Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24]Cl)[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[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.[I-:79].[Na+].C(O)(C)C>CN(C)C=O>[I-:79].[C:1]([NH:9][CH:10]([C:44]([O:46][CH:47]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][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)[CH2:22][S:23][C@H:18]12)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(CCCC(NC(=O)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of benzhydryl 7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-chloromethyl-3-cephem-4-carboxylate (102 g) in N,N-dimethylformamide (150 ml) were added triphenylphosphine (48.5 g) and sodium iodide (18.4 g), and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was added dropwise to isopropyl alcohol (5000 ml), and the precipitated material was collected by filtration and washed with diisopropyl ether to obtain [7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyl-triphenylphosphonium iodide (123.5 g), mp 165°-175° C. (dec.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH2:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[CH3:14][O:15][CH2:16][N:17]=[C:18]=[O:19]>>[CH3:14][O:15][CH2:16][NH:17][C:18]([NH:1][CH:2]1[CH2:3][C:4]([CH3:12])([CH3:13])[N:5]([CH2:10][CH3:11])[C:6]([CH3:8])([CH3:9])[CH2:7]1)=[O:19]
Reactant: COCN=C=O
Reactant: CCN1C(C)(C)CC(N)CC1(C)C
Product: CCN1C(C)(C)CC(NC(=O)NCOC)CC1(C)C

Procedure:
46 parts of N-methoxymethyl-N'-1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl urea were obtained by reacting 36.6 parts of 4-amino-1-ethyl-2,2,6,6-tetramethylpiperidine with methoxymethyl isocyanate in the same way as described in Example 22b).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5](O)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOCC(O)CNC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCC(CNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 3.73 g of rac-tert-butyl (3-ethoxy-2-hydroxypropyl)carbamate (17 mmol, 1 equivalent), 2.50 g of phthalimide (17 mmol, 1 equivalent) and 6.69 g of triphenylphosphine (25.52 mmol, 1.5 equivalents) were initially charged in 70 ml of dry THF. 5.06 ml of diisopropyl azodicarboxylate (25.5 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with methanol, acetonitrile and water to 90 ml and purified by preparative HPLC (column material: Sunfire C18 5 μm 75×30 mm; flow rate 56 ml/min; mobile phase: 45% Milli-Q-water/50% acetonitrile/5% 1% aqueous formic acid; injection volume: 0.5 ml; detection wavelength: 210 nm). This gave 4.88 g of the title compound (82% of theory).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 47 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (100 mg, 0.248 mmol) was suspended in dichloromethane (3.0 mL), and the suspension was added with triethylamine (0.104 mL, 0.744 mmol) and methanesulfonyl chloride (0.029 mL, 0.372 mmol), followed by stirring at room temperature for 13 hours. The solvent was evaporated under reduced pressure, and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(methanesulfonylamino)propoxy]-7-iodoisoindolinone (51.8 mg, yield 47%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][N:13]2[N:12]=1.[N:21]1([C:25]([C:27]2[CH:31]=[N:30][N:29]([CH3:32])[C:28]=2[C:33](O)=[O:34])=[O:26])[CH2:24][CH2:23][CH2:22]1>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH:19][C:33]([C:28]3[N:29]([CH3:32])[N:30]=[CH:31][C:27]=3[C:25]([N:21]3[CH2:24][CH2:23][CH2:22]3)=[O:26])=[O:34])[CH:17]=[CH:18][N:13]2[N:12]=1
Reactant: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3OCCF)nc2c1

Procedure:
This compound was prepared in analogy to 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-dimethylamide 3-({2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide) (Example 100) from 2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (127 mg, 0.47 mmol) and 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (130 mg, 0.62 mmol). Yield: 95 mg (33%); off-white solid; LC-MS: m/z=464.2 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[NH:26][C:27]([C:29]2[N:30]=[N:31][N:32]([OH:34])[CH:33]=2)=[O:28])=[CH:20][CH:19]=1.CC(C)=O.CCN(CC)CC>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[NH:26][C:27]([C:29]2[N:30]=[N:31][N:32]([O:34][CH2:2][C:3]3[O:4][C:5](=[O:9])[O:6][C:7]=3[CH3:8])[CH:33]=2)=[O:28])=[CH:22][CH:23]=1
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: Cc1oc(=O)oc1CCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1oc(=O)oc1COn1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3Cl)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (14.9 mg, 100 μmol) was added to a solution of (R)-3-[N-(2′,5′-dichlorobiphenyl-4-ylmethyl)-N′-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound (10.0 mg, purity 99%) as a white solid. MS m/z [M+H]+ calc'd for C24H21Cl2N5O8, 578.08. found 578.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=O)=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26].Cl.[NH2:29][OH:30]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=[N:29][OH:30])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26]
Reactant: NO
Reactant: CC(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(C(=NO)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone, prepared as described in Procedure 3, 4, 59 and 68, (207 mg, 0.53 mmol) in pyridine (1.5 mL) was added hydroxylamine hydrochloride (192 mg, 2.8 mmol) and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 mL). The organic portion was washed with 1 N HCl (2×20 mL), water (20 mL) and sat. NaCl (20 mL), then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO (40 g silica gel column, 0-30% EtOAc/hexane over 30 min) to yield (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone oxime (216 mg, 77% yield) as a colorless oil. LCMS: RT=2.13 min [M+H] 408.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([C:18]#[N:19])=[N:8]2)=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:3]=1.[O:26]=[C:27]1[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:30](=[O:36])[CH2:29][S:28]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:29]4/[C:30](=[O:36])[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:27](=[O:26])[S:28]/4)=[CH:13][CH:14]=3)[C:9]([C:18]#[N:19])=[N:8]2)=[C:4]([C:22]([F:24])([F:25])[F:23])[CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=O
Reactant: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Product: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(CC(=O)O)C3=O)cc12

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 1-(4-chloro-2-trifluoromethyl-benzyl)-5-formyl-1H-indazole-3-carbonitrile and (2,4-dioxothiazolidin-3-yl)-acetic acid following General Procedure F.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]1[CH2:29][CH2:28]1)(=[O:24])[NH2:25]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=395.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:22][NH2:23]>C(O)C>[CH3:18][Si:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:22][NH2:23])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(NN)nn2)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a suspension of 3-chloro-6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-pyridazine (640 mg, 2.06 mmol) in ethanol (5 mL) was added hydrazine monohydrate (1.34 mL, 1.4 g, 28 mmol). The reaction mixture was stirred at 50° C. for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide title compound as a white solid (500 mg, 1.6 mmol, 79% yield): 1H NMR (DMSO-d6) δ 0.00 (9H, s), 0.89 (2H, t), 3.61 (2H, t), 4.34 (2H, bs), 5.48 (2H, s), 7.09 (1H, d), 7.69 (1H, d), 7.94 (1H, bs), 8.08 (1H, s), 8.44 (1H, s); MS (m/z) 307 [M+H+]+.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: CNC
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)N(C)C

Procedure:
Three g of the product of Example 65 was reacted with 4 ml of 45% aqueous dimethylamine, substantially as shown in Example 60, to obtain 1.2 g of the desired product, m.p. 102°-104°.
Reaction SMILES: [Si]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18](=[N:20][OH:21])[NH2:19])[S:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[CH2:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][CH:27]=1)[CH:23]([CH3:25])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:22]([C:26]1[CH:27]=[CH:28][C:29]([C:30]2[O:21][N:20]=[C:18]([C:16]3[S:17][C:13]4[CH2:12][CH2:11][CH2:10][CH:9]([OH:8])[C:14]=4[CH:15]=3)[N:19]=2)=[CH:33][CH:34]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C(N)=NO)cc21
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)Cc1ccc(-c2nc(-c3cc4c(s3)CCCC4O)no2)cc1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 2 (2c) using 4-{[t-butyl(dimethyl)silyl]oxy}-N′-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboximidamide (0.15 g, 0.50 mmol) that was obtained in Example 8 (8e), 4-isobutylbenzoic acid (89 mg, 0.50 mmol), N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (0.75 ml, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (92 mg) in a yield of 52% as a colourless oily product.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH2:2][CH:3]=[CH2:4].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CN(C=O)C.CCOCC>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][N:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[C@H:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[CH3:21]
Reactant: C=CCCN[C@@H](C)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCCN(CC(=O)OCC)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of But-3-enyl-((S)-1-phenyl-ethyl)-amine (6.37 g, 36.4 mmol) in 150 mL of DMF at 0° C. is added K2CO3 (10.0 g, 72.8 mmol) in small portions. After stirring at 0° C. for 10 min, ethylbromoacetate (8.35 g, 54.6 mmol) is added slowly. The reaction mixture, a white suspension, is stirred at r.t. overnight/16 hrs. The solution is diluted with 200 mL of ether, and washed with 3×100 ml of water. The crude product is purified by chromatography (hexane/CH2Cl2: 50/50) to give a pale liquid (8.5 g, 94.5%). (NMR and MS data confirmed, U-4117-58).
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:11]=1[F:24])C1C=CC=CC=1.[OH-].[K+].O.Cl>O1CCCC1>[Cl:16][C:15]1[C:10]([C:9]([OH:25])=[O:8])=[C:11]([F:24])[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Yield: 85.6 %

Procedure:
To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (49, 6.00 g, 15.6 mmol) in tetrahydrofuran (100 mL) was added 1.0 M aqueous potassium hydroxide (100 mL). The reaction was heated to reflux overnight. The reaction was poured into water, acidified to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid 115 (3.95 g, 85.8%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]([NH:26][CH2:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:23]([N:26]([CH2:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:25])([CH3:24])[CH3:22]
Reactant: Cn1nnnc1CNC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnnc1CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-methyl-N-((1-methyl-1H-tetrazol-5-yl)methyl)propan-2-amine hydrochloride in the presence of TBTU and DIEA to obtain the title compound as yellow solid; MS (EI): m/e=436.5 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.[I:24](O)(=O)=O.II>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([I:24])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: [O-][I+2]([O-])O
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2n1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2n1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 400.7 %

Procedure:
2 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 3) in 20 ml of glacial acetic acid is combined with 0.5 ml of water, 0.12 ml of concentrated sulfuric acid, 336 mg of iodic acid, and 878 mg of iodine and agitated for 2.5 hours at 90° C. After concentrating the reaction mixture, the latter is combined with 50 ml of water, gently made alkaline with ammonia, and suctioned off, thus obtaining 2.81 g of 8-iodo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 264°-266° C. under decomposition.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[I:20].B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[I:20]
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1I
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
To a solution of 2-(4′-methylamino-3′-iodophenyl)-6-methoxy benzothiazole (12 mg, 0.03 mmol) dissolved in CH2Cl2 (4 mL) was added BBr3 (400 μl, 0.4 mmol, 1M in CH2Cl2) under N2. The reaction was allowed to stir at room temperature for 18 hr. Water was then added to quench the reaction and the solution was neutralized with NaHCO3, extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over MgSO4 and evaporated. The residue was purified with preparative TLC (Hexane:EA=7:3) to give 2-(4′-methylamino-3′-iodophenyl)-6-hydroxy benzothiazole (5 mg, 43%) as brown solid. 1HNMR (300 MHz, CDCl3) δ(ppm): 8.37 (d, H=2.0 Hz, 1H), 7.88 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 6.96 (dd, J1=2.5 Hz, J2=8.8 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 2.96 (s, 3H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28]O)=[O:25])([CH3:22])([CH3:21])[CH3:20].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1cc(CC=C(C)C)c(OC)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(CC=C(C)C)c(OC)cc1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 49 %

Procedure:
2.00 g of methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate, 1.29 g of N-(t-butoxycarbonyl)-2-aminoethanol, and 2.31 g of triphephenylphosphine were dissolved in 50 ml of tetrahydrofuran. The obtained mixture was cooled on ice. Thereafter, 1.73 ml of diisopropylazodicarboxylate was added to the reaction solution at the same temperature, and the temperature was then raised to a room temperature. After completion of the reaction, the reaction solution was concentrated. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.54 g of methyl 2-(2-t-butoxycarbonylaminoethoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate. The obtained product was dissolved in 15 ml of methanol, and the obtained mixture was cooled on ice. Thereafter, 10 ml of a 4 N hydrochloric acid-ethyl acetate solution was added to the reaction solution. After completion of the reaction, the reaction solution was concentrated under a reduced pressure. Ethyl acetate was added to the residue, and the obtained mixture was adjusted to be approximately pH 11 with addition of a 5 N sodium hydroxide aqueous solution and a saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. 1.06 g of the obtained residue was dissolved in 20 ml of toluene, and the obtained solution was heated to reflux. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 601 mg of the subject compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:30]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: Cc1cc(CCl)no1
Reactant: Nc1nc(NCC2CCCN2)nc2cc(-c3ccco3)nn12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN2CCCC2CNc2nc(N)n3nc(-c4ccco4)cc3n2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 7-furan-2-yl-N2-pyrrolidin-2-ylmethyl-pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.3 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 3 H). MS: m/z: 395 [M+H]+.