chromatographed (50-80% ethyl acetate/hexanes) to give rac.-N-[2-chloro-4-[[(3-methoxymethoxybenzyl) amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (0.24 g, 45% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
The mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (130 mg, 0.32 mmol), tert-butyl 4-aminobenzoate (185 mg, 0.96 mmol), EDC (122 mg, 0.64 mmol) and DMAP (78 mg, 0.64 mmol) in 10 mL of DMF was stirred at room temperature for 2 hours. Excess of DMF was removed under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate, washed with brine (2×10 mL), dried over anhydrous sodium sulfate. The crude residue was purified by silica gel chromatography (200-300 mesh, eluting with ethyl acetate) to give tert-butyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoate (130 mg, 70%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.76 (s, 1H), 10.18 (s, 1H), 9.41 (s, 1H), 8.97 (s, 1H), 8.62 (d, 1H, J=8.1 Hz), 8.10 (d, 1H, J=7.8 Hz), 7.95 (s, 4H), 7.85 (s, 1H), 7.71 (t, 1H, J=7.7 Hz), 7.54 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.75 (s, 3H), 1.57 (s, 3H). LC-MS: 584 [M+H]+, tR=1.78 min. HPLC: 98.03% at 214 nm, 98.38% at 254 nm, tR=7.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:11][Li].O>C1COCC1>[C:5]([C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)(=[O:7])[CH3:11]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccnc(Cl)c1
Temperature: -70 °C

Procedure:
In 440 ml of THF was suspended 22 g of 2-chloroisonicotinic acid, and under nitrogen flow, the mixture was cooled to −70° C. or lower, 245 ml of methyl lithium (1.14 M solution in diethyl ether) was added dropwise to the mixture. After stirring at the same temperature for an hour, a temperature of the mixture was raised to 0° C. over an hour, and stirred at the same temperature for further an hour. To the reaction mixture was added 500 ml of water, and the reaction mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Activated charcoal was added to the mixture, and after filtration, the filtrate was concentrated under reduced pressure to give 19.5 g of 4-acetyl-2-chloropyridine as colorless crystals. Melting point: 36° C.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)=O)C.[NH:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>C1(C)C=CC=CC=1>[OH:20][C:4]1[N:22]2[N:21]=[CH:25][CH:24]=[C:23]2[N:26]=[C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]2)[CH:5]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)C1
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of tert-butyl 3-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (7.00 g, 25 mmol) and 1H-pyrazol-3-amine (2.08 g, 25 mmol) in toluene 30 mL) was heated at 110° C. under argon for 18 h and concentrated in vacuo. The residue was triturated with EtOAc and the solid was collected by filtration and dried in high vacuum to give 6.84 g (90%) of the title compound as a white solid. LC/MS RT=1.40 min (5 min method). Mass calculated for, M+H 305.15, observed 305.15.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[O:26]=[S:2]1(=[O:1])[CH:3]=[CH:4][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of methyl (5R)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate (Step 2, 0.73 g, 1.87 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.27 g, 5.6 mmol) in dioxane (9 mL) is heated to 100° C. for two days. The solution is cooled and treated with 20 mL of 10% aqueous Na2SO3 and stirred for 30 minutes. The solution is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with satd NaHCO3 and saline and dried (MgSO4), filtered and concentrated. The crude residue is purified by column chromatography (0→5% ethyl ether-dichloromethane) to provide the title compound (0.28 g, 38%); 1H NMR (300 MHz, CDCl3): δ 3.31-3.35 (m, 2H), 3.89 (s, 3H), 4.00-4.15 (m, 3H), 4.25 (t, 1H), 5.11 (m, 1H), 5.45 (d, 1H), 6.54 (d, 1H), 7.29 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[CH:29][C:30]=1[CH3:31])=[O:25])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:29][C:30]=1[CH3:31])=[O:25])[CH3:35]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)cc1C

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (105 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 67.8 (30%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]([CH2:29][N+:30]#[C-:31])([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[C-]#N.[Na+]>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[C@H:11]1[O:12][CH:31]=[N:30][C@@H:29]1[S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc([C@H]2OC=N[C@@H]2S(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1

Procedure:
In a manner analogous to Preparation 1, 2-benzyloxy-4-methoxybenzaldehyde (2.54 g, 10.5 mmol), tosylmethylisocyanide (1.95 g, 10.0 mmol) and NaCN (49 mg, 1.00 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 438.5 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:9][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1ccc(C2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2ccccc2)cc1
Temperature: 78 °C
Yield: 14.1 %

Procedure:
To 2-(4-fluorophenyl)oxirane (6.50 g, 54.0 mmol) was added toluene (85 ml), 4-hydroxybenzaldehyde (9.89 g, 81.0 mmol), PEG4000 (polyethylene glycol, 1.15 g) and 1M NaOH (85 ml) and the stirring mixture was heated at 78° C. overnight. After cooling to RT the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on a medium silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing predominantly the higher Rf spot were combined and evaporated in vacuo to give 1.85 g (14%) of the title compound as a yellow oil. Fractions containing predominantly the lower Rf spot were combined and evaporated in vacuo to give 0.64 g of the regioisomer as a colorless, viscous oil. Mixed fractions were combined and rechromatographed eluting with 30% EtOAc/hexanes. Fractions containing the higher Rf material were combined and evaporated in vacuo to give an additional 2.64 g (20%) of the title compound as a colorless oil. Fractions containing the lower Rf material were combined and evaporated in vacuo to give an additional 1.82 g of the regioisomer as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[N:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1cccnc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (694 mg) and ethyl 2-chloronicotinate (608 mg) were reacted in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O-:20].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reaction time: 30 h
Yield: 76.8 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium methylate (208 mg, 3.85 mmol) were dissolved in methanol (20 ml) and then the solution was refluxed on heating under stirring for 30 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (151 mg, yield 77%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12]C)=O.[NH3:14].O>CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Reactant: N
Solvent: O
Solvent: CO
Product: NC(=O)c1cc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1) (880 mg, 5.0 mmol) in MeOH (2 mL) was added NH3.H2O (6 mL). The reaction was heated at 80° C. overnight. After being cooled to room temperature, the mixture was concentrated in vacuo to afford the title compound (805 mg) as a yellow solid, which was used for the next step without further purification. MS (m/z): 162 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:11])\[C:7]#[N:8])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: Cc1cc(Cl)ccc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Yield: 62.2 %

Procedure:
Step C In a manner similar to the method described in Example 1b, 4-chloro-2-methylbenzyl cyanide (3.5 g, 21 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (100 mL) at 50° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile as a white powder (4 g, 62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15](=[O:16])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2ccccc2O1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: O=C(CCc1ccccc1O)N1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 108.9 %

Procedure:
1-Benzylpiperazine (2.38 g) was added to 3,4-dihydrocoumarine (2.00 g) and stirred for 3 hours at 90° C., thereby yielding the entitled compound (4.77 g) as pale brown syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])O[C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1>C(O)(=O)C>[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:36](=[O:37])[C:31]7=[CH:30][C:29]([F:28])=[CH:39][CH:38]=[C:32]7[C:33]6=[O:34])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Solvent: CC(=O)O
Product: O=C1c2ccc(F)cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc(F)cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of 9,9-bis(4-aminophenyl)fluorene (17.4 g, 50 mmol), 4-fluorophthalic anhydride (18.3 g, 110 mmol), and 250 ml of acetic acid was stirred and heated under reflux for five hours and then stirred at ambient temperature overnight. A colorless precipitate formed which was filtered, washed twice with 150 ml of ethanol, washed twice with 100 ml of hexane, suction-dried for two hours, and then dried in a vacuum oven at 120° C. for 16 hours. The title compound was isolated as a colorless powder (29.2 g, 90.6% yield) that had melting point of 323.5°-326° C. and a 1H NMR spectrum (DMSO-d6) corresponding to δ8.02 (m, 4H), 7.86 (dd, 2H), 7.72 (m, 2H), 7.60 (d, 2H), 7.46 (t, 2H), and 7.35 (m, 10H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.S(Cl)([Cl:18])(=O)=O.C(Cl)Cl>C(Cl)(Cl)Cl>[Cl:18][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCN(CC1CC1)C(=O)CC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(CC1CC1)C(=O)C(Cl)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N-cyclopropylmethyl-N-propyl-3-oxo-butanamide (scheme 2: (H)) (900 mg, 4.57 mmoles) in chloroform (30 mL) at 0° C. was treated with sulfuryl chloride (1M in methylene chloride, 5.48 mL, 5.48 mmoles). The mixture was stirred at room temperature for 30 minutes and then poured into methylene chloride and washed with 5% sodium bicarbonate solution, brine, and dried over Na2SO4. The solution was concentrated in vacuo and the crude product used without further purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]>C(Cl)Cl>[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Diisopropylethylamine (0.75 ml, 4.45 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.45 g, 2.26 mmol) in DCM (5 ml) at room temperature. To this mixture was added 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (0.5 g, 2.26 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (0.76 g, 88% yield) as an off-white solid. Tr=1.98 min, m/z (ES+) (M+Na)+ 411.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([O:18]C)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:21][NH2:22])=[O:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 133.5 %

Procedure:
To a room temperature solution of methyl 2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150 mg, 0.58 mmol) in ethanol (40 mL) was added hydrazine hydrate (293 mg, 5.85 mmol). The reaction mixture was then heated at 80° C. for 16 h, concentrated in vacuo and the residue dissolved in DCM (50 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) which was taken on to the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[CH:17][C:18]=1[F:19]>CN(C=O)C.C(OCC)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1ccc2c(Cl)ncnc21
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (398.8 mg, 2.4 mmol) and 3-chloro-4-fluoro-phenylamine (378 mg, 2.6 mmol) in DMF (6 mL) was stirred at room temperature for 2 minutes. To it was added silver triflate (672 mg, 2.6 mmol), the mixture was then stirred at 90° C. for 2 hours. The reaction was then diluted with ethyl acetate and filtered off the precipitate, washing the precipitate with 10% ammonia solution. The filtrate was extracted with ethyl acetate, dried and concentrated. The residue was triturated with ethyl acetate and filtered to give 549.1 mg (83%) of (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-amine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) 9.48 (s, 1H, NH), 8.35 (s, 1H), 8.29 (dd, J=2.7 & 6.8Hz, 1H), 7.75-7.80 (m, 1H), 7.37 (t, J=9.3 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 3.75. (s, 3H, CH3). MS 277 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:19])=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Reactant: OCCCCO
Product: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(OCCCCO)c1ccc(Cl)cc1
Yield: 47.2 %

Procedure:
The named compound was synthesised from 3-(4-chloro-phenyl)-2-[1-(4-chloro-phenyl)-ethyl]-3-hydroxy-2,3-dihydro-isoindol-1-one (498 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure B and obtained as a clear oil (304 mg, 64%). 1H NMR (300 MHz, CDCl3): 7.87-7.84 (m, 1H, C(O)═C═CH), 7.53-7.46 (m, 2H, Ar—H), 7.07-7.00 (m, 9H, Ar—H), 4.41 (q, J=7.2 Hz, 1H, N—CH), 3.70 (m, 2H, HO—CH2), 3.31-3.24 and 3.02-2.95 (m, 2H, OCH2), 1.86 (d, J=7.2 Hz, 3H, CH3), 1.76-1.66 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3): 168.32, 145.27, 141.48, 137.77, 134.80, 133.15, 133.06, 132.84, 130.20, 129.67, 128.74, 128.41, 123.72, 123.27, 95.45, 63.36, 62.88, 52.49, 29.96, 26.48, 20.08. m/z (ES): 470 [M+H]+. Anal.: calc. for C26H25Cl2NO3+0.3 H2O: C, 65.62; H, 5.43; N, 2.94. Found: C, 65.58; H, 5.77; N, 2.45.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH2:16][CH3:17])[C:3]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1COCC1>[CH2:21]([O:20][C:18]([NH:1][C@@H:2]([CH2:15][CH2:16][CH3:17])[C:3]([O:9][CH2:10][CH3:11])([O:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC[C@H](N)C(OCC)(OCC)C(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](NC(=O)OCc1ccccc1)C(OCC)(OCC)C(=O)OCC

Procedure:
To (S)-ethyl 3-amino-2,2-diethoxyhexanoate (prepared analogously to examples 1, 10, 11 and 15) (1000 mg, 4 mmol) in THF (20 mL) at ambient temperature was added K2OC3 (829 mg, 6 mmol), followed by CbzCl (628 μL, 4.4 mmol). After 20 h water was added and the aqueous layer was extracted with Et2O. The combined organic layers were dried and the solvent was removed under reduced pressure. Column chromatography (silicagel, cyclohexane:EtOAc 10:1→5:1) gave 1000 mg of the carbamate.