Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:10](=[O:21])[NH:9][C:8]2=[O:22].[CH:24]([O-])=[O:25].[NH4+].O>C(#N)C.O1CCOCC1>[F:23][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:16][CH2:17][N:18]([CH:24]=[O:25])[CH2:19][CH2:20]1)[C:10](=[O:21])[NH:9][C:8]2=[O:22]
Reactant: O=c1[nH]c(=O)n(C2CCNCC2)c2ccc(OCC(F)F)cc12
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: O=CN1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1
Yield: 67.1 %

Procedure:
A mixture of 6.13 g of 6-(2,2-difluoroethoxy)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained in stage 3.6 and 3.12 g of ammonium formate in 28 ml of ACN and 28 ml of dioxane is irradiated under a microwave field at 140° C. for 1 h 00. The reaction mixture is run into water. The mixture is filtered and the precipitate is washed with water and then with ether to give 4.47 g of the expected product.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:15][C:16]1[N:24]=[C:23](Cl)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Cl-].[Na+].O>[NH2:15][C:16]1[N:24]=[C:23]([S:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: SC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SC2CCCCC2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (256 mg, 6.4 mmol, 60% in mineral oil) were added cyclohexanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was heated at 100° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 86%).
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][OH:7])[CH3:3].[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:7][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:24][CH2:23]1)=[O:26])[CH3:3]
Reactant: CCN(CC)CCO
Reactant: O=C(NC1CCN(C(=O)Cl)CC1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCOC(=O)N1CCC(NC(=O)c2ccccc2)CC1
Yield: 59.8 %

Procedure:
Sodium (0.432 g., 0.0188 mole) was added to β-diethylaminoethanol (2.23 g., 0.0190 mole) in dry toluene (80 ml) and the mixture was refluxed to give a complete solution. 4-Benzamidopiperidine-1-carbonyl chloride (4.2 g., 0.01575 mole) in suspension in dry toluene (150 ml.) was added in portions and the mixture refluxed for 21/2 hours. Water was added to the mixture, the toluene layer was collected, dried and evaporated to give the title compound (3.27 g. 37%), melting point 78°-82° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:33][CH:34]=2)[S:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1sc(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (385 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [4-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]thiazol-5-yl]acetate (750 mg, yield 82%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18]([OH:20])=O)[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:58]1([CH2:64][CH2:65][CH2:66][CH2:67][NH2:68])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][CH:17]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])[C:18]([NH:68][CH2:67][CH2:66][CH2:65][CH2:64][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Reactant: NCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC(c2ccc(CC(NS(=O)(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)cc2Cl)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.4 %

Procedure:
(2S)-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]propanoic acid (15.0 mg, 0.0317 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.8 mg, 0.0381 mmol) and stirred at rt for 5 minutes. A solution of 4-phenylbutan-1-amine (10 μL, 0.0634 mmol) and N,N-diisopropylethylamine (28 μL, 0.16 mmol) in DMF (1 mL) was added and the reaction stirred at rt for 1 h. Purification by preparative LCMS afforded product as a white solid (12.9 mg, 67%). 1H NMR (400 MHz, CD3OD): δ 7.68–7.64 (m, 2H), 7.54–7.34 (m, 4H), 7.27–7.11 (m, 7H), 5.59–5.57 (m, 1H), 3.92–3.87 (m, 1H), 3.42–3.35 (m, 1H), 3.35–3.28 (m, 1H), 2.99–2.84 (m, 3H), 2.79–2.74 (m, 1H), 2.56 (t, J=7.5 Hz, 2H), 1.53–1.47 (m, 2H), 1.33–1.29 (m, 2H); LCMS found for C28H31ClN3O6S2 (M+H)+: m/z=604.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].[Li+].[OH-]>C1COCC1.CO.O>[CH2:1]([C:4]1[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(CC(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCc1c(CC(=O)O)c2ccccc2n1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
To a solution of tert-butyl 2-allyl-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (0.94 g, 2.74 mmol) in THF (15 mL) and MeOH (5 mL) was added a solution of LiOH (170 mg, 6.8 mmol) in H2O (5 mL). The solution was stirred for 2 h. The reaction was partitioned between EtOAc and 20% aqueous KH2PO4. The organics were separated, dried over sodium sulfate, and the solvents removed in vacuo to provide 2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acid (900 mg). MS (m/z) 316 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[P:24]([CH2:28][CH2:29][C:30](O)=[O:31])([OH:27])([OH:26])=[O:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([F:23])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C@@H:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][P:24](=[O:25])([OH:27])[OH:26])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=2)[CH:21]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)CCP(=O)(O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)CCP(=O)(O)O
Reaction time: 0.11 h
Yield: 11.8 %

Procedure:
(R)-ethyl 3-amino-4-(5′-chloro-2′-fluoro-[1,1-biphenyl]-4-yl)butanoate (114 mg, 0.306 mmol), 3-phosphonoproprionic acid (47.2 mg, 0.306 mmol), EDC (58.7 mg, 0.306 mmol) and HOBT (46.9 mg, 0.306 mmol) were mostly dissolved in DMF (1 mL), and DIPEA (0.321 mL, 1.837 mmol) was added. The reaction mixture was stirred and heated at 70° C. approximately 18 hours, then filtered and purified by HPLC: 30-80% ACN/H2O 0.1% TFA, 40 mL/min over 15 min 30×100 Sunfire C18, product elutes approximately 5.5-8 min. A mixed fraction was repurified on a 20-55% gradient over 20 min, and product eluted ˜12.5-13 min. The fractions were evaporated to dryness to afford (R)-(3-((1-(5′-chloro-2′-fluoro-[1,1-biphenyl]-4-yl)-4-ethoxy-4-oxobutan-2-yl)amino)-3-oxopropyl)phosphonic acid (17 mg) LCMS (ES+) C21H24ClFNO6P: Calc.: 471.1; Found: 472.0[M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]2[C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>O1CCOCC1.CC(O)(C)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>[C:48]1([CH3:51])[CH:49]=[CH:50][C:45]([NH:44][C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]3[C:28](=[O:37])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)[C:5]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:46][CH:47]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(Nc4ccc(C)cc4)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.4 %

Procedure:
A white suspension of 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (104 mg, 0.2 mmole), K2CO3 (64 mg, 0.46 mmole), and p-toluidine (46 mg, 0.43 mmole) in a mixture of 1,4-dioxane/t-BuOH 5:1 (2 ml) was stirred at room temperature under nitrogen for 5 minutes. Thereafter, tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 μmole) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 48 hours. Upon cooling, the mixture was diluted with water and extracted three times with ethyl acetate (brine added). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography on silica using an ethyl acetate/n-hexane mixture as the mobile phase (in a ratio gradually ranging from 1:1 to 3:1), resulting in the pure title compound (30 mg, yield 25%) which was characterized by its mass spectrum as follows: MS (m/z): 590 ([M+H]+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].Cl[S:34]([C:37]1[O:41][C:40]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:34]([C:37]5[O:41][C:40]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:38]=5)(=[O:35])=[O:36])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: COC(=O)c1ccc(S(=O)(=O)NCCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)o1

Procedure:
Methyl 5-({2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}sulfamoyl)furan-2-carboxylate was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and methyl 5-(chlorosulfonyl)-2-furoate following General Procedure U.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1.COC(=O)C(C(=O)C1C=CC(C)=C(C)C=1)=COC.[F:43]C1C=C(C=CC=1)N>>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:43])[CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1ccc(C)c(C)c1
Agent: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1cccc(F)c1)C(=O)c1ccc(C)c(C)c1
Yield: 50.1 %

Procedure:
Compound 2h was prepared following the procedure described in Step 1 of Example 1 using from 2g (8.06 mmol) of crude 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a and 0.806 g (7.26 mmol) 3-fluoroaniline. The crude product 2h was purified by recrystalization with dichloromethane/hexane to yield 1.19 g of 2-(3,4-Dimethyl-benzoyl)-3-(3-fluoro-phenylamino)-acrylic acid methyl ester as a brown solid.
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].CI.[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]>C1COCC1>[CH3:1][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(O)cccc21
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Cs2CO3 (7 g; 21.5 mmol) followed by CH3I (10 g; 70 mmol) was added to a solution of 4-hydroxy-1-indanone (5.0 g; 34 mmol) in THF (30 mL) and the mixture was stirred at RT for 60 h. The reaction mixture was filtered and concentrated, and the crude product was purified using flash chromatography (SiO2; methylene chloride) to yield 3.1 g (56%) of the sub-title substance.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1)([OH:7])=[O:6].[CH3:21]O>>[CH3:21][O:6][C:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16])=[CH:12][CH:13]=1)=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (0.33 ml, 4.5 mmol) was added dropwise to a stirred solution of (4-carboxyphenylsulphonyl)nitromethane (1.0 g, 4 mmol) in methanol (12 ml) cooled in an ice-salt bath. The mixture was stirred for 16 hours at ambient temperature and the solvent evaporated. The residue was purified by MPLC eluting with dichloromethane, gradually increasing to methanol/dichloromethane (1:50 v/v), to give (4-methoxycarbonylphenylsulphonyl)nitromethane (0.45 g), m.p. 106°-108° C.; microanalysis, found: C, 41.8; H, 3.5; N, 5.2%; C9H9NO6S requires: C, 41.7; H, 3.5: N, 5.4%.
Reaction SMILES: N#N.[CH:3]1[C:20]2=[C:21]3[C:10]([C:11]4[C:22]5[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=5)[CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:30]([O:33]C(CCl)CCl)CCl.Cl>O.ClC1C=CC=CC=1Cl>[CH:18]1[C:19]2=[C:22]3[C:11]([C:10]4[C:21]5[C:6](=[CH:5][CH:4]=[CH:3][C:20]2=5)[CH:7]=[CH:8][CH:9]=4)=[CH:12][CH:13]=[CH:14][C:15]3=[C:16]([CH:30]=[O:33])[CH:17]=1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reaction time: 16 h

Procedure:
A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with perylene (Aldrich Chemical Co., Milwaukee, WI, 53201, 25 g, 99 mmol) and o-dichlorobenzene (500 mL). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 51.2 g, 0.897 mol, 23 mL), was added in one portion. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 14.9 g, 0.13 mol, 11.7 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40° over 2 h and further stirred for 16 h. Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted perylene from the aldehyde and a more polar product. Fractions (5 L) containing the aldehyde were combined and the PhCH3 removed. The resulting oily solid was shaken with CH3OH (200 mL) and the orange-brown crystals which formed were collected by filtration to give after drying 23.2 g (83%) of 3-perylenecarbaldehyde mp 223°-233°, (C,H), (lit. mp 236° (darkens >230°), N. P. Buu-Hoi and C. T. Long, Recueil 75 1121 (1956).
Reaction SMILES: ClC1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:13][CH3:14])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.ClC(Cl)(O[C:31](=[O:37])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.Cl[CH2:47][Cl:48]>>[Cl:48][C:47]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:14])[C:31](=[O:37])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:18][CH:17]=4)[C:5]=3[C:4]=2[N:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: CNCc1cnc2ccc(Cl)nc2c1Nc1ccc(C(C)(C)C#N)cc1
Solvent: CCN(CC)CC
Product: CN1Cc2cnc3ccc(Cl)nc3c2N(c2ccc(C(C)(C)C#N)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-((6-chloro-3-((methylamino)methyl)-1,5-naphthyridin-4-yl)amino)phenyl)-2-methylpropionitrile (2.0 g, 5.5 mmol) was dissolved in dichloromethane (25 mL), to the reaction flask in an ice bath added triphosgene (1.8 g, 6.1 mmol) and triethylamine (0.7 mL). Then, the mixture was stirred at room temperature for 2 h. The reaction was quenched with a saturated aqueous solution of sodium carbonate, extracted with 100 mL of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give 1.6 g of a pale yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cnn(CCN3CCCC3)c2c1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (0.220 g, 0.955 mmol) and triethylamine (0.240 mL, 1.72 mmol) in 1 mL of THF at 0 C was slowly added phenyl chloroformate (0.246 ml, 1.72 mmol). The mixture was stirred cold for 1 hours and the formed precipitate collected by filtration with rinsing with ether to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.97 (m, 2 H), 2.97 (m, 2 H), 3.49 (m, 2 H), 3.69 (m, 2 H), 4.71 (t, J=6.27 Hz, 2 H), 7.19 (m, 1 H), 7.28 (m, 3 H), 7.46 (m, 2 H), 7.74 (m, 1 H), 7.99 (m, 1 H), 8.10 (s, 1 H), 10.51 (s, 1 H); MS (DCI/NH3) m/z 351 [M+H]+.
Reaction SMILES: S1C=C[C:3]([C:6]([N:8]2[CH2:13]CCC(C(OCC)=O)[CH2:9]2)=O)=C1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([OH:35])=O)[CH2:28]1)=[O:26].C[N:37](C)CCN>>[CH3:9][N:8]([CH3:13])[CH2:6][CH2:3][CH:28]1[CH:29]([C:33]([NH2:37])=[O:35])[CH2:30][CH2:31][CH2:32][N:27]1[C:25](=[O:26])[CH2:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Reactant: O=C(O)C1CCCN(C(=O)Cc2cccs2)C1
Reactant: CN(C)CCN
Product: CN(C)CCC1C(C(N)=O)CCCN1C(=O)Cc1cccs1

Procedure:
The reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with 1-(2-thiopheneacetyl)-3-piperidine carboxylic acid (572.1 mg; 2.26 mmol) and commercially available N,N-dimethyl ethylenediamine (250 μl; 2.28 mmol). The crude product was purified by chromatography on silica, eluting with 70% methanol in dichloromethane, giving 2-dimethylaminoethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxamide (128.3 mg) as a colorless oil. MS m/z (positive ion) 324 (MH+; 100).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[N:1]1([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: c1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(CN2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline x158 (400 mg, 3 mmol, 1 eq) in DMF (7 ml) maintained under argon is added NaH (60% in mineral oil; 120 mg, 3 mmol, 1 eq). The reaction mixture is stirred for three hour at room temperature, then a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 in DMF (1 M, 3 ml, 3 mmol, 1 eq) is added. The reaction mixture is stirred for 20 hours at the same temperature. Water (70 ml) is added and the resulting mixture is extracted with ethyl acetate (30 ml). The organic phase is washed twice with water and dried over Na2SO4. After filtration and evaporation, the crude product is purified by two consecutive chromatographies on silicagel (CH2Cl2/MeOH gradient, then CH2Cl2). Pure 1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one 295 is obtained as syrup (231 mg).