Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([OH:9])=[O:8].[CH:20](O)([CH3:22])[CH3:21]>>[CH:20]([O:8][C:7](=[O:9])[CH:6]([NH2:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:22])[CH3:21]
Reactant: CCCCCCCCCCC(N)C(=O)O
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCC(N)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of isopropanol is stirred at 0° C. under argon and mixed drop by drop with 3.12 ml (41.6 mmol) of thionyl chloride. 30 minutes later, 7.40 g (34.4 mmol) of α-aminolauric acid is added in portions, stirred for one hour at room temperature and the batch then is allowed to reflux for two hours. After cooling off to room temperature, the batch is completely concentrated by evaporation, the residue is taken up in tert-butyl methyl ether and shaken out from aqueous sodium carbonate solution. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]1([C:33]([F:36])([F:35])[F:34])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:5][CH:4]=[C:3]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([C:33]([F:34])([F:36])[F:35])[CH2:7][C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:47]4[CH2:46][CH2:45][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:49][CH2:48]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:5][CH:4]=[C:3]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C(F)(F)F)CC(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)=CC=C1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)C2=CC=C(c4ccccc4)C(C)(C(F)(F)F)C2)C3)CC1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
10-(2-Methyl-2-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.0 g, 2.04 mmol), 1-(tert-butoxycarbonyl)piperazine (0.46 g, 2.47 mmol) and 1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) were dissolved in N,N-dimethylformamide (8 mL). 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.43 g, 2.24 mmol) was then added followed by N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography using a solvent gradient from 30% to 50% of ethyl acetate in hexane provided 1.1 g of the desired title compound as a white foam, m.p. 104–121° C. This material was redissolved in dichloromethane and concentrated in vacuo to a white foam.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].Cl.O=[C:9]1[CH:14]([C:15](OCC)=[O:16])[CH2:13][CH2:12][N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1>C(O)C>[CH3:4][C:3]1[N:6]=[C:13]2[CH2:12][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:9][CH:14]2[C:15](=[O:16])[N:5]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Sodium metal (4.4 g, 0.19 mol) was dissolved in ethanol (300 ml) and acetamidine hydrochloride (9.3 g, 0.1 mol) was added. After 30 min, commercially available ethyl 3-oxo-1-(phenylmethyl)-piperidine-4-carboxylate hydrochloride (25 g, 0.084 mol) was added and the reaction mixture was refluxed for 18 h. The reaction mixture was filtered and the concentrated in vacuo to give the title compound (20 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:45]=[C:35]5[CH2:36][N:37]([C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:45]=[C:35]5[CH2:36][N:37]([C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of 148e (90 mg, 0.141 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added NaBH4 (10.7 mg, 0.282 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with aqueous NH4Cl and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 148 (40 mg, 44%) as a white solid. MS-ESI: [M+H]+ 640.8. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.35-8.28 (m, 1H), 8.06 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (dd, J=1.0, 13.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 6.01 (s, 1H), 4.90-4.88 (m, 1H), 4.78-4.76 (m, 1H), 4.64-4.62 (m, 1H), 4.42-4.41 (m, 2H), 4.03-3.92 (m, 4H), 3.59 (s, 3H), 3.00-2.96 (m, 1H), 1.40 (s, 9H), 1.04-1.01 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH2:10]S[C:8]2=[N:11][N:12]=[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=3[CH3:25])[N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.Cl.[PH2](O)=O>>[C:1]([C:5]1[CH:10]=[C:8]2[NH:11][N:12]=[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=3[CH3:25])[N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1-c1nnc2n1N=C(C(C)(C)C)CS2
Agent: Cl
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)c([N+](=O)[O-])c(C)c1-c1n[nH]c2cc(C(C)(C)C)nn12

Procedure:
Process of claim 2 wherein 6-t-butyl-3-(3-nitro-2,4,6-trimethylphenyl)-7H-1,2,4-triazolo-[3,4-b][1,3,4]thiadiazine is reacted with acetic anhydride and the acylated intermediate thereby produced is reacted with HCl in the presence of hypophosphorous acid to produce 6-t-butyl-3-(3-nitro-2,4,6-trimethylphenyl)-1h-pyrazolo-[5,1-c]-1,2,4-triazole.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][N+:5]([O-:7])=O.[O:10]1[CH2:14][CH:13]=[CH:12][CH2:11]1>>[CH3:9][O:8][CH:3]([O:2][CH3:1])[C:4]1[C@H:12]2[CH2:11][O:10][CH2:14][C@H:13]2[O:7][N:5]=1
Reactant: COC(C[N+](=O)[O-])OC
Reactant: C1=CCOC1
Product: COC(OC)C1=NO[C@@H]2COC[C@H]12

Procedure:
Starting from the commercially available 1,1-dimethoxy-2-nitroethane (CAS69425-53-2) and 2,5-dihydro-furan following general procedure A, the product (3aS,6aS)-rel-3-dimethoxymethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole was obtained as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[N+:7]([O-:9])=[O:8].S(OC)(O[CH3:14])(=O)=O>C(O)=O>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:14][N:5]1[C:6]([N+:7]([O-:9])=[O:8])=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: COS(=O)(=O)OC
Agent: Cc1nc[nH]c1[N+](=O)[O-]
Solvent: O=CO
Product: Cc1ncn(C)c1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
127 parts of 4-methyl-5-nitroimidazole is heated under reflux with 350 parts of formic acid and 126 parts of dimethyl sulfate for 4 hours. The formic acid is distilled off in vacuo and the residue is dissolved in 500 parts of water and adjusted to pH 1.8 with aqueous ammonia solution. The mixture is cooled to 5° C. and the unreacted 4-methyl-5-nitroimidazole is suction filtered. The filtrate is adjusted to pH 10 with aqueous ammonia solution and is continuously exhaustively extracted with ethyl acetate. The extract is evaporated in vacuo. The oily residue crystallizes on standing. 47 parts of unreacted 4-methyl-5-nitroimidazole and 66 parts of 1,4-dimethyl-5-nitroimidazole melting at 45° C. are obtained; this is equivalent to a yield of 74% of theory.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[Na+].CCOCC>[CH2:11]([O:18][C:19]([NH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(C(=O)O)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(NC(C(=O)O)c1ccsc1)OCc1ccccc1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
2-Amino-2-(3-thienyl)acetic acid (10 g) is dissolved in 1N sodium hydroxide solution, and 1N sodium hydroxide solution and a solution of benzyloxycarbonyl chloride (13 g) in ether are simultaneously added dropwise thereto at 5° to 10° C. with vigorous stirring. The mixture is stirred at the same temperature for 3 hours. After the reaction mixture is washed, the mixture is acidified and extracted with ethyl acetate. The extract is washed, dried and concentrated to remove solvent. The residue is crystallized with a mixture of ethyl acetate and diisopropyl ether, whereby 2-benzyloxycarbonylamino-2-(3-thienyl)acetic acid (13.6 g) is obtained.
Reaction SMILES: Br[C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Cl-].[Na+].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>[N:12]1([C:3]2[S:4][C:5]3[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[C:2]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCCc2c1sc(N1CCOCC1)c2Br
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: O=C1CCCc2c1sc(N1CCOCC1)c2-c1ccccc1
Temperature: 85 °C
Yield: 19.1 %

Procedure:
To a stirred solution of Example 3 (0.16 g, 0.50 mmol) and Pd(PPh3)4 (0.06 g, 0.05 mmol) in DME (5 mL) was added phenylboronic acid (0.07 g, 0.60 mmol) and aqueous 2M Na2CO3 solution (0.50 mL). The reaction mixture was then heated to 85° C. for 18 h before it was poured into brine (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 1:9 Et2O/DCM) gave the title compound as a white solid (0.03 g, 19%). δH (DMSO-d6) 7.49-7.32 (5H, m), 3.57-3.54 (4H, m) 2.92-2.89 (4H, m), 2.56-2.44 (4H, m), 2.02-1.94 (2H, m). δ 13C (DMSO-d6) 189.9, 162.8, 153.9, 135.2, 129.6 (2×CH), 129.1 (2×CH), 127.8, 124.0, 123.3, 65.7 (2×CH2), 51.6 (2×CH2), 37.8, 25.8, 24.3. LCMS (ES+) 314.0 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(OC(C)(C)C)(=O)CCC(OC(C)(C)C)=O.C([C:27]1[C:28]([NH:37][C:38](=[O:43])[C:39]([CH3:42])(C)C)=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=O.[Cl-].[NH4+]>C1COCC1>[NH:37]1[C:28]2[N:29]=[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]3=[CH:36][C:27]=2[CH:42]=[CH:39][C:38]1=[O:43]
Reactant: CC(C)(C)C(=O)Nc1nc2ccccc2cc1C=O
Agent: CC(C)(C)OC(=O)CCC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=c1ccc2cc3ccccc3nc2[nH]1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 101.9 %

Procedure:
To absolution of THF (15 mL) and LDA (2M in THF, 15.9 mmol, 7.95 mL), cooled to −78° C., was slowly added a solution of di-t-butyl succinate (15.9 mmol, 3.28 g) in THF (3.0 mL). After 15 minutes at −78° C. 3-Formyl-2-pivaloylaminoquinoline (1.92 g, 7.50 mmol) dissolved in THF (10 mL) was added. The clear yellow solution was stirred at −78° C. for 15 minutes and then allowed to warm to room temperature. The solution was poured into saturated aqueous ammonium chloride (200 mL) and extracted with dichloromethane (2×100 mL). The organic phase was dried (MgSO4) and evaporated in vacuo. The crude product of diastereomeric alcohols was heated to reflux for 24 hours in a mixture of THF (5 mL) and HCl (3M, aqueous) and then poured into water (100 mL) and neutralized with K2CO3. The tan precipitate was washed with water (2×25 mL) and dried in vacuo overnight. The crude product (1.60 g) was heated in acetonitrile (50 mL) and filtered while hot. The product was washed with ether (2×25 mL) and dried in vacuo to give 1.50 g (79%) of a material judged to be 61% pure according to HPLC (260 nm).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3CC[CH:24]([NH2:27])[CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[C:37]([F:40])([F:39])[F:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>CO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:27][CH2:24][CH2:23][NH:22][C:20]([NH:19][C:17]2[S:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([O:9][CH3:8])[C:11]=3[N:18]=2)=[O:21])=[CH:31][C:30]=1[C:37]([F:38])([F:39])[F:40]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(N)C3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2sc(NC(=O)NCCNCc3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A solution of the trifluoroacetic acid salt of 3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (176 mg, 0.46 mmol) in methanol (6 ml), 4-fluoro-3-(trifluoromethyl) benzaldehyde (90 mg, 0.46 mmol) and sodium triacetoxyborohydride (293 mg, 1.38 mmol) at 25° C. The resulting solution was stirred at 25° C. overnight. At this time, the reaction mixture was treated with triethylamine (200 mL, 1.44 mmol) and then was stirred for an additional 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 95/5 methylene chloride/methanol) afforded 1-[2-(4-fluoro-3-trifluoromethyl-benzylamino)-ethyl]-3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-urea (37 mg, 18%); ES-HRMS m/e calcd for C17H16F4N6O2S (M+H)+ 445.1065, found 445.1065.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1.Cl.[NH2:31][CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]([NH:31][CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:29])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: NCC(=O)c1ccccc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C/C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.22 mL) in DMF (1 mL) at 0° C. The reaction solution was stirred at 0° C. for 30 minutes, and then α-aminoacetophenone hydrochloride (133 mg) was added in small portions to the reaction solution over 30 minutes. The reaction solution was stirred at 0° C. for 2.5 hours. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 200 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: N1C2C(=CC(CN3C4=NC(C(=O)C)=CN=C4N=N3)=CC=2)C=CC=1.C([O:26][C:27]([C:29]1[N:34]=[C:33]2[N:35]([CH:38]([C:40]3[CH:41]=[C:42]4[C:47](=[CH:48][C:49]=3[F:50])[N:46]=[CH:45][CH:44]=[CH:43]4)[CH3:39])[N:36]=[N:37][C:32]2=[N:31][CH:30]=1)=[CH2:28])C>>[F:50][C:49]1[CH:48]=[C:47]2[C:42]([CH:43]=[CH:44][CH:45]=[N:46]2)=[CH:41][C:40]=1[CH:38]([N:35]1[C:33]2=[N:34][C:29]([C:27](=[O:26])[CH3:28])=[CH:30][N:31]=[C:32]2[N:37]=[N:36]1)[CH3:39]
Reactant: C=C(OCC)c1cnc2nnn(C(C)c3cc4cccnc4cc3F)c2n1
Agent: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: CC(=O)c1cnc2nnn(C(C)c3cc4cccnc4cc3F)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound of 52.4 from 6-(1-(6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-7-fluoroquinoline. 1H-NMR (400 MHz, CDCl3) δ ppm 9.44 (s, 1H), 8.93 (m, 1H), 8.13 (d, 1H), 7.94 (s, 1H) 7.79 (d, 1H), 7.41 (dd, 1H), 6.88 (q, 1H), 2.76 (s, 3H), 2.37 (d, 3H). LCMS (method B): [MH]+=337, tR=2.21 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][N:12]([CH3:16])[C:11](=[O:17])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][N:12]([CH3:16])[C:11](=[O:17])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)n(C)nc2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nn(C)c(=O)cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A solution of the product from step 1 (3.2 g, 14 mmol) in CH2Cl2 (40 mL) was cooled to 0° C. and BBr3 (6.6 mL, 5.0 eq.) was added dropwise. The ice-bath was removed and the reaction was stirred at rt for 1 h, after which the reaction mixture was poured into 50 mL of ice cold saturated NH4Cl solution with stirring. The resulting solid was filtered, and washed with water (3×15 mL) then Et2O (2×15 mL) to give the product of step 2 (0.66 g, 22%): MS m/z 217 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:34]([N:36]([CH2:40][CH3:41])[C:37](Cl)=[O:38])[CH3:35].O>C(Cl)Cl.O1CCCC1>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[N:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
10 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 0.5 mL of methylene chloride and 0.2 mL of tetrahydrofuran, to which 33 mg of triethylamine and 41 mg of N,N-diethylcarbamoyl chloride were added, and stirred at room temperature for 3 days. To the reaction mixture, water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1, developed twice) to obtain 9 mg (69%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Br:21]N1C(=O)CCC1=O>C(Cl)Cl>[Br:21][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[C:2]1=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Product: BrC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Reaction time: 12 h

Procedure:
To a solution of 3 mmols (804 mg) adamantylideneadamantane in 40 cm3CH2Cl2, 6.6 mmols (1.175 g) N-bromosuccinimide was added. The reaction mixture was refluxed and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 and washed twice with water and a saturated Na2S3O3 -solution. The organic layer was dried with MgSO4 and evaporated. The yield of 4-eq.-bromoadamantylideneadamantane having formula 20 was 1.05 g (97%). An analytically pure sample could be obtained by crystallization from acetone and sublimation (115° C./0.002 mm); melting point 130.5-131.5° C. 1H NMR (CDCl3); δ 4.4 (br s, 1H); 3.05 (br s, 1H); 2.8 (br s, 3H); 2.6-1.2 (br m, 22H); 13C NMR (CDCl3); δ 136.9 (s); 131.0 (s); 63.8 (d) and 12 signals between 39.9 and 27.6. Analysis, calculated: 69.16 C; 7.84 H; 23.01 Br; found: 69.21 C; 7.82 H; 22.99 Br. Mass m/e 346:348 (1:1).
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@H:6]1[C:11]([OH:13])=[O:12])=O.C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[C:11]1(=[O:12])[C@@H:6]2[C@@H:5]([CH2:10][CH:9]=[CH:8][CH2:7]2)[CH2:3][O:13]1
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC[C@@H]2CC=CC[C@H]12
Reaction time: 2 h
Yield: 62.3 %

Procedure:
In a stream of nitrogen gas, 20 g of (1R, 2S)-2-methoxycarbonylcyclohex-4-ene-1-carboxylic acid was dissolved in 120 ml of dry tetrahydrofuran, and to the solution, was added 18.2 ml of triethylamine while the solution being cooled by ice. A dry tetrahydrofuran (40 ml) solution of ethyl chloroformate (12.4 ml) was slowly added dropwise to the mixture. While the mixture was being cooled by ice, the mixture was stirred for 2 hours. After filtration of the resulting triethylamine hydrochloride, the filtrate was added dropwise to a H2O (100 ml) solution of NaBH4 (10.3 g) with ice-cooling and the mixture was stirred for 2 hours at room temperature. Then, 2N-HCl was added to the mixture to adjust the pH thereof to 4-5, and THF was distilled off under a reduced pressure. The residue was extracted by ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under a reduced pressure, and the residue was dissolved in 100 ml of toluene. 2.07 g of p-toluenesulfonic acid monohydrate was added to this solution, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Then, the organic layer was dried over anhydrous magnesium sulfate, and after filtration, the filtrate was concentrated under a reduced pressure. The residue was distilled under a reduced pressure, and thus 9.35 g of the titled compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[O:11]=[C:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=2)[NH:13]1>>[OH:21][C:20]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=2)[NH:13][C:12]1=[O:11]
Reactant: N#Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(C#N)cc21
Yield: 50.8 %

Procedure:
With 7.06 g of 2-bromo-1-methoxy-4-methyl benzene and 4.03 g of 2,3-dioxo indoline-5-carbonitrile as starting materials, 3.50 g of the title compound (brown amorphous) was obtained by a similar method to Step 21-1.