Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH2:24][C:23](=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)[N:16]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH2:24][C:23](=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)[N:16]=1
Reactant: O=C1CC(c2ccccc2OCc2ccccc2)=Nc2ccc(N3CCOCC3)cc21
Agent: [Pd]
Solvent: CO
Product: O=C1CC(c2ccccc2O)=Nc2ccc(N3CCOCC3)cc21
Yield: 81.5 %

Procedure:
To a suspension of 113 (0.4 g, 1.0 mmol) in MeOH (400 ml) was hydrogenated in the presence of 10% Pd/C (0.1 g) at 25□ for 3 h. The catalyst was filtered off and the filtrate was evaporated. The crude product was purified by column chromatography (SiO2, CHCl3:MeOH=25:1) to give 134 as yellow solid. (0.3 g, 0.9 mmol). Yield: 81.5%; mp 290-291° C.; MS (EI, 70 eV): m/z 322.2 (M+); IR (KBr): 1612.56 (C═O), 2969.54 (—NH) cm−1; 1H-NMR (MeOD-d4, 400 MHz) δ 3.30 (m, 4H), 3.87 (m, 4H), 4.48 (s, 1H), 6.64 (s, 1H), 7.02 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H); 7.40 (t, J=8.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.65 (d, J=2.0 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H); Anal. Calcd for C19H18N2O3; C, 70.79; H, 5.63; N, 8.69.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)#[N:9].[Cl-].[CH3:28][O:29][C:30](=[O:39])[CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([OH:36])=O>C(Cl)Cl>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH2:25][CH3:26])[C:34](=[O:36])[CH2:33][C:32]([CH3:38])([CH3:37])[CH2:31][C:30]([O:29][CH3:28])=[O:39])=[CH:20][CH:21]=1)#[N:9]
Reactant: COC(=O)CC(C)(C)CC(=O)O
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CC(C)(C)CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.83 ml of triethylamine are added to a solution of 2.19 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine and 2.37 g of 3,3-dimethylglutaric acid monomethyl ester monochloride in 100 ml of CH2Cl2 and the mixture is stirred at room temperature for 2 hours. Extraction twice with 50 ml of water each time and extraction of the aqueous phase with 40 ml of CH2Cl2 produces an organic phase which, after being concentrated by evaporation, yields by the customary procedure 3,3-dimethyl-4-methoxycarbonyl-butanoic acid N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amide that has an Rf value of 0.66 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:23][C:22](=[O:24])[CH2:21][C@@:15]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1
Reactant: C[C@@H]1CC[C@@](CC(=O)O)(Cc2ccccc2)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@]1(Cc2ccccc2)CC[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trimethylsilyldiazomethane (31.5 mL of a 2 M solution in hexanes, 63 mmol) was added dropwise to a stirring solution of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid (10 g, 43 mmol) in toluene (80 mL) and methanol (20 mL) at 0° C. under argon, and the mixture was allowed to warm to room temperature. The mixture was stirred for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (50 mL), washed with saturated sodium hydrogen carbonate solution, dilute hydrochloric acid, dried (MgSO4), and the solvent removed in vacuo to give 10.6 g (100%) of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester;
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH3:20])[CH:3]=1.[C:21](Cl)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]>N1C=CC=CC=1>[C:21]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:12])([F:13])[F:14])=[C:4]([N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[CH3:20])[CH:3]=1)([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22]
Reactant: Cc1nccn1-c1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1cc(-n2ccnc2C)c(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 14.5 g (~50.7 mmol) of 4-amino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride in 200 ml dry pyridine was added dropwise 11,3 ml (~102 mmol) ethoxalyl chloride, and stirring was continued overnight at room temperature. The reaction mixture was filtered and the filtrate was evaporated to give the title compound as a crude oil (19 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:12]1[N:13]([CH2:18][CH3:19])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: OB(O)c1ccccc1Cl
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccccc1Cl)CCNCC2
Yield: 48.2 %

Procedure:
The title compound (73 mg) was prepared according to Example 263 using 227 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 120 mg of 2-chlorophenylboronic acid. MS (ESI): exact mass calculated for C15H18ClN3, 275.12; found, m/z 276.4 [M+H]+, 278.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.64-7.62 (m, 1H), 7.58-7.48 (m, 2H), 7.41-7.39 (m, 1H), 3.97-3.86 (m, 2H), 3.44-3.42 (m, 2H), 3.20-3.17 (m, 2H), 2.70-2.63 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9](O)(=O)[CH:10](C)[CH3:11].S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[OH-].[NH4+]>[N+]([O-])([O-])=O.[Ag+].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:10]([CH3:11])[CH3:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)C(=O)O
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)c1cc(Cl)nnc1Cl

Procedure:
Fifty g. of 3,6-dichloropyridazine was slurried in 500 ml. of water with 28.5 g. of silver nitrate and 66.5 g. of isobutyric acid at 50°. Five hundred ml. of water and 98.6 g. of sulfuric acid were added, and the mixture was heated to 60°. To it was added 228 g. of ammonium persulfate, dissolved in 500 ml. of water. The mixture warmed to 75° as the persulfate was slowly added, and after the addition the mixture was cooled to 10° and ice was added to it. The pH was then adjusted to 9-10 with ammonium hydroxide, and the mixture was extracted three times with 400 ml. portions of diethyl ether. The organic layers were combined and washed twice with 400 ml. portions of 0.5N sodium hydroxide. The organic layer was then washed with brine, dried over magnesium sulfate, and evaporated under vacuum to obtain 52 g. of impure product. It was chromatographed by high performance liquid chromatography, eluting with 5:1 hexane:ethyl acetate, and the desired product was obtained as an oil, amounting to 25 g.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][C:18]1[C:26]2[C:25](=[O:27])[NH:24][C:23]([C:28]([O:30]CC)=O)=[N:22][C:21]=2[S:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C([N:88]1[CH:92]=[N:91][C:90]([O:93][CH2:94][C:95]2[CH:96]=[C:97]([C:101]3[CH:106]=[CH:105][CH:104]=[C:103]([CH2:107][NH2:108])[CH:102]=3)[CH:98]=[CH:99][CH:100]=2)=[N:89]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:17][C:18]1[C:26]2[C:25](=[O:27])[NH:24][C:23]([C:28]([NH:108][CH2:107][C:103]3[CH:102]=[C:101]([C:97]4[CH:98]=[CH:99][CH:100]=[C:95]([CH2:94][O:93][C:90]5[N:91]=[CH:92][NH:88][N:89]=5)[CH:96]=4)[CH:106]=[CH:105][CH:104]=3)=[O:30])=[N:22][C:21]=2[S:20][CH:19]=1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Reactant: NCc1cccc(-c2cccc(COc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: Cc1csc2nc(C(=O)NCc3cccc(-c4cccc(COc5nc[nH]n5)c4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-(3′-{[(1-trityl-1H-1,2,4-triazol-3-yl)oxy]methyl}biphenyl-3-yl)methanamine obtained in Reference Example 135, the title compound was obtained as a white powder (4.7 mg, 2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH:54][CH3:55]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:54]([CH3:55])[CH3:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Solvent: CCO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN(C)C)CCC3)cc1

Procedure:
In analogy to the procedure described in example 8(c), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy -benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] was treated with dimethylamine in ethanol to yield the (3R,4R)-3-[1-(2-dimethylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 688 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:9]1([NH:8][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3,3-dimethylacryloyl chloride (4.8 mL, 43.2 mmol) in dry DCM (100 mL), was added aniline (4.02 g, 43.2 mmol) followed by diisopropylethylamine (14.28 mL, 86.4 mmol). The mixture was stirred at ambient temperature for 2 hrs. Saturated sodium bicarbonate was added to quench the reaction. The organic layer was separated and washed with sat NaHCO3 (50 mL) and water (50 mL×2). The resulting solution was dried over MgSO4 and the filtrate evaporated to afford 3-methyl-but-2-enoic acid phenylamide as a brown solid in quantitative yield (7.6 g). MS: 176.0 (M+H)+; tR=2.40 min (method 1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:13][CH2:14][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:12]
Reactant: CCOCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccccc1[N+](=O)[O-]
Yield: 42.2 %

Procedure:
2-Nitrophenol (91.0 g., 0.65 mole), 2-bromoethyl ethyl ether (100.0 g., 0.65 mole), anhydrous potassium carbonate (9.0 g, 0.72 mole), and acetone (1 liter) were refluxed for 65 hours. The reaction mixture was filtered, and the acetone removed by rotary evaporation. The residue was partitioned between 200 ml. of dichloromethane and 100 ml water. The organic phase was further washed with 200 ml. of 10% sodium hydroxide followed by 100 cc of water. The product (58.0 g) was obtained in 42% yield by a vacuum distillation (100°-120° C./0.5 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].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>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([O:8][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(CCOc1ncc(Br)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
To a suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (500 mg) in 1,4-dioxane (10 ml), tert-butyl 2-hydroxyethyl(methyl)carbamate (475 mg) and triphenylphosphine (684 mg) were added. Then diisopropyl azodicarboxylate (556 mg) was dropwised and stirred at 20° C. for 1.5 h. The mixture was evaporated off the solvent and purified by Biotage SNAP cartridge KP-Sil column (50 g, heptane:ethyl acetate=1:0, 5:1, 4:1, 3:1 to 2:1) to give 630 mg yellow oil as tert-butyl 2-(5-bromo-3-(trifluoromethyl)pyridin-2-yloxy)ethyl(methyl)carbamate (76%).
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].C[O-].[Na+].CS(O)(=O)=O.N[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[NH:22][CH2:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:17]#[N:18]>CO.O>[Cl:1][CH2:2][C:3]1[N:22]([CH2:23][C:24](=[O:32])[NH:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[N:4]=1
Reactant: N#Cc1ccc(NCC(=O)NC2CCCCC2)c(N)c1
Reactant: N#CCCl
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)nc(CCl)n2CC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of chloroacetonitrile (3.9 ml) in methanol (166 ml) was added sodium methoxide (3.29 g), and the mixture was stirred at room temperature for 40 min under a nitrogen atmosphere. Methanesulfonic acid (7.91 ml) and 3-amino4-(cyclohexylcarbamoylmethylamino)benzonitrile (8.3 g) were added, and the mixture was stirred for 3 hours. After completion of the reaction, water (166 ml) was added and the precipitated solid was collected by filtration, and washed with a small amount of water. The obtained solid was stirred in a mixture of hexane and tetrahydrofuran, collected by filtration and dried under reduced pressure to give the title compound (9.30 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:37].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[NH2:22][C:21]1[C:16]2[C:15]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=3)=[C:14]([F:37])[N:13]([C@@H:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(F)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
A suspension of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (1.0 g, 2.1 mmol) in MeCN (30.0 mL) was cooled to 0° C. with ice bath. Selectfluor (1.5 g, 4.2 mmol) was added to the reaction mixture in one portion. After addition, the ice-water bath was removed, and the stifling was continued for 1 hr at r. t. The reaction mixture was susequently partitioned between water (30 mL) and DCM (50 mL). The layers were separated and the aqueous phase was extracted with DCM (10 mL×3). Combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatographic (silica gel, 0 to 50% ethyl acetate in DCM) to afford (R)-tert-butyl 3-(4-amino-6-fluoro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (3) (175 mg, 17% yield) as a yellow solid. LC-MS (ESI): (M+1) 490.1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20]>>[CH:19]([C:5]1[NH:6][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:20]
Reactant: CN(C)C=O
Reactant: Cc1cc(CCC(=O)O)c[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(CCC(=O)O)c(C=O)[nH]1

Procedure:
3-(5-Methyl-1H-pyrrole-3-yl)propionic acid was formylated using phosphorus oxycloride (POCl3) and N,N-dimethylformamide (DMF) to give 3-(2-formyl-5-methyl-1H-pyrrole-3-yl)propionic acid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH:28]C(OC(CC)(C)C)=O)[S:26][CH:27]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1>C(O)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=CO
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (2.30 g.) in 98% formic acid (25 ml.) was stirred for 2.5 hours at room temperature. After the reaction, formic acid was distilled off under reduced pressure. The residue was pulverized in acetonitrile (25 ml.), collected by filtration, washed with a small amount of acetonitrile and then dissolved in 5% sodium bicarbonate aqueous solution (14 ml.). The solution was adjusted to pH 6 with acetic acid and subjected to alumina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluate containing the object compound (300 ml.) was adjusted to pH 3 with 10% hydrochloric acid and then washed twice with ethyl acetate (50 ml.). The aqueous layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm & Haas Co.), and the column was washed with water and then eluted with 20% methanol aqueous solution (100 ml.), 50% methanol aqueous solution (100 ml.) and 70% methanol aqueous solution (400 ml.) in turn. The eluates containing the object compound (500 ml.) were collected and then methanol was distilled off at 30° to 35° C. under reduced pressure. The remaining aqueous solution was lyophilized to give pale yellow powder of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.60 g.).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:13]=[N:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:22]CCl>>[Cl:22][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[N:15]=[C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH:13]=[N:12][CH:11]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: ClCCl
Reactant: c1cc2cc(-c3cncc(N4CCOCC4)n3)cnc2[nH]1
Product: Clc1c[nH]c2ncc(-c3cncc(N4CCOCC4)n3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)morpholine (148) (40 mg, 0.142 mmol, 1.0 eq) in dichloromethane (6 mL) was added n-chlorosuccinamide (38 mg, 0.283 mmol, 2.0 eq) and the resulting reaction mixture was stirred at room temperature overnight. After completion of the reaction the solvents were removed and extracted into CH2Cl2. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 to retain the crude material. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed by rotary evaporator. The crude material was purified by flash column with 100-200 mesh silica gel employing 70% EtOAc/hexane eluents to obtain the pure off-white colored solid of 4-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)morpholine 149 (10 mg). 1H NMR (400 MHz, CDCl3) δ: 9.0 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.34 (d, J=2.31 Hz, 1H), 3.89 (m, 4H), 3.70 (m, 4H); MS m/z 315.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]#[N:16])[CH:8]=2)[CH:2]=1.[OH-].[K+].C([OH:21])C.C>C(O)(C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]([NH2:16])=[O:21])[CH:8]=2)[CH:2]=1
Reactant: N#Cc1cc(-c2cccnc2)n2c1CSC2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: NC(=O)c1cc(-c2cccnc2)n2c1CSC2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A suspension of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carbonitrile (11.35 g) and of potassium hydroxide powder (14 g) in tert-butyl alcohol (100 cc) is heated at 85° C. for 1 hour. After 16 hours' stirring at a temperature of about 20° C., the reaction mixture is poured into distilled water (2 liters). The suspension is stirred at a temperature of about 20° C. for 15 minutes and then the crystals which have appeared are separated off by filtration, washed 8 times with distilled water (1,200 cc in total) and then 3 times with ethanol (150 cc in total) and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. A crude product (10.5 g) is thus obtained which is combined with a product (3.9 g) prepared in the same manner in an earlier operation and dissolved in boiling ethanol (850 cc). The solution is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 3 days. The crystals which have appeared are separated off by filtration, washed 3 times with ethanol (30 cc in total) cooled to a temperature of about 4° C. and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 5-(3-Pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (11.3 g) is thus obtained in the form of cream crystals melting at 215° C.