Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[CH:15]=[CH2:16].Cl.[CH3:18]O>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:18])=[CH:4][C:3]=1[CH:15]=[CH2:16]
Reactant: CO
Reactant: C=Cc1cc(OC[C@H]2CCCN2)cnc1Cl
Agent: Cl
Solvent: CCOCC
Product: C=Cc1cc(OC[C@H]2CCCN2C)cnc1Cl

Procedure:
To a solution of 6-chloro-5-ethenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: mp 173-175° C.; 1H NMR (D2O) δ 2.04-2.18 (m, 2H), 2.23 (m, 1H), 2.40 (m, 1H), 3.04 (s, 3H), 3.29 (m, 1H), 3.73 (m, 1H), 3.95 (m, 1H), 4.37 (dd, 1H, J=6.0, 11.0 Hz), 4.53 (dd, 1H, J=3.0, 11.0 Hz), 5.61 (d, 1H, J=11.0 Hz), 5.94 (d, 1H, J=17.5 Hz), 7.02 (dd, 1H, J=11.0, 17.5 Hz), 7.73 (d, 1H, J=3.0 Hz), 8.04 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 253 (M+H)+. Anal. Calcd for C13H17ClN2O.1.1 HCl: C, 53.32; H, 6.23; N, 9.57. Found: C, 53.51; H, 6.48; N, 9.20. [α]25D +7.4 (c 0.66, MeOH).
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13]([CH3:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].[Br:16]Br>>[Br:16][CH2:15][C:13](=[O:14])[C:7](=[N:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrBr
Reactant: CCCCON=C(C(C)=O)C(=O)OCC
Product: CCCCON=C(C(=O)CBr)C(=O)OCC
Yield: 90.3 %

Procedure:
76 g (0.35 mole) of ethyl 2-n-butoxyimino-acetoacetate and 18 ccs (0.35 mole) of bromine react analogously to Example 4, stage 2, to give 93 g of ethyl 4-bromo-2-n-butoxyimino-acetoacetate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17]>O1CCCC1.C(O)C>[NH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[C:16]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:17]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To an ice-cold solution of 28 ml (134 mmol) of 4-amino-1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran were added, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. The resulting suspension was stirred for 2½ hours at room temperature and 2½ hours at reflux temperature, then freed from solvent. The residue was dissolved in 100 ml of hot ethanol, the resulting solution was filtered whilst hot after the addition of 5 g of activated charcoal. The crystal mass precipitated after cooling was suction filtered, washed with diisopropylether and dried in vacuo at 50° C. 28.3 g of colourless crystals were obtained. A further 5.1 g of a product of the same quality were isolated from the combined mother liquors. Total yield: 33.4 g (80.6% of theory).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8](Cl)=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[NH3:29]>CO>[NH2:29][C:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:28])[C:7]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:26])(=[O:27])[N:17]=1
Reactant: N
Reactant: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(Cl)c2cccnc21
Solvent: CO
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(N)c2cccnc21
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of the product of Example 165 (0.10 g, 0.24 mmol) and ammonia (2 ml of a 2 M solution in methanol, 4.0 mmol) was stirred in a sealed tube at 100° C. for 2 hours, allowed to cool to room temperature. The resulting solid collected by filtration and washed with methanol (2 ml) to give the title compound as a brown solid (0.019 g, 20%). MS (ESI−) m/z 396 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.35 Hz, 3H), 1.38 (m, 2H), 1.66 (m, 2H), 4.44 (t, J=7.35 Hz, 2H), 7.48 (m, 2H), 7.55 (d, J=8.09 Hz, 1H), 7.70 (t, J=8.46 Hz, 1H), 7.84 (dd, J=7.72, 1.10 Hz, 1H), 8.77 (d, J=8.09 Hz, 1H), 8.82 (dd, J=4.78, 1.47 Hz, 1H), 9.84 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 63.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (example 39 step 1) (1.75 g, 2.475 mmol) was deprotected in TFA/DCM (2/20 mL). This afforded 950 mg (63.3% yield) of the titled compound after purification by column (Silica gel 60/120) using 4% methanol in DCM as eluent. MS: m/z=608.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](Cl)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCCC1=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:23][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc(-c2nc3c(c(NC4CCCC4)n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.265 g of 2-(4-chlorophenyl)-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, 0.4 g of cyclopentylamine and 1 ml of N-methylpyrrolidone were heated to 130° C. in an oil bath. After 5 hours, the mixture was diluted with 20 ml of water and stirred at room temperature. The precipitated product was filtered off with suction, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3F)[O:8][C:4]=2[CH:3]=1.[C:22](=O)([O-])[O-:23].[K+].[K+].CO>O>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[O:23][CH3:22])[O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Temperature: 60 °C
Yield: 44.7 %

Procedure:
A mixture of 0.28 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.24 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 6-chloro-2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 91”).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]#[N:32])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:30][C:31]1[NH:37][N:36]=[N:35][N:32]=1)[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(-c3ccccc3)ccc2-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)cc1
Yield: 30.8 %

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 48 mmol), prepared in the previous step, ammonium chloride (0.077 g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). The solids were isolated by vacuum filtration and dissolved in methylene chloride. The organic solution was dried (MgSO4), filtered and the solvent removed under reduced pressure to give 5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H -tetraazole as an amorphous beige solid (0.203 g, 92%), mp 190–200° C. (dec). Elemental Analysis for C29H23N5O.0.49 H2O.0.21 C3H7NO Calc'd: C, 73.90; H, 5.32; N, 15.15. Found: C, 73.05, H, 5.25; N, 15.03.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]NC(=O)C.O>C(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(=O)NBr
Solvent: ClCCl
Solvent: O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 7.8 mmol) in CH2Cl2 (25 ml) was added N-bromoacetamide (1.186 g, 8.6 mmol) in CH2Cl2 (25 ml). The mixture was heated at reflux temperature for 40 mins, then cooled to room temperature, and concentrated under vacuum to give an off-white solid. Cold water (40 ml) was added to the solid, which was then collected by filtration, washed with cold water (5 ml), and dried under vacuum. The product was recrystallized from a minimum amount of isopropanol to yield pure 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.475 g, 81.5%).
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][NH:4][C@H:5]([CH3:21])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.S(=O)(=O)(O)O.[CH2:33](O)[CH3:34]>>[OH:1][C@H:2]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][NH:4][C@H:5]([CH3:21])[CH2:6][C:7]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([O:20][CH2:33][CH3:34])=[O:19])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CCO
Reactant: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1cccnc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12

Procedure:
{3-[(2R)-2-((2R)-2-Hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetic acid (65 mg, 0.176 mmol) is dissolved in ethanol (5 mL), and thereto are added conc. sulfuric acid (0.1 mL) and Molecular Sieves 4A powder (trade name, 0.3 g), and the mixture is refluxed for 20 hours. After cooling, the insoluble materials are removed by filtration, and a saturated aqueous sodium hydrogen carbonate solution is added to the filtrate. The mixture is evaporated under reduced pressure to remove ethanol, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (ethanol/chloroform=1/5→1/1). The obtained purified product is dissolved in ethanol (3 mL), and thereto is added 1N HCl/diethyl ether (0.5 mL). The mixture is concentrated under reduced pressure to give the desired ethyl {3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetate.2 hydrochloride (63 mg, yield: 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23](CC)CC)C>ClCCl>[NH2:23][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([N:16]2[CH2:20][CH2:19][S:18][CH2:17]2)=[O:15])[CH2:10]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)N1CCSC1

Procedure:
3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (title compound of Reference Example 9, 56.3 g) and triethylamine (28.5 mL) were dissolved in dichloromethane (1.0 l), and methanesulfonyl chloride (15.1 mL) was added thereto under ice-cooling. After stirring under ice-cooling for 1 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure to give 3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (70.5 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH2:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: C=Cc1ccc(C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared as described in Example 67 using 1-chloro-4-methyl-2-nitrobenzene and tributyl(vinyl)stannane, further purified by flash column chromatography and reverse phase chromatography and isolated as a yellow liquid (1.26 g, 65%): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=0.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.46-7.35 (m, 1H), 7.13 (dd, J=17.3, 11.0 Hz, 1H), 5.71 (dd, J=17.3, 0.9 Hz, 1H), 5.43 (dd, J=11.0, 0.9 Hz, 1H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.71, 138.91, 133.92, 132.31, 130.52, 128.22, 124.63, 118.10, 20.88; EIMS m/z 163 ([M]+).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[OH:4][CH2:3][CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1)=[S:14])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: Cc1ccc(C(N)CO)cc1
Product: Cc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1

Procedure:
The title compound was prepared with 2-amino-2-(p-tolyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 71%): mp 145-156° C.; 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.12 (d, J=6.8 Hz, 2H), 8.05 (d, J=2.2 Hz, 2H), 7.65 (d, J=7.4 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.24-7.23 (m, 2H), 7.18-7.16 (m, 2H), 5.60 (s, 1H), 3.90-3.84 (m, 2H), 2.34 (s, 3H) (NH, OH not observed); ESIMS m/z 514 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:34])=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[S:35]1[C:39]2[CH2:40][CH2:41][CH2:42][CH2:43][C:38]=2[N:37]=[CH:36]1>>[NH2:1][C:2]1[S:3][C:4]([Cl:34])=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:37]4[C:38]5[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=5[S:35][CH:36]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nc(N)sc1Cl
Reactant: c1nc2c(s1)CCCC2
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3csc4c3CCCC4)CS[C@H]12)c1nc(N)sc1Cl

Procedure:
7β-[2-(2-Amino-5-chlorothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid is reacted with 4,5,6,7-tetrahydrobenzothiazole in the same manner as described in Example 1 to give the above-identified compound.
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.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][O:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:22]4[CH2:28][C@H:25]3[CH2:24][O:23]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1O[C@@H]2CN[C@H]1C2
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: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2C[C@H]1CO2

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 (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (31560-06-2) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=366.5 [MH+].
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 8.2 g. dipropylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from a mixture of toluene and petroleum ether (b.p. 60° - 80°C.) to give 1-dipropylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, m.p. 80° - 81°C. Elemental analysis satisfactory.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.P(=O)(O)(O)O>O.C1(C)C(C)=CC=CC=1>[F:9][C:10]([F:25])([F:26])[C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(Cl)C(=O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
132.5 Parts of 2-chloropropionic acid (98% strength) and 199 parts of 50% sodium hydroxide solution are added simultaneously but separately at 110°-115° C. to a solution of 254 parts of 4-(4'-trifluoromethylphenoxy)-phenol in 1,000 parts of xylene. During the addition, the reaction temperature is maintained by azeotropic distillation of water in a water trap. The addition being complete, stirring is continued for 15 minutes at 110°-115° C., the batch is cooled to 90° C. and after addition of 400 parts of water, it is stirred for a further 10 minutes at 85° C., then acidified at this temperature with 120 parts of phosphoric acid, and stirred for a further 10 minutes. After elimination of the water phase, xylene is distilled off in a water jet vacuum, and the solids are dried at 60° C. and 250 mbar. 326 parts of 2-[4'-(4" -trifluoromethylphenoxy)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.6% corresponding to a yield of 99.6% of theory. The residual content of 4-(4'-trifluoromethyl-phenoxy)-phenol is 0.35%.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.[NH2:28][C:29]1[NH:33][N:32]=[C:31]([C:34]([NH2:36])=[O:35])[CH:30]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[NH:28][C:29]3[N:33]([N:32]=[C:31]([C:34]([NH2:36])=[O:35])[CH:30]=3)[C:3](=[O:2])[C:4]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:12][CH:11]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(C(=O)c1ccc(OCc2ccccc2)cc1)C1CCCCC1
Reactant: NC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Yield: 1.8 %

Procedure:
A mixture of 1.0 g (2.7 mmol) of 3-(4-benzyloxy-phenyl)-2-cyclohexyl-3-oxo-propionic acid methyl ester, 340 mg (2.7 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid amide, 51 mg (10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 15 mL of toluene was heated at reflux for 72 h. The reaction mixture was then concentrated to a residue which chromatographed on silica gel (Biotage; gradient elution 15% ethyl acetate in dichloromethane to 6% methanol in dichloromethane) to give a residue which was further purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) 22 mg (2% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid amide as indicated by 1H-NMR; LC-MS calcd for C26H26N4O3 [M++H]+: 443.2, found: 443.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH2:11][CH2:12]Cl.C([Li])CCC.CCCCCC>C1COCC1>[Br:9][C:4]1[C:3]2[O:10][CH2:11][CH2:12][C:2]=2[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(Br)c(OCCCl)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1cc(Br)c2c(c1)CCO2
Reaction time: 1 h
Yield: 19 %

Procedure:
To the compound (2.5 g, 7.4 mmol) obtained in Step 1, THF (50 mL) was added. At −78° C., a 2.6 M n-butyllithium/n-hexane solution (2.9 mL, 7.5 mmol) was added thereto and stirred for 1 hour, and then stirred at room temperature overnight. The solvent was distilled away under reduced pressure. The resulting residue was subjected to reversed-phase HPLC using ODS as a filler, and eluted with a mixture solution of water and acetonitrile, which contained trifluoroacetic acid at 0.1% (v/v). The target fraction was lyophilized to thus obtain the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)cc1
Yield: 107.8 %

Procedure:
In xylene (10 mL), 2-chlorobenzoxazole (1.00 g, 6.51 mmol) and ethyl 4-aminophenylacetate (1.67 g, 6.51 mmol) were heated and refluxed for 10 hours. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1, v/v) eluate fractions, ethyl 4-(2-benzoxazolylamino)phenylacetate (2.08 g, 99%) was obtained as a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:11]1[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[C:7](=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cn1c(C)cccc1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(=O)n1CC(=O)NN
Yield: 88 %

Procedure:
As described for example 112a, (6-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Petride, Horia; Raileanu, Dan. Revue Roumaine de Chimie (1988), 33(7), 729-39.) in ethanol was reacted with hydrazine hydrate (1.8 equivalents) at rt for 96 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 88%). MS: m/e=204.2 [M+Na]+.