Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][OH:26].CCOC(/N=N/C(OCC)=O)=O.O[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[C:42](=[O:58])[N:43]([CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[C:44]2=[O:49]>C1COCC1.CO>[O:57]=[C:51]1[CH:50]([N:43]2[C:44](=[O:49])[C:45]3[C:41](=[CH:40][CH:48]=[CH:47][C:46]=3[O:26][CH2:25][C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[C:42]2=[O:58])[CH2:55][CH2:54][C:53](=[O:56])[NH:52]1
Reactant: OCc1ccco1
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a solution of triphenylphosphine (630 mg, 2.4 mmol) and furan-2-yl-methanol (0.17 mL, 2.0 mmol) in THF (10 mL) was added a solution of DEAD (0.38 mL, 2.4 mmol) in THF (0.6 mL) at 0° C. After 5 min, 4-hydroxy-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (550 mg, 2.0 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and kept for 4 h. The solvent was removed in vacuo, and the residue was purified by column chromatography (Silca Gel) to give an oil. The oil was slurried in methanol (10 mL) for 3 h to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(furan-2-ylmethoxy)-isoindole-1,3-dione as a yellow solid (310 mg, 44% yield): mp, 184-186° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H, CHH), 2.42-2.61 (m, 2H, CH2), 2.80-2.95 (m, 1H, CHH), 5.07 (dd, J=5, 13 Hz, 1H, NCH), 5.35 (s, 2H, CH2), 6.49 (dd, J=2, 3 Hz, 1H, Ar), 6.68 (d, J=8 Hz, 1H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.68-7.71 (m, 2H, Ar), 7.83 (t, J=8 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.93, 48.77, 62.55, 110.72, 111.38, 115.72, 116.64, 120.35, 133.35, 136.89, 143.99, 149.15, 155.12, 165.21, 166.73, 169.88, 172.76; Anal Calcd for C18H14N2O6+0.1H2O: C, 60.71; H, 4.02; N, 7.87; H2O, 0.51. Found: C, 60.47; H, 3.97; N, 7.73; H2O, 0.38.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)=O>C(O)(=O)C>[CH3:19][C:15]1[N:14]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(C(=O)C=CN(C)C)n1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Cc1cccc(-c2ccnc3ccnn23)n1

Procedure:
A mixture of 0.84 g. of 3-aminopyrazole and 1.90 g. of 3-dimethylamino-1-(6-methyl-2-pyridyl)-2-propen-1-one and 25. ml. of glacial acetic acid is heated on a steam bath for 4 hours. The solvent was removed under reduced pressure. The residue is dissolved in dichloromethane and the solution passed through a short column of hydrous magnesium silicate. The element is concentrated and diluted with hexane to give 1.15 g. of crystals, m.p. 126°-127° C.
Reaction SMILES: C(O[C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:14])[CH:9]2[NH2:13])[C:6]=1[C:15]([OH:17])=[O:16])(=O)C.[NH2:18][C:19]([CH:27]([F:29])[F:28])([CH2:23][CH2:24][CH2:25][NH2:26])[C:20](Cl)=[O:21].[CH2:30]([O:32][C:33](=[O:35])[CH3:34])C>>[NH2:18][C:19]([CH:27]([F:29])[F:28])([CH2:23][CH2:24][CH2:25][NH2:26])[C:20]([NH:13][CH:9]1[C:8](=[O:14])[N:7]2[CH:10]1[S:11][CH2:12][C:5]([CH2:30][O:32][C:33](=[O:35])[CH3:34])=[C:6]2[C:15]([OH:17])=[O:16])=[O:21]
Reactant: CCOC(C)=O
Reactant: NCCCC(N)(C(=O)Cl)C(F)F
Reactant: CC(=O)OC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)(CCCN)C(F)F)C2SC1

Procedure:
A mixture of 1 g of 3-acetyloxy-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 2,5-diamino-2-difluoromethylvaleric acid chloride wherein the free amino groups are protected with tert-butoxycarbonyl in 50 ml of ethylacetate is refluxed for 2 hours after which the solvent is removed leaving a residue which is treated with mild acid and chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[2,5-diamino-2-difluoromethylvaleryl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])=[O:4].[OH-].[Li+]>C1COCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:3]([OH:4])=[O:2])=[O:11])[CH:13]=1
Reactant: COC(=O)C1CCCN1C(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCN1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 1-(pyridine-3-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester (1.3 g, 5.4 mmol), in THF (13 mL) was added lithium hydroxide (0.34 g, 8.1 mmol) in water (1.3 mL) at room temperature (25° C.). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 h. THF was evaporated from the reaction mixture, dissolve the residue in methanol acidified to pH=4, filtered and evaporated the sticky liquid on evaporation was triturated with diethyl ether, to obtain required compound as off-white solid (1.0 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(SC)cc1O
Reactant: CC(C)(C)OC(=O)NCCCO
Product: COC(=O)c1ccc(SC)cc1OCCCNC(=O)OC(C)(C)C

Procedure:
Methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoate was prepared (7.0 g, 82%) as described in Example 1-D from methyl 2-hydroxy-4-(methylthio)benzoate and 3-tert-butoxycarbonylaminopropanol.
Reaction SMILES: O=C(C)[CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[Na].P([O-])(OCC)OCC.[C:23]([NH2:27])(=[O:26])C=C.[CH3:28][C:29]([CH3:31])=[O:30].[CH3:32][C:33]([CH3:35])=O.C(O)(=O)C>C(O)C>[CH3:32][C:33]([NH:27][C:23](=[O:26])[C:4]([P:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])=[O:12])=[CH2:3])([CH3:35])[CH2:28][C:29](=[O:30])[CH3:31]
Reactant: CC(C)=O
Reactant: C=CC(N)=O
Reactant: CCOP(=O)(CCC(C)=O)OCC
Agent: CCOP([O-])OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: C=C(C(=O)NC(C)(C)CC(C)=O)P(=O)(OCC)OCC
Yield: 97 %

Procedure:
Using the same procedure of Example 1 for the preparation of diethyl 3-oxobutylphosphonate, a solution prepared from the reaction of 3.1 grams (0.135 mole) of sodium with 63 ml of anhydrous ethanol was added under nitrogen and drying conditions with stirring at room temperature to 152 grams (1 mole) of diethyl phosphite. To this solution was then added over a one hour period maintaining the internal temperature at 30°-40° C. with external cooling, 169 grams (1 mole) of diacetone acrylamide. The solution was then stirred for another hour at 24° C. before 8.2 grams (0.135 mole) of acetic acid was slowly added to bring the pH to 5. The solution was dried at 70° C./16 mm and topped off by distillation for 30 minutes with a maximum pot temperature of 120° C. at 0.2 mm. The pot residue (316 grams) was the desired N-(1,1-dimethyl-3-oxybutyl)-2-diethylphosphonoacrylamide in a 97% yield. Structure of the desired product with a purity of about 95% was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Cl:12])[CH:5]=1.[C:14]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=O)(=[O:16])[CH3:15].O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[C:14]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[N:11][C:7]1[C:6]([Cl:12])=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:9][C:8]=1[Cl:10])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)N1CCNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Cl)c(N=C2NCCN2C(C)=O)c(Cl)c1
Yield: 75.2 %

Procedure:
Methyl-4-amino-3,5-dichlorobenzoate (16.8 g, 31 mmole), 1-acetyl-2-imidazolidone (4.3 g, 33.5 mmole) in phosphoryl chloride (44 ml) were stirred at 50° C. for 3 days. After cooling the phosphoryl chloride was evaporated to give an oily residue. Iced water was added to the residue which was then basified with aqueous sodium hydroxide. The mixture was extracted with methylene chloride which was then washed with water, dried (magnesium sulphate) and evaporated to give a creamy solid. This solid was recrystallised from toluene to give the title compound (7.7 g) mp 188°-189° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH3:15][N:16]([CH2:27][CH2:28][CH2:29][CH2:30]Br)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>CN(C)C=O>[CH3:15][N:16]([CH2:27][CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CN(CCCCBr)S(=O)(=O)c1ccc(F)cc1
Reactant: COc1cccc2c1CC(CN)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC(CNCCCCN(C)S(=O)(=O)c1ccc(F)cc1)CC2

Procedure:
The compound is prepared from 1 g of 2-aminomethyl-8-methoxytetralin (5.2mmol), 1.7 g of N-methyl-N-(4-bromobutyl)-4-fluorophenylsulphonamide (5.2 mmol) and 0.73 ml of triethylamine (5.2 mmol) in 20 ml of dimethylformamide analagously to the working directions of Example 47.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:57]/[O:58][CH3:59])/[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][I:38])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]1([P:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C1C=CC=CC=1>[I-:38].[CH3:59][O:58]/[N:57]=[C:26](/[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:22][CH:23]=1)\[C:27]([NH:29][CH:30]1[C:55](=[O:56])[N:32]2[C:33]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:34]([CH2:37][P+:66]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH2:35][S:36][C@H:31]12)=[O:28]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-1, 7.8 g, 8.4 mmoles) and triphenylphosphine (4.4 g, 16.8 mmoles) in benzene (160 ml) was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration to afford 8.0 g of the title compound VIII-1. The mother liquor was concentrated and the residue was triturated with n-hexane to yield an additional amount (1.3 g) of VIII-1. Total yield 9.3 g (93%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:27])[C:14]([NH:16][CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+].O>C1COCC1>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[NH:16][C:14](=[O:15])[N:13]([CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=1)[CH3:27])[CH2:19]2
Reactant: COC(=O)c1ccc(OCCN(C)C(=O)NC2C3CC4CC(C3)CC2C4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCOc1ccc(C(=O)O)cc1)C(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 8 h

Procedure:
A solution of 4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid methyl ester 562 mg (1.45 mmol), NaOH 1N 3 ml in THF 5 ml was stirred at RT overnight. Then NaOH 1N 4 ml was added and the reaction mixture stirred overnight. Water was added and the mixture acidified until pH=2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]12([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2>>[C:20]([O:19][C:18](=[O:24])[NH:17][C:11]12[CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12]2)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Product: CC(C)(C)OC(=O)NC12CC1CN(c1ccc([N+](=O)[O-])nc1)C2
Yield: 95.2 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine (50 mg, 0.246 mmol), was combined with tert-butyl 3-azabicyclo[3.1.0]hexan-1-ylcarbamate (48.8 mg, 0.246 mmol), which gave 75 mg of [3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester in 95% yield. MS (ESI) m/e (M+H+): 321.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N-]1C=CN=C1.[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([NH:51][C:52](=[O:55])[CH2:53][CH3:54])[CH:48]=[CH:47][C:46]=2[Cl:56])[N:21]=1)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH:39][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([NH:51][C:52](=[O:55])[CH2:53][CH3:54])[CH:48]=[CH:47][C:46]=2[Cl:56])[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: O=C(O)c1ccccc1Cl
Agent: c1c[n-]cn1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 74 %

Procedure:
By the procedure of Example 1, Step H, 2-chlorobenzoic acid was converted to its imidazolide and reacted with 3-n-butyl-1-[2-chloro-5-(propionylamino)phenyl]-4-[[3-fluoro-2'-sulfamoylbiphenyl-4-yl]methyl]-1H-pyrazole-5-carbonitrile (from Step K). The crude product was purified by semipreparative HPLC on a Zorbax C8 reverse phase column (elution with 75:25 acetonitrile-H2O containing 0.1% TFA), affording a 74% yield of the title compound as a cream-colored, stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 732 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.93 (t, J=7.3 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.40 (m, 2H), 1.68 (m, 2H), 2.39 (q, J=7.5 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H), 3.93 (br s, 2H), 7.1-7.7 (m, 12H), 7.77 (d, J=2.3 Hz, 1H), 8.37 (dd, J=7.9, 1.4 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH3:33])=[O:5].C(N(CC)CC)C.O>C(#N)C>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][N:32]([CH3:33])[C:8]1[CH:9]=[C:10]([O:30][CH3:31])[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[CH:3]=[CH2:2]
Reactant: COc1cc(N(C)CCN(C)C)c(NC(=O)CCCl)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
To a stirred solution of 3-chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide (Intermediate 174, 31.5 g, 58.76 mmol) in acetonitrile (310 mL) was added triethylamine (17.84 g, 176.28 mmol) at r.t. The resulting mixture was heated to 80° C. for 6 h then cooled to r.t. Water (130 mL) was then added and the mixture stirred for 12 h. The mixture was then filtered, washed with a mixture of water and acetonitrile (160 mL, 1:1) and dried at 50° C. for overnight to give the title compound (19.2 g, 94%) as a solid form identified herein as polymorphic form D. 1H NMR: 2.69 (3H, s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.28 (1H, d), 6.67 (1H, dd), 7.05-7.23 (2H, m), 7.29 (1H, t), 7.43 (1H, d), 7.56 (1H, d), 8.21 (2H, s), 8.81 (1H, s), 9.47 (1H, s), 9.52 (1H, s), m/z: ES+ MH+ 500.26.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C@H:12]([CH2:20][OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(N(CC)CC)C>[C:14]1([CH2:13][CH:12]([NH:11][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[Cl:1])[CH2:20][OH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N[C@H](CO)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC(CO)Cc1ccccc1)c1cccnc1Cl

Procedure:
10.0 g of chloronicotinic acid were reacted with 9.7 g of phenylalaninol in 250 ml of CH2Cl2 in the presence of 13.0 g of EDC, 2.9 g of HOBT and 9.6 g of triethylamine analogously to Example 1c, 17.3 g (94%) of the product being obtained.
Reaction SMILES: [CH:1]1([C:6](=O)[C:7]([O:9]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:13][C:14]1[CH:33]=[CH:32][CH:31]=[CH:30][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][CH:23]=N[CH:25]=[C:20]2[C:19]([C:26](=[NH:29])[NH:27][NH2:28])=[N:18]1.[CH2:34](O)C>>[CH:1]1([C:6]2[N:28]=[N:27][C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:34][CH:25]=4)[N:17]([CH2:16][C:15]4[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=4[F:13])[N:18]=3)=[N:29][C:7]=2[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(=O)C1CCCC1
Reactant: CCO
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1

Procedure:
1.197 g (7.035 mmol) of ethyl cyclopentyl(oxo)acetate in 15 ml of ethanol were initially introduced and heated to reflux. Then, 2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 20 ml of ethanol were added and the mixture was heated under reflux overnight. After cooling, the mixture was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, ratio 45:55). This gave 749 mg of the target compound (26% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][Br:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C>CN(C)C=O>[Br-:12].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(CBr)cc1OC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC
Product: [Br-]
Yield: 80.3 %

Procedure:
3,4-Dimethoxy-α-bromotoluene (11.6 g) [Gordon N. Walker et al., J. Org. Chem., 26, 2740 (1961)] and triphenylphosphine (13.11 g) are heated in dimethylformamide (150 cc) at 75° C. for 1 hour 30 minutes. After addition of ethyl ether (700 cc) to the reaction mixture and filtration, 3,4-dimethoxyphenylmethyltriphenylphosphonium bromide (19.8 g) is obtained in the form of a white solid melting at 260° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]([O:15]CC)(=[O:14])C>>[CH2:1]([NH:5][C:12](=[O:14])[O:15][C:8]1[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: CCCCNC(=O)Oc1ccccc1
Yield: 71.97 %

Procedure:
n-Butylamine (4.9 ml, 50 mmol) was used for the same reaction as in Production Example 310-1, and purification was performed by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (8.11 g, 41.97 mmol, 71.97%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 79 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-xylopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-xylopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35](O)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33].CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)c(F)c4)c3)c2c1
Yield: 11 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 3,4-difluorophenylacetic acid (0.12 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 25 mg (10% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.52–7.3 (m, 4H), 7.2 (m, 1H), 3.7 (s, 2H), ES-MS (m/z) 407 [M+H]+.