Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CCCCC(O)C(=O)O
Product: CCCCC(OC(C)=O)C(=O)O

Procedure:
The compound obtained in step A is treated with acetyl chloride according to the process described in example 90 B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13].[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:18]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1C(F)(F)F
Product: COC(=O)c1nc(C)sc1-c1ccccc1C(F)(F)F

Procedure:
prepared by reaction of 3-chloro-3-(2-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=302.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Cl.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH:46]([CH3:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH:46]3[CH3:50])=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC1CN(C)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC1CN(C)CCN1C(=O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added DIEA (209 mg, 1.62 mmol), 1,3-dimethylpiperazine hydrochloride (146 mg, 0.97 mmol) and HATU (16 mg, 0.04 mmol). The resulting solution was stirred at room temperature overnight. Water (50 mL) and DCM (30 mL) was added. Phases were separated. The aqueous phase was extracted with DCM and the organic layers combined. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 12 min; Detector, UV 254 nm. This resulted in 59.1 mg (33%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 25) [M+H]+=559.2, RT=1.63 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz), 8.69-8.67 (m, 2H), 8.34-8.31 (m, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.31-5.11 (m, 2H), 4.52-4.47 (m, 0.5H), 4.20-4.11 (m, 1H), 3.78-3.69 (m, 0.5H), 3.32-3.21 (m, 0.5H), 2.97-2.83 (m, 0.5H), 2.75 (d, 1H, J=11.1 Hz), 2.63 (d, 1H, J=11.4 Hz), 2.20-1.71 (m, 5H), 1.38-1.12 (m, 3H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[C:12]=1[C:21]([C:20]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:19]=1[O:18][CH3:17])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)c(OC)c1

Procedure:
Prepared from 2-benzyl-benzofuran and 2, 4-dimethoxybenzoyl chloride according to the procedure in Example 207. White solid (6.88g): mp 74-76C.; NMR (CDCl3); δ7.47(d, J=8Hz, 1 H), 7.40 (dd, J=2,1 Hz, 1 H), 7.31 - 7.24 (m, 5 H), 7.24 -7.19 (m, 2 H), 7.16 - 7.12 (m, 1 H), 6.55 (d, J=2, Hz, 1 H), 6.48 (s, 1 H), 4.29 (s, 2 H), 3.89 (s, 3 H), 3.58 (s, 3 H), MS (EI): [M*+m/z] 372(55%), 165(100%), 234(88%), Anal. Calc. for C24H20O4, C,77.40, H, 5.41, N, 0.00. Found: C, 77.48, H, 5.44, N, 0.09.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:25][CH:24]([S:26][C:27]3[C@H:28]([CH3:51])[C@@H:29]4[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:30]4[C:31]=3[C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:23]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:23][CH:24]([S:26][C:27]3[C@H:28]([CH3:51])[C@@H:29]4[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:50])[N:30]4[C:31]=3[C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:25]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Yield: 65.7 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-(4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (690 mg, 0.914 mmol) (obtained as described in Example 41(1)) in tetrahydrofuran (35 ml) were added acetic acid (157 μl, 2.74 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (2.74 ml, 2.74 mmol) in an ice bath and the mixture was stirred for 2 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-1-hydroxymethyl-2-methylpropylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (388 mg, yield 66%) as a pale yellow solid.
Reaction SMILES: [CH2:1](O)[CH3:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11][CH2:1][CH3:2])=[O:10]
Reactant: CCO
Reactant: O=C(O)c1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccco1
Yield: 88.3 %

Procedure:
Toluene (100 ml), ethanol (12.33 g, 267.67 mmol) and 2-furancarboxylic acid (25 g, 223.05 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (6.65 g, 34.96 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (5.64 g, 55.76 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl 2-furancarboxylate (27.60 g, 88%) was isolated in distillation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[CH:9]1([NH:14][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1nccc(Cl)n1
Reactant: NC1CCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nccc(NC2CCCC2)n1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
A mixture of 2-amino-4-chloropyrimidine (22.8 g, 176 mmol), cyclopentylamine (20.9 mL, 211 mmol) and triethylamine (29.4 mL, 211 mmol) in EtOH (200 mL) was heated at reflux (105° C., oil bath) for 48 h. Upon workup, the volatile was removed in vacuo. The residue was poured into ice and saturated Na2CO3 aqueous solution and extracted with ethyl acetate (3×). The combined organics were washed with saturated Na2CO3 aqueous solution (1×), dried over Na2SO4, and concentrated in vacuo to give N4-cyclopentylpyrimidine-2,4-diamine (315) (26.5 g) as a light yellow solid of 92% purity. This batch of material was taken onto the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 179.1, Calculated 179.1.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3C)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[N+](C1C=C(C=CC=1)C(O)=O)([O-])=O>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=4)[CH:24]=3)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Agent: O=C(O)c1cccc([N+](=O)[O-])c1
Product: Nc1nccc2c(C(=O)Nc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cccc12
Yield: 11 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 3-nitrobenzoic acid instead of benzoic acid in Step (1) of Example 2 to obtain the title compound (10 mg, 11%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[CH3:31])[C:6]=1[C:7]([C:9](=[CH:15][NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:10]([O:12]CC)=[O:11])=[O:8].[H-].[Na+]>CN1C(=O)CCC1>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:5]1[C:6]2[C:7](=[O:8])[C:9]([C:10]([OH:12])=[O:11])=[CH:15][N:16]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[C:2]=2[N:3]=[CH:4]1
Reactant: CCCC(CCC)NC=C(C(=O)OCC)C(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCC(CCC)n1cc(C(=O)O)c(=O)c2c1ncn2-c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To 0.60 g (1.2 mmol) of ethyl 2-[4-bromo-1-(2,4-dimethylphenyl)-1H-imidazole-5-carbonyl]-3-(heptan-4-ylamino)acrylate in 10 mL of NMP was added 0.15 g (3.7 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at room temperature for 1 h and subsequently heated to 140° C. for 25 min. The reaction mixture was cooled to room temperature, quenched with 2 mL of saturated ammonium bicarbonate, diluted with ten volumes of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated to an oil. The oil was purified by flash chromatography eluting with a 3% methanol/dichloromethane mixture to give 0.12 g of the title compound as a light yellow solid. Dirty fractions were combined, concentrated and purified to give an additional 0.15 g of the title compound. The overall yield of the title compound was 0.27 g (57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=[C:13]1C(OCC)=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: COc1ccc2ccn(C)c2c1
Yield: 95 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 6-methoxy-1H-indole for the ethyl indole-2-carboxylate, the title compound (2.3 g, 95%) was obtained as an oil: MS (ES) m/e 162.2 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:39])/[CH:21]([CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:40][CH3:41])[C:15]([CH3:42])=[C:14]2[C:10]=1[C:11](=[O:43])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(#N)C>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:39])/[CH:21]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:40][CH3:41])[C:15]([CH3:42])=[C:14]2[C:10]=1[C:11](=[O:43])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(CCCO[Si](C)(C)C(C)(C)C)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: CC#N
Product: CCOC(=O)CC(CCCO)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
Ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-isobenzofuran-5-yl)-3-(3-tert-butyldimethylsilyloxypropyl)-4-methylhex-4-enoate (2.92 g) was dissolved in acetonitrile (50 ml). To this was added a solution of 40% aqueous HF (5 ml) in acetonitrile (45 ml), and the reaction mixture stirred for 10 minutes. Most of the acetonitrile was then evaporated, and the remaining solution diluted with ether. The ether was washed with water, saturated sodium bicarbonate (3X), brine, and dried. Evaporation of the solvent gave an oil which was chromatographed on silica gel (40% ethyl acetate in hexmnes) to give ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-isobenzofuran-5-yl)-3-(3-hydroxypropyl)-4-methylhex-4-enoate (2.10 g), a compound of Formula 803, as an oil.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([CH:16]1[NH:20][C:19](=[O:21])[C:18]([CH3:23])([CH3:22])[C:17]1=[O:24])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([CH:16]1[N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C:19](=[O:21])[C:18]([CH3:23])([CH3:22])[C:17]1=[O:24])[CH3:15]
Reactant: CCC1NC(=O)C(C)(C)C1=O
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-iodo-2-(trifluoromethyl)benzonitrile (526 mg), 5-ethyl-3,3-dimethylpyrrolidine-2,4-dione (250 mg), cesium carbonate (787 mg), tris(dibenzylideneacetone)dipalladium(0) (148 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (186 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a pale-yellow oil (yield: 298 mg, 57%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1cccc(C=O)c1O
Product: Cc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(2-Hydroxy-3-methyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-3-methylbenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 2.58-2.63 (m, 4H), 3.48-3.63 (m, 4H), 3.71 (s, 2H), 5.39 (s, 1H), 6.69-6.73 (m, 1H), 6.82-6.83 (m, 1H), 7.05-7.07 (m, 1H), 7.84 (s, 1H), 10.60 (br s, 1H), 12.60 (br s, 1H). Mass spectrum (ES) MH+=301.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH2:29][N:1]3[CH:2]([C:11]4[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=4[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1ccnc(-n2cccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 394.85 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][C:16]([NH:18][NH:19]C(OC(C)(C)C)=O)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][C:16]([NH:18][NH2:19])=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N2CCCC2CC(=O)NNC(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2CCCC2CC(=O)NN)ccc(C#N)c1Cl

Procedure:
Mix a solution of tert-butyl 2-{[1-(3-chloro-4-cyano-2-methylphenyl)pyrrolidin-2-yl]acetyl}hydrazinecarboxylate (0.897 g, 2.35 mmol) in trifluoroacetic acid at ambient temperature for 30 min. Remove the solvent under reduced pressure, dissolve the residue into methanol and apply to a cationic exchange column (10 g Isolute SCX-2). Elute the column with methanol then 2N methanolic ammonia. Concentrate the methanolic ammonia fractions under reduced pressure to obtain the title compound. (0.577 g, 88%) mass spectrum (m/e): 279.1 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 1H), 6.82 (d, 1H), 7.30 (bs, 1H), 4.28 (t, 1H), 3.82 (m, 1H) 3.73 (s. 2H), 3.00 (m, 1H), 2.54 (m, 1H), 2.56 (s, 3H), 2.40 (s, 3H), 1.80-2.10 (m. 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1)([O-])=O>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCO)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnn(CCO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol (9.12 g, 58.07 mmol) in EtOAc (20 mL, degassed) and EtOH (60 mL, degassed), PtO2 (1.13 g, 5.81 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain 2-(4-amino-1H-pyrazol-1-yl)ethanol as a red oil, which was used in the next step without further purification. LC-MS conditions A: tR=0.14 min, [M+H]+=128.24.
Reaction SMILES: [OH-].[Na+].CC(O[CH2:7][C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12]([NH2:15])[C:13](=[O:14])[N:10]2[C:9]=1[C:18]([OH:20])=[O:19])=O.[Na].[Na].[C:23]([CH2:26][C:27]1[N:31]=[C:30]([SH:32])[NH:29][N:28]=1)([OH:25])=[O:24].C(CC1N=C(S)NN=1)(O)=O>C(O)C>[NH2:15][CH:12]1[C:13](=[O:14])[N:10]2[C:9]([C:18]([OH:20])=[O:19])=[C:8]([CH2:7][S:32][C:30]3[N:31]=[C:27]([CH2:26][C:23]([OH:25])=[O:24])[NH:28][N:29]=3)[CH2:17][S:16][C@H:11]12
Reactant: O=C(O)Cc1n[nH]c(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3n[nH]c(CC(=O)O)n3)CS[C@H]12

Procedure:
10% Aqueous sodium hydroxide (8 ml.) was added to a suspension of 5.4 g. (20 mmol.) of 7-aminocephalosporanic acid and 5.5 g. (27 mmol.) of 3-carboxymethyl-1,2,4-triazole-5-thiol disodium salt, prepared by addition of a sodium hydroxide solution to a solution of 3-carboxymethyl-1,2,4-triazole-5-thiol in aqueous ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)(=[O:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH3:26].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:16])=[O:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN(C)CCCCN
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCCN(C)C)c(C(=O)O)c1Cl
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of Example 389B (133 mg, 0.4 mmol), 4-(N,N-dimethylamino)butylamine (346 mg, 3.0 mmol), acetonitrile (3 mL), and triethylamine (0.3 mL, 1.9 mmol) was sealed in a vial and shaken at to 80° C. for 72 hours. The mixture was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mmol aqueous ammonium acetate over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 454 (M+H)+; (ESI(−)) m/e 452 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, 1H), 7.43 (d, 1H), 7.36 (m, 1H), 7.16 (d, 1H), 6.77 (d, 1H), 6.61 (t, 1H), 5.78 (br s, 1H), 3.31 (br s, 2H), 3.23 (m, 2H), 3.04 (m, 2H), 2.76 (s, 6H), 2.59 (q, 2H), 1.86 (m, 2H), 1.66 (m, 2H), 1.09 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:31]3[C:23]([F:22])=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:33])=[CH:25]4)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccccc1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCc1ccccc1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy cinnoline (2 g, 6.66 mmol), (prepared as described for the starting material in Example 1), 4-fluoro-5-hydroxy-2-methylindole (1.32 g, 7.99 mmol), (prepared as described for the starting material in Example 1), and cesium carbonate (3.2 g, 9.98 mmol) in DMF (40 ml) was heated at 95° C. for 1.5 hours. 4-Fluoro-5-hydroxy-2-methylindole (82 mg, 0.5 mmol) and cesium carbonate (3.2 g, 9.98 mmol) were added. The mixture was stirred for 1.5 hours at 115° C. The mixture was cooled, the solid was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography, eluting with methylene chloride/ethyl acetate (90/10 followed by 80/20) followed by methylene chloride/ethyl acetate/methanol (80/18/2). The fractions containing the expected product were combined and evaporated and the residue was triturated with ether/pentane (1/1). The solid was filtered, washed with pentane and dried under vacuum to give 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (1.1 g, 39%).