Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.Cl.[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:1][C:2]1([C:28]2[CH:29]=[C:24]([NH2:23])[CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]2[CH:8]=[CH:9][N:10]=[C:5]2[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cn2ccnc2c(-n2ccnc2-c2ccncc2)n1
Agent: [Pd]
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Nc1cccc(C2(Br)Cn3ccnc3C(n3ccnc3-c3ccncc3)=N2)c1
Temperature: 95 °C
Yield: 66 %

Procedure:
A mixture of 6-bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazine (4) (4.0 g), 3-aminophenylboronic acid hydrochloride (2.41 g), tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) (1.36 g), 2.5 Maqueous potassium phosphate (K3PO3) (10 ml), and 1,2-dimethoxyethane (DME) (80 ml) is heated at 95° C. for 16 hours. The mixture is cooled to rt, treated with water (50 ml) and extracted with ethyl acetate (3×80 ml). The extracts are washed with water (1×50 ml) and brine (1×50 ml), dried over Na2SO4, and evaporated in vacuo. Purification on SiO2 (5% MeOH, DCM) yielded 3-[6 -Bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (3.36 g) as a cream solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CO[C:9]([C@@H:11]1[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33].[ClH:39]>C1COCC1.O1CCOCC1.O>[ClH:39].[OH:10][CH2:9][C@H:11]1[NH:12][CH2:13][C@H:14]([NH:16][C:32](=[O:34])[CH3:33])[CH2:15]1
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CN[C@H](CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To an ice-cold suspension of lithium aluminium hydride (0.6 g, 15 mmol) in THF (10 ml) was added a solution of (2S,4R)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.0 g, 4 mmol) in THF (5 mL) and the mixture stirred for 1 h. Water was then cautiously added to the reaction and the mixture filtered and concentrated. The residue was then taken up in CH2Cl2 (10 ml) and saturated sodium carbonate (10 ml) and acetic anhydride (0.3 ml, 3 mmol) added. The mixture was stirred for 2 h after which time the organic was collected, dried (Na2SO4) and concentrated. The residue (0.6 g, 2 mmol) was then treated with 4 M hydrochloric acid in dioxane (5 ml) for 1 h, evaporation of the solvent afforded the title compound (0.5 g, 80%) as a yellow solid. MS: 159.1 (MH+).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[O:15]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=1)[CH2:12]2
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester (0.500 g, 1.6 mmol), 4-phenoxy-benzylamine (0.342 mL, 1.92 mmol), and K2CO3 (0.484 g, 3.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-methyl-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.212 g, 32%). GC-MS: m/z 407 (M)+, 314 (M−93)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([O:15]C)=[O:14])=[N:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)c1cc(-c2ccccc2)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(C(=O)O)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Methyl 1-methyl-5-phenylpyrazole-3-carboxylate (3.6 g) was dissolved in a mixed solvent of ethanol (20 ml) and water (20 ml) and sodium hydroxide (0.8 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (2.2 g), melting point: 149–150° C.
Reaction SMILES: [CH2:1]([C:6]1[S:7][C:8]2[N:9]=[C:10]([NH2:21])[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:13]=2[N:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1>>[NH2:21][C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:32]=[CH:33][C:23]([Cl:22])=[CH:24][CH:25]=3)[CH2:17][CH2:16]2)[C:13]2[N:14]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[S:7][C:8]=2[N:9]=1
Reactant: CCCCCc1nc2c(N3CCNCC3)nc(N)nc2s1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: CCCCCc1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Yield: 30 %

Procedure:
This compound was prepared from 2-pentyl-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 30%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=O)=[CH:5][CH:4]=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[CH:27][C:28]=1[F:29].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:31])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC(N)c1ccc(F)c(F)c1
Reactant: COc1ccc(C(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(F)c([N+](=O)[O-])c2)cc1
Yield: 86.9 %

Procedure:
Following a similar procedure to that described in Example (1a), 2.0 g of 4-fluoro-3-nitrophenyl 4-methoxyphenyl ketone, 2.81 g of 1-(3,4-difluorophenyl)ethylamine hydrochloride, 6.08 ml of triethylamine, 0.96 ml of titanium tetrachloride, 2.03 g of sodium cyanoborohydride and 0.62 ml of acetic acid were reacted, to obtain 2.63 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:24])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:17])=[CH:11][CH:10]=1.O=O>C(OCC)C>[C:21]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:22])[CH2:20][CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:24])=[CH:14][CH:13]=1)=[O:17]
Reactant: Cc1ccc(OC(=O)CCCC(=O)Cl)cc1
Reactant: CC(C)(C)OO
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCCC(=O)OOC(C)(C)C)cc1
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a vigorously stirred solution of 4.9 g. (0.045 mole) of 82.0% t-butyl hydroperoxide and 18.0 g. (0.045 mole) of aqueous 10% sodium hydroxide at 10°-14°C was slowly added 8.2 g. (0.034 mole) of 4-(p-tolyloxycarbonyl)butyryl chloride (prepared from p-tolyl 4-carboxybutyrate and thionyl chloride) in 25 ml. of diethyl ether. The reaction mixture was then stirred for 3.5 hours at 8°-10°C. After a work-up similar to that in Example I 8.2 g. (theory, 10.0 g.) of white solid, m.p. 50°-55°C, was obtained. The assay according to "active oxygen" content was 93.6% and the corrected yield was 76.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[N:28]([CH:32]([CH3:42])[C:33]([CH:35]2[C:40](=O)[CH2:39][CH2:38][O:37][CH2:36]2)=O)[N:27]=1>CCO>[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[N:28]([CH:32]([C:33]2[C:35]3[CH2:36][O:37][CH2:38][CH2:39][C:40]=3[N:17]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:18]=2)[CH3:42])[N:27]=1
Reactant: Cc1cc(C)n(C(C)C(=O)C2COCCC2=O)n1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 3.9 %

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (86 mg, 0.28 mmol) and potassium carbonate (77 mg, 0.56 mmol) in EtOH (7 mL) were heated to 60° C. for 10 min followed by the addition of 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (70 mg, 0.28 mmol). The reaction was stirred over night. Solvent was evaporated and the crude product was taken up in DCM and washed with water. The product was purified on a prepHPLC yielding 4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (5.00 mg, 3.89%). MS (ES+) m/z 460.2 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CC(C)=O>[N:20]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (2.1 equivalents). FAB-MS: (M+H)+ =372 (corresponds to C21H17N5O2); Rf value (toluene-acetone--4:6)=0.36.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:11]=[C:12]([CH3:24])[CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C([OH:29])(C)C.[Na]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2].S(=O)(=O)(O)O>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH:11]=[C:12]([CH3:24])[CH2:13][P:14]([O:16][CH:17]([CH3:18])[CH3:19])([O:20][CH:21]([CH3:23])[CH3:22])=[O:15])[C:9]([OH:29])=[O:10])=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(=C[C@H](CO)NC(=O)OC(C)(C)C)CP(=O)(OC(C)C)OC(C)C
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(C)=O
Product: CC(=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)CP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.6 g of alcohol 2 according to b) in 60 ml of acetone there are added at 0°-5° 3.3 ml of a solution that is 3.25 molar in chromium(VI) oxide and 5.29 molar in sulphuric acid. The mixture is stirred at 0° for 6 hours and at room temperature for 12 hours. After the addition of 5 ml of isopropanol and 40 ml of 20% sodium chloridesolution, the mixture is stirred for 10 minutes and is then extracted continuously with methyl acetate for 15 hours in a Kutscher-Steudel apparatus. The organic phase is dried over sodium sulphate and concentrated by evaporation, and the residue is chromatographed on 75 g ofsilica gel with hexane/ethyl acetate/acetic acid 16:10:1. This yields 0.92 g of 3, [α]D =-94.5° (c=1.2, CHCl3). 1H-NMR (300 MHz, CDCl3): 1.2-1.3 (4d, (2-propo)2); 1.4 (s, (CH3)3CO); 1.95 (d, J=3, CH3 --C(4)); 3.5 and 3.62 (2 d×d, J=23 and 15, 2H--C(5)); 4.66 (m, (2-propo)2); 4.92 (m, H--C(2)); 5.30 (m, H--C(3)); 5.42 (d, J=7, NH); 9.0-10.0 (broad, CO2H).
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:4]1[C:5]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C4CCOCC4)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C4CCOCC4)c(C=O)nc32)ncc1C#N

Procedure:
Concentrated hydrochloric acid (0.28 ml) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 310, 640 mg, 0.689 mmol) in THF (6 ml) and water (2 ml) at room temperature. After stirring for 4 h at room temperature saturated aqueous NaHCO3 was added, the mixture extracted with DCM, the organic layers dried over MgSO4 and evaporated. The residue was triturated with EtOAc and then filtered to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:11]1[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[C:15]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[N:16]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)nc(-c2ccccc2)n1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
A solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (172 mg, 1.4 mmol) in 5 ml of THF was added dropwise to a solution of 2,4-dichloro-6-phenyl-[1,3,5]triazine (452 mg, 2 mmol) (ref: WO 0125220, p. 190) and diisopropylethylamine (0.35 ml, 2 mmol) in 15 ml of THF at room temperature then stirred for 18 hours. The reaction was filtered and the filtrate evaporated in vacuo and the residue purified by flash chromatography (SiO2) eluting with 8:2 dichloromethane:ethyl acetate to afford 233 mg of the desired product. HPLC: Rt 6.803 mins. MS: m/z 313.0 (M+H)
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].C(Cl)(Cl)(Cl)[Cl:51]>C(#N)C.ClCCl>[Cl:51][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O

Procedure:
The same product is obtained from 8.05 g of 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 1b) by a 3.5-hour reaction with 8.66 g of triphenylphosphine in 85 ml of carbon tetrachloride and 30 ml of acetonitrile at room temperature. The reaction mixture is diluted with dichloromethane, shaken out with saturated bicarbonate solution and with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with dichloromethane and ethyl acetate, whereby 4.08 g of 7α-(5-chloropentyl)-estr-4-ene-3,17-dione is obtained, [α]D22 =+68° (c=0.5% in chloroform)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[F:24][C:25]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:4]1[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5c([nH]4)CCCC5)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 4-chloro-6-[2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-morpholinyl]-2-pyrimidinamine (208 mg, 0.623 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (200 mg, 0.809 mmol), Na2CO3 (165 mg, 1.557 mmol) and Pd(PPh3)4 (72 mg, 0.062 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washed by EtOAc (150 mL), evaporated, and chromatographed (PE-EtOAc, 3:1) to afford the title compound (150 mg) as a yellow solid. LC-MS (ES) m/z=420 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(CC)CC.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 4-methylpyridin-2-amine (25.0 g, 0.230 mol) and Et3N (35.0 g, 0.350 mmol) in CH2Cl2 (200 ml) was added pivaloyl chloride (33.1 g, 0.270 mol) drop-wise. The mixture was stirred for 4 h under N2 atmosphere. The reaction mixture was quenched with water and was extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, evaporated under vacuum and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford N-(4-methylpyridin-2-yl)pivalamide (36.2 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 8.08-8.09 (m, 2H), 8.00 (br s, 1H), 6.83 (dd, J=4.8, 0.6 Hz, 1H), 2.33 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]12)=[O:8].[N+](=[CH2:29])=[N-]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([O:24][CH3:29])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: C=[N+]=[N-]
Solvent: CCO
Product: COC(=O)C1=C(COC(N)=O)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12

Procedure:
7-(2-(2-Thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (50 milligrams) in ethanol was reacted with excess diazomethane. After five minutes the excess diazomethane was evaporated and the desired methyl ester crystallized with ethanol, then with chloroform, and with acetone. Nine milligrams of the desired 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, methyl ester were obtained, m.p., 212°-214° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.[F-].[Cs+]>COCCOC.CO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[C:5]([NH2:10])=[CH:4][N:3]=[C:2]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)[N:7]=1
Reactant: COc1nc(Cl)ncc1N
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: COCCOC
Product: COc1nc(-c2cnn(C)c2)ncc1N
Temperature: 150 °C
Yield: 92.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) was added to a solution of 2-chloro-4-methoxypyrimidin-5-amine (41 mg, 0.257 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg, 0.514 mmol) and cesium fluoride (117 mg, 0.771 mmol) in DME/MeOH (2/1, 1.6 mL). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes. The reaction was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified via Biotage silica gel column chromatography eluting with DCM/EtOH 99/1 to 90/10 followed by filtration through a SCX-2 column to afford the title product as a white solid (49 mg, 93%). 1H NMR (500 MHz, CDCl3): δ 3.68 (br s, 2H), 3.93 (s, 3H), 4.06 (s, 3H), 7.88 (s, 1H), 7.92 (s, 1H), 8.04 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.33 min, 206 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].CN(C=O)C.[CH3:10][C:11]1[C:19]2[O:18][N:17]=[C:16]([OH:20])[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO.O.C(OC(=O)C)C>[Cl:4][CH2:3][CH2:2][O:20][C:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[C:19]=2[O:18][N:17]=1
Reactant: Cc1cccc2c(O)noc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1cccc2c(OCCCl)noc12
Reaction time: 12 h
Yield: 68.5 %

Procedure:
1-Bromo-2-chloroethane (168 μl, 2.0 mmol) was added to 5 ml DMF in a 50 ml flask. 7-Methyl-benzo[d]isoxazol-3-ol (298 mg, 2.0 mmol), potassium carbonate (276 mg, 2.0 mmol) and additional DMF (5 ml) were added and the mixture was stirred for 12 h. Ethylacetate (50 ml) and H2O (50 ml) were added. The two phases were separated and the aqueous phase was extracted with ethylacetate. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to dryness to give 420 mg of the crude product. The crude product was subjected to column chromatography (0-5% methanol in dichloromethane) to give the pure title compound 41 (290 mg, 70%). 1H NMR (CDCl3) 2.5 (s, 3H), 3.9 (t, 2H), 4.7 (t, 2H), 7.2 (t, 1H), 7.3 (d, 1H), 7.5 (d, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O.CO>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[N:9][C:8]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 6-(2-chloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester (0.15 g) in tetrahydrofuran (2 mL), water (0.5 mL) and methanol (0.5 mL) was added at room temperature 1 ml of a 1M solution of lithium hydroxide in water and the mixture was stirred for 2 h. The resulting solution was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer was washed with water and brine. The organic phase was dried over magnesium sulfate and evaporated to yield 0.14 g of the title compound as white solid, MS (ISP) 304.1 (M+H)+.