Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.CN(C)CC(O)=O.[CH3:38][S:39]([O-:41])=[O:40].[Na+]>[Cu]I.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([S:39]([CH3:38])(=[O:41])=[O:40])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1n[nH]c2cc(Cl)ncc12

Procedure:
6-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 13B; 1.0 g, 1.917 mmol), N,N-dimethylglycine (39.5 mg, 0.383 mmol), copper(I) iodide (36.5 mg, 0.192 mmol), and sodium methanesulfinate (276 mg, 2.300 mmol) were combined in a 20 mL microwave tube, evacuated under N2 and charged with DMSO (7.7 mL). The reaction was degassed via vacuum under nitrogen (×3) and irradiated in a microwave reactor to 110° C. for 90 min. The crude reaction mixture was poured into water and filtered. The precipitate was purified by flash chromatography (10-50% EtOAc/DCM) to afford 6-chloro-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. For C7H6ClN3O2S [M+1]+ 232. found 232.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].[C:34]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35]1>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:3]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(S(=O)(=O)NC(=O)CCCC(=O)O)cc2)nn1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (2.0 g, 5.1 mmol) and THF (200 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (6.1 mL, 1.0 M solu in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then glutaric anhydride (0.69 g in 10 mL THF, 6.0 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. A few drops of acetic acid was added, then the mixture was concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/8:2) to afford the desired product Compound 11 (670 mg, 26%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.75 (d, J=7.0 Hz, 2H), 7.68 (m, 1H), 7.50 (d, J=6.9 Hz, 2H), 7.15 (t, J=6.9 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 1.80 (t, J=6.8 Hz, 2H); MS (ESI) m/z: 493 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at room temperature, solid K2CO3 (30 mmol) was added followed by addition of 4-hydroxybiphenyl (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to room temperature to room temperature, the reaction mixture was poured into EtOAc (100 mL), washed with water (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[C:6](OC)(=O)[CH3:7].[CH3:11][OH:12]>>[C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2].[CH3:11][OH:12]
Reactant: COC(C)=O
Solvent: CO
Product: C=CCOC(C)=O
Yield: 89 %

Procedure:
The tandem tube reactors are operated as described in Example 2, with substitution of 740 grams per hour of pure methyl acetate for the methyl acetate-methanol azeotrope. Analysis of the condensed phases indicates the collection per hour of 157 grams of methyl acetate (21% unconverted), 705 grams of allyl acetate (89% yield based on 79% conversion), and 227 grams of methanol (90% yield).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][CH:12]2[CH2:14][C:15]3[C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=3[CH:11]2[CH2:10]1)C1C=CC=CC=1>[Pd].CO>[ClH:1].[CH3:22][O:21][C:17]1[CH:18]=[CH:19][C:20]2[CH:11]3[CH2:10][NH:9][CH2:13][CH:12]3[CH2:14][C:15]=2[C:16]=1[O:23][CH3:24]
Reactant: COc1ccc2c(c1OC)CC1CN(Cc3ccccc3)CC21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CC1CNCC21

Procedure:
4.36 g. of the resultant compound of Example 5 was hydrogenated with 0.9 g. 5% Pd/C in 100 ml. methanol at 3 atmospheres, affording 2.95 g. of product (92%), m.p. 176°-178° C.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].[CH3:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32]Cl)=[O:30].C(N(CC)CC)C.CN(C)C=O>C(Cl)Cl>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:32][O:31][C:29](=[O:30])[C:28]([CH3:35])([CH3:34])[CH3:27])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)OCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (0.33 g, 0.80 mmol), chloromethyl 2,2-dimethylpropanoate (0.24 g, 1.60 mmol), triethylamine (0.22 ml) and dimethylformamide (DMF) (3 ml) is stirred at RT for 2 days. The reaction is then diluted with methylene chloride, washed, dried and evaporated to dryness, followed by purification by preparative thin layer chromatography (prep. TLC) (silica gel, eluting with 40% ethyl acetate/hexane) to yield 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: C1COCCN1
Product: Clc1ccc2c(c1)N=C(N1CCOCC1)c1ccccc1N2
Yield: 16.1 %

Procedure:
Crude 8-chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (90 mg, purity 50%, 0.218 mmol) and morpholine (38 mg, 0.44 mmol) were reacted as described for Example 62 to give 11 mg of the title compound (166JO69B). MS (ESI) 314 (MH+). Purity for MH+ (UV/MS) 100/98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)C>[C:32]([C:31]1[CH:30]=[N:29][CH:28]=[CH:27][C:26]=1[C:10]1([CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[NH:16][CH2:17][CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:24])([OH:34])=[O:33]
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: O=C(O)c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cnccc1C1(C(=O)Nc2ccc(Cl)cn2)C=CC=CC1NCC1CCNCC1

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloronicotinic acid (91 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL) yielded, after RPHPLC purification, 45 mg (33%) of the title compound as a trifluoroacetate salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:18][NH2:19].[O-]S([O-])(=O)=O.[Mg+2]>C(O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[N:19]/[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CN
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: C/N=C/c1ccc(-c2ccc(OC)c(Br)c2)cc1
Yield: 98 %

Procedure:
A mixture of 3′-bromo-4′-methoxy-1,1′-biphenyl-4-carbaldehyde (7.56g, 26.0 mmol), prepared in the previous step, methylamine (16.2 mL of an 8.03 M solution in ethanol; 130 mmol) and 20.0 g of anhydrous MgSO4 in 150 mL of methylene chloride was stirred under nitrogen at room temperature for 22 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give N-[(E)-(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methylidene]-N-methylamine (7.77 g, 98%) as a brown solid, mp 115-117° C. Elemental Analysis for C15H14BrNO. Calc'd: C, 59.23; H; 4.64; N, 4.60. Found: C, 58.99; H, 4.38; N, 4.63
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(N)c2)cc1
Yield: 64.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 4-methoxyaniline (6.25 g, 50.7 mmol) to afford the product (4.45 g); m.p. 164-167° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2>>[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH:31][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:26][CH:25]=2
Reactant: CC(C)(O)c1cccc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(C(C)(C)O)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-[6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-propan-2-ol and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.05 (d, 1H), 7.83 (s, 1H), 7.75 (m, 2H), 7.53 (d, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 6.95 (d, 1H), 6.56 (d, 1H), 6.10 (s, 1H), 2.40 (s, 3H), 1.54 (s, 6H); RP18-HPLC RT: 5.05 minutes; API MS: 415 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:27]2[CH:35]=[CH:34][C:30]([C:31]([Cl:33])=[O:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[ClH:33].[C:21]1([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[O:32])=[CH:34][CH:35]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1ccc(-c2ccccc2)cc1
Yield: 61.3 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.89 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 1.08 ml (4.98 mmol) of 4-phenylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 980 mg of the desired compound (free base) (67.8%, pale yellow powder), mp: 169.0°-170.0° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:9]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc[nH]n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
To a solution of benzyl bromide (0.29 g) in N,N-dimethylformamide (9 ml) was added 1H-pyrazole-3-carboxaldehyde (0.15 g) and potassium carbonate (0.24 g). The mixture was stirred at room temperature for 24 hours, silica gel was added, the solvent removed by evaporation and the crude material purified by chromatography (isohexane:ether, 2:1) to give the product as an oil (0.18 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([OH:12])=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[NH2:7][C:5]1[CH:4]=[C:3]([C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[N:2]([CH3:1])[CH:6]=1
Reactant: C1COCCN1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Product: Cn1cc(N)cc1C(=O)N1CCOCC1

Procedure:
(4-amino-1-methyl-1H-pyrrol-2-yl)(morpholino)methanone was prepared as in Example 239 (Steps i-ii) using 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid and morpholine:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)=[CH:4][CH:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.C(O)(=O)C>[CH2:27]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:7][N:8]2[C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(N)cc32)n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(NCc4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of the compound of Example 4 (10 mg) in dichloromethane (350 μL, manufactured by Kanto Chemical Co., Inc.), acetic acid (10 μL, manufactured by Wako Pure Chemical Industries, Ltd.), benzaldehyde (4 mg, manufactured by Nacalai Tesque, Inc.) and sodium triacetoxyborohydride (17.7 mg, manufactured by Sigma-Aldrich Corp.) were added, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 2.4 mg of the title compound. LC-MS: HPLC retention time 5.83 minutes, m/z 519 (M+H), condition B-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 63 %

Procedure:
Upon boiling a solution of 15.1 g 3-nitrobenzaldehyde and 26.0 g amidinoacetic acid ethyl ester in 250 ml ethanol for 2 hours, 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 175° - 176°C (ethanol) is obtained. Yield: 63% of theory.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=1)(=[O:7])[CH3:6].C(OC1C=C(C(Cl)=O)SC=1)(=O)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([NH2:41])=[O:40])[C:34](=[O:42])[CH2:33]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([NH2:41])=[O:40])[C:34](=[O:42])[CH:33]2[C:14](=[O:16])[C:11]1[S:12][CH:13]=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(=O)Oc1csc(C(=O)O)c1
Agent: CC(=O)Oc1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 81.5 %

Procedure:
The title compound was prepared according to the procedure of Example 32. The reaction of 15 ml of thionyl chloride with 3.58 g (19.23 mmoles) of 4-acetoxy-2-thiophenecarboxylic acid (prepared according to Bohlmann, F., et al., Chem. Ber. 106:497 (1973)) gave a yellow oil. A 3.32 g (16.22 mmoles) sample of 4-acetoxy-2-thiophenecarbonyl chloride was coupled to 2.85 g (13.52 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 4.16 g (34.07 mmoles) 4-(N,N-dimethylamino)pyridine to give 5.40 g of crude yellow product. Purification by recrystallization gave 4.18 g (11.02 mmoles, 82%) of pure title compound as a yellow solid, m.p. 222-224° C. (acetic acid).
Reaction SMILES: CN(C)C.[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH2:20][CH2:21][OH:22])[C:14]=1[CH3:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O.CO>[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH2:20][CH2:21][O:22][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=1[CH3:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Agent: CN(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)(C)C
Reaction time: 16 h
Yield: 60 %

Procedure:
Trimethylamine (4.7 ml) was added with stirring to a solution of 3-benzyloxy-1-(2-hydroxyethyl)-2-methylpyridin-4-one (2 g) in dimethylformamide (40 ml) and the solution was then heated under reflux while pivaloyl chloride (1 ml) was added dropwise. The mixture was refluxed at 78° C. for two hours whilst monitoring by thin layer chromatography (1:1 v/v ethyl acetate:methanol) when very little change of the mixture was obtained. Further trimethylacetylchloride (3 ml) was therefore added and refluxing continued for another 16 hours. The solution was evaporated to dryness, the resultant solid was dissolved in dichloromethane (100 ml) and this solution was washed with sodium bicarbonate solution (0.05M, 4000 ml) and the organic phase was then dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resultant crude product was flash chromatographed (silica gel, Kieselgel 60,7754, 20 mm×300 mm column; eluting with acetonitrile:ethyl acetate, 1:9 v/v) to provide the title compound in 60% yield as a colourless solid, m.p. 103°- 105.8° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[O:13][C:10]3([CH2:12][CH2:11]3)[CH2:9][NH:8][C:7]=2[CH:14]=1.[N:17]([O-])=O.[Na+]>C(O)(=O)C.CO.O>[NH2:17][N:8]1[C:7]2[CH:14]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=[CH:5][C:6]=2[O:13][C:10]2([CH2:11][CH2:12]2)[CH2:9]1
Reactant: FC(F)(F)c1ccc2c(c1)NCC1(CC1)O2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: NN1CC2(CC2)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
3,4-Dihydro-6-trifluoromethyl-2H-1,4-benzoxazine-2-spiro-cyclopropane (930 mg) was dissolved in 0.6 ml of acetic acid and 10 ml of methanol. Added dropwise to the resulting solution was a solution of 616 mg of sodium nitrite in 2 ml of water. The reaction mixture was stirred for 3 hours at room temperature, poured into water and then extracted with chloroform. The organic layer was washed with saturate saline and then dried over anhydrous magnesium sulfate. The chloroform was distilled off and the residue was dissolved in 1.1 ml of acetic acid and 12 ml of ethanol. Zinc powder (1.13 g) was added little by little, followed by stirring for 2 hours at room temperature. Insoluble substance was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform. The solution so formed was successively washed with a 10% aqueous solution of sodium hydroxide, water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography, whereby 707 mg of the title compound were obtained (yield 71%).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH:43]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CCN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 23.3 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol), 3-methylbutanal (20 μl, 0.186 mmol), acetic acid (11 μl, 0.181 mmol), and sodium triacetoxyborohydride (53 mg, 0.248 mmol) were processed as described in Example 27 to provide the title compound (23 mg, 23%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.79 (s, 2H), 7.29-7.07 (m, 10H), 5.20 (s, 4H), 4.79 (br s, 2H), 3.85 (m, 2H), 2.83 (dd, 2H), 2.73 (m, 2H), 2.43 (m, 5H), 1.46 (m, 2H), 1.17 (m, 2H), 0.82 (d, 6H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]([NH2:36])[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1>>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]([NH:36][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:22])[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(Cc1cccs1)c1cccs1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1cccs1)c1cccs1
Yield: 40 %

Procedure:
The title compound was prepared in a yield of 40% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1,2-di(2-thienyl)ethylamine.