Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[CH:5]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN1CCOCC1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:3]=1
Reactant: COC(=O)Nc1cc(=O)[nH]c(N)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1

Procedure:
A stirred suspension of 500 g of methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate in 1.45 l of N-methylmorpholine and 9 l of methylene chloride is heated to reflux temperature. Subsequently, 815 g of toluene-4-sulfonyl chloride are added thereto and the mixture is stirred at reflux for 16 hours. The mixture is evaporated at 40° in a water-jet vacuum and the residue is treated with 9 l of water. The insoluble material is filtered off under suction and washed firstly with 5 l of water and thereafter with 5 l of ether. After drying at 40° in vacuo, there is obtained light brown methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate of melting point 188°-190°. A sample recrystallized from acetonitrile has a melting point of 190°-192°.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16](=[O:18])[CH3:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:20][C:21]1[C:22]([Cl:37])=[N:23][C:24]([S:35][CH3:36])=[N:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].CO>C1COCC1>[Cl:37][C:22]1[C:21]([CH2:20][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:18])=[C:26]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[N:25]=[C:24]([S:35][CH3:36])[N:23]=1
Reactant: CSc1nc(Cl)c(CBr)c(-c2ccc(F)cc2F)n1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1nc(Cl)c(CCC(=O)OC(C)(C)C)c(-c2ccc(F)cc2F)n1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of LiHMDS (4.1 mL) in 3 mL of THF was added t-butylacetate (0.6 mL). After stirring for 10 min, 1.0 g of 5-(bromomethyl)-4-chloro-6-(2,4-difluorophenyl)-2-(methylthio)pyrimidine (COMPOUND VV-3) in 4 mL of THF was added dropwise. The mixture was stirred at −78° C. for 1.5 h, then warmed to −50° C. The reaction mixture was recooled to −78° C. and 3 mL of methanol was added. The solution stirred for 24 h at rt. The crude mixture was purified by flash chromatography, eluting with 2% diethyl ether/hexanes. Mass spectrum m/z (ESI) 401.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1.O.NN>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2ccncc2)o1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1ncc(-c2ccncc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of (2-methyl-5-nitro-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (1 g, 3.39 mmol) in ethanol (50 mL) was treated with 10% Pd/C (120 mg) and hydrazine hydrate (3.50 mL, 112.5 mmol) was added drop wise over 10 min. The reaction mixture was stirred at room temperature for 30 min and then refluxed for 2 h. The hot solution was filtered through a short pad of Celite, and the catalyst was washed with hot ethanol. The filtrates were concentrated under reduced vacuum to give the crude product. This was silica gel column chromatographed (dichloromethane/ethanol: 97/3). 720 mg (80%) of (2-methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine was obtained as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40](O)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH2:77][CH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>CN(C=O)C.O>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][C:21]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:22][C:23]=3[C:24]3[S:25][CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[N:28]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([NH:77][CH:78]2[CH2:83][CH2:82][O:81][CH2:80][CH2:79]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C(COC)COC)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NC2CCOCC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(1,3-Dimethoxypropan-2-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 4, 0.112 g, 0.18 mmol) was suspended in DMF (1 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.105 g, 0.28 mmol) was added, followed by diisopropylethylamine (0.193 mL, 1.11 mmol). The reaction mixture was stirred for 15 min at RT. The 4-aminotetrahydropyran hydrochloride (0.038 g, 0.28 mmol) was added in one portion and the mixture was stirred at RT for 2 days. Water was added and the resultant solid was purified by column chromatography (silica, 95:5 methylene chloride/methanol) to provide the product as a solid. The solid was further purified by trituration with CH2Cl2 and hexanes.
Reaction SMILES: [O:1]=[C:2]1[NH:23][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]4)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH:24]1([NH:30][CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[CH:24]1([N:30]([CH3:31])[C:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:10]3[CH:9]=[CH:8][C:7]4[N:6]=[C:5]5[NH:23][C:2](=[O:1])[NH:3][C:4]5=[CH:13][C:12]=4[CH:11]=3)[CH2:15][CH2:16]2)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CNC1CCCCC1
Reactant: O=C(O)C1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1)C1CCCCC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
A stirred mixture of 1-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)-4-piperidinecarboxylic acid (3.12 g, 10 mmol) and N-cyclohexyl-N-methylamine (1.36 g, 12 mmol) were combined in dimethylformamide (200 mL) and cooled to -20° C. Triethylamine (2.91 mL, 21 mmol) and diphenylphosphoryl azide (2.59 mL, 12 mmol) were added, the mixture stirred at -20° C. for 3 hours, and allowed to warm to room temperature. After 18 hours, the mixture was diluted with CH2Cl2 (200 mL), scratched to initiate crystallization, and stirred for an additional 72 hours. The resultant precipitate was collected, washed with CH2Cl2, and dried to give 2.09 g of a pale yellow solid (51%). Crystallization from dimethylformamide (80 mL) gave 1.02 g of pale yellow crystals, m.p. 318°-321° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([NH2:26])=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (5.2 g), 1-hydroxybenzotriazole monohydrate (3.6 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.5 g) and N,N-dimethylformamide (200 mL) was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature and 10% aqueous ammonia (12 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (5.18 g, yield 100%) as pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=3)[CH2:39][CH2:38]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(c3ccc(F)cc3)CC2)C1

Procedure:
Compound 748 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 1-(4-fluoro-phenyl)-piperazine using the method described for compound 747. The title compound was isolated as an amber foam (0.009 g, 25% yield). HRMS (M+H) calcd for C24H28N4Cl2O3F: 521.15226. found: 521.1531.
Reaction SMILES: [Br:1][CH2:2][C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[F:15]C1C=CC(NC(C)C)=CC=1.BrCC(Br)=O>>[Br:1][CH2:2][C:3]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:15])=[CH:8][CH:7]=1)[CH:12]([CH3:14])[CH3:13])=[O:4]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: CC(C)Nc1ccc(F)cc1
Agent: O=C(Br)CBr
Product: CC(C)N(C(=O)CBr)c1ccc(F)cc1

Procedure:
Following the procedure described for Preparation 1(A); (4-fluoro-phenyl)-isopropyl-amine (13.70 g, 89.54 mmol) was alkylated with bromoacetyl bromide (7.78 mL, 89.54 mmol) to provide 15.02 g of 2-bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide as an oil. 1H NMR (CD2Cl2) δ 7.14-7.23 (m, 4H), 4.90 (m, 1H), 3.53 (s, 2H), 1.05 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1.S(Cl)([Cl:39])=O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:39])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(Cl)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Yield: 75 %

Procedure:
At room temperature, 8.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-(benzoylamino)benzamide and 1.0 g of pyridine were introduced to 40 ml of thionyl chloride. Thereafter, the mixture was heated and stirred under a reflux condition. After disappearance of the starting raw material was confirmed by means of TLC, the reaction solution was cooled down and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent (development solvent; hexane:ethyl acetate=3:1) to obtain 6.2 g of the desired product (Yield: 75%) in the form of powder.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[N:5][N:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.C(N(C(C)C)CC)(C)C.[C:21]1([C:27]2[N:28]=[C:29]3[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][N:30]3[CH:36]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:21]1([C:27]2[N:28]=[C:29]3[N:34]=[C:33]([NH:35][C:9]([C:3]4[N:4]([CH3:8])[N:5]=[C:6]([CH3:7])[C:2]=4[Cl:1])=[O:11])[CH:32]=[CH:31][N:30]3[CH:36]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: Cc1nn(C)c(C(=O)O)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.57 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) were added to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 100 mg, 0.48 mmol) in ethyl acetate (3 ml). At 0° C., propylphosphonic acid anhydride (1-propanephosphonic acid cyclic anhydride, 50% in ethyl acetate, 0.7 ml, 2.5 eq.) was added dropwise to the mixture. After stirring for 30 min at 0° C., the mixture was stirred overnight at RT. The mixture was taken up in ethyl acetate, washed (water), dried (Na2SO4), and concentrated under reduced pressure. The title compound (16 mg, 9%) was obtained from the residue by preparative HPLC (254 nm, Agilent Zorbax XdB-C18, Run: 7 min, Flow: 30 ml/min, Gradient: 0.0 min: 95/5 H2O/CH3CN; 0.5 min: 95/5 H2O/CH3CN 4.5 min: 5/95 H2O/CH3CN; 6.9 min 5/95 H2O/CH3CN; 7 min 95/5 H2O/CH3CN).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:28][C:29]1[C:30]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[ClH:28].[ClH:28].[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[C:30]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)c1cc2ncnn2nc1Cl
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: Cl
Temperature: 0 °C
Yield: 171 %

Procedure:
150 mg of 60% sodium hydride was suspended in 20 ml of tetrahydrofuran; 1.05 g of 4-(diphenylmethyl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine in oil was added, followed by heating and refluxing for 1 hour. After cooling, 650 mg of 6-chloro-7-t-butyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 2 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected; the residue was dissolved in 5 ml of ethyl acetate; 2.1 ml of a 4 N hydrogen chloride solution in ethyl acetate was added; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.55 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][S:11]([O:13][Na])=[O:12]>C(O)C>[CH3:10][S:11]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:13])=[O:12]
Reactant: CS(=O)O[Na]
Reactant: BrCc1ccc(Br)cc1
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(Br)cc1

Procedure:
p-Bromobenzyl bromide (500 mg, 2 mmol) was refluxed with MeSO2Na (306 mg, 3 mmol) in Ethanol for 1 hour. The reaction was cooled, concentrated and purified by flash column (50% acetone/hexanes) to give the desired product.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH2:19]([C:23]1[N:24]([CH3:32])[CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([C:23]1[N:24]([CH3:32])[CH:25]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[N:27]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1nc(C(=O)OC)cn1C
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CCCCc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile (664 mg, 2.55 mmol) and methyl 2-butyl-1-methyl-1H-imidazole-4-carboxylate (500 mg, 2.55 mmol). The product was purified with flash chromatography. Yield 291 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.88 (t, 3H), 1.09 (t, 3H), 1.28-1.36 (m, 2H), 1.54-1.61 (m, 2H), 2.62 (t, 2H), 3.57 (s, 3H), 4.26-4.39 (m, 3H), 6.95 (bs, 1H), 7.47 (s, 1H), 7.82 (d, 1H), 7.90 (d, 1H), 7.96 (s, 2H), 8.09 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 59.6 %

Procedure:
Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G38) (151 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (175 mg, 0.76 mmol) according to the general procedure K. Obtained as an orange solid (141 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:28])([F:27])[C:21]1([CH3:26])[CH2:25][CH2:24][CH2:23][NH:22]1.Cl>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:21]1([C:20]([F:28])([F:27])[F:19])[CH3:26])=[O:5]
Reactant: CC1(C(F)(F)F)CCCN1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C(F)(F)F)CCCN1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 8.83 g (0.05 mol) of 2,6-difluorobenzoyl chloride in 10 ml of tetrahydrofuran (THF), to which 5.6 g (0.055 mol) of triethylamine had been added, was added dropwise to a solution of 7.65 g (0.05 mol) of 2-trifluoromethyl-2-methylpyrrolidine in 25 ml of tetrahydrofuran (THF). The reaction is exothermic, and slow dropwise addition prevented the temperature from rising above +35° C. Stirring was continued for one hour at room temperature, and the mixture was then poured into 250 ml of ice-water and acidified using dilute hydrochloric acid, and the precipitate obtained was filtered off with suction, washed thoroughly with water and dried. 9.96 g (68% yield of theory) of N-(2,6-difluorobenzoyl)-2-trifluoromethyl-2-methyl-pyrrolidine of melting point 119°-120° C. are obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:65]=[CH:64][C:33]([CH2:34][O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][S:42][C:43]2[N:44]=[CH:45][N:46]3[CH:50]=[C:49]([Sn](CCCC)(CCCC)CCCC)[S:48][C:47]=23)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:49]3[S:48][C:47]4=[C:43]([S:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][CH2:34][C:33]5[CH:64]=[CH:65][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)=[O:37])[N:44]=[CH:45][N:46]4[CH:50]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCCNC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 63.6 %

Procedure:
The procedure of Example 1a) was repeated, except that 628 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.24 g of 7-[3-(4-nitrobenzyloxycarbonyl)aminopropyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]-thiazole were used as the starting compounds. Thus, 812 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[3-(4-nitrobenzyloxycarbonyl)aminopropyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate were prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.O1CCCC1.[OH-].[Na+].Cl>CO.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccn(C)n6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccn(C)n2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate is dissolved in methanol (1 mL) and tetrahydrofuran (1 mL) and aqueous NaOH solution (0.2 mL, 1 Mol/L) was added. The reaction mixture is shaken for 72 hours at room temperature. Aqueous hydrochloric acid (0.2 mL, 1 Mol/L) and dimethylformamide (1 mL) are added and the product is purified by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. LC (method 14): tR=0.69 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]([O-])=O.[Na+].ClCC=O>O>[N:7]1[C:2]2[NH:1][CH:10]=[CH:11][C:3]=2[C:4]([OH:9])=[N:5][C:6]=1[OH:8]
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Reactant: CC(=O)[O-]
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Product: Oc1nc(O)c2cc[nH]c2n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a suspension of 6-aminouracil (15.0 g, 0.118 mol) in H2O (600 mL) was added NaOAc (15.0 g, 0.183 mol) and ClCH2CHO (50% in H2O, 30 mL). The mixture was heated at reflux for 4 h and was cooled to room temperature. The resulting dark brown precipitates were collected by filtration to afford crude 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (14.4 g, 81% yield).