Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])[CH:3]=1
Reactant: N#Cc1ccccc1F
Reactant: CC1(C)CC(=O)c2c(Br)c[nH]c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(Br)cn(-c3ccccc3C#N)c2C1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-4-one (670 mg, 2.77 mmol), 2-fluorobenzonitrile (0.3 mL, 2.77mmol) and K2CO3 (957 mg, 6.9 mmol) in DMSO (10 mL) was stirred at 100° C. for 3 h. The mixture was cooled to room temperature, poured into water and extracted into EtOAc (3×). The combined organic layers were washed with water (2×), dried (MgSO4) and evaporated. The title compound (858 mg, 91%) was isolated as a beige solid and used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.10 (6H,s), 2.42 (2H,s), 2.51 (2H,s), 6.83 (1H,s), 7.42 (1H,dd, J=7.9 and 0.9Hz), 7.64 (1H,dd, J=7.7 and 1.1 Hz), 7.78 (1H,dd, J=7.9 and 1.5 Hz), 7.85 (1H,dd, J=7.7 and 1.4 Hz). MS (ES+) 343/345 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[N:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 38.8 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1.0 mmol) was reacted with tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (419 mg, 1.5 mmol) to afford the desired product (215 mg, 39%) as a yellow solid. ESI MS m/z 553 [C26H29BrN6O3+H]+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:2]12.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:33]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:23]>>[CH3:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][C:22]([C:21]1[CH:33]=[C:17]([N:1]2[CH2:5][CH2:4][C@H:3]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:2]23)[CH:18]=[N:19][CH:20]=1)=[O:23]
Reactant: Cc1ccccc1CNC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN[C@@H]2C1
Product: Cc1ccccc1CNC(=O)c1cncc(N2CC[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]32)c1

Procedure:
Prepared from (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (prepared as described in WO2001081347) and the product from Example 31A using the procedure as described in Example 31B. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]1([NH:29][CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:29]([CH2:30][CH2:31][OH:32])[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OCCNC1CCCCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N(CCO)C1CCCCC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(cyclohexylamino)ethanol (1.2 equiv) to give 173 (14.1 mg, M+1 439.1)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[C:17]12[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH:22]C(=O)O[C:18]2=[O:19].C(OCC)(=O)C>CN(C)C=O.O>[N:16]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:18](=[O:19])[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:22])[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(c2ncccn2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccccc1C(=O)NCCCN1CCN(c2ncccn2)CC1
Reaction time: 1 h

Procedure:
0.02 mol of 1-(3-aminopropyl)-4-(2-pyrimidinyl)piperazine is dissolved in 100 ml of absolute dimethylformamide, 0.02 mol of isatoic anhydride is added, and the mixture is stirred for 1 hour. It is diluted with 50 ml of water, shaken with ethyl acetate and the organic phase is evaporated. Purification is by column chromatography over silica gel 60. After elution with methylene chloride/methanol 93:7, the resulting oil can be crystallised from ethyl acetate with isopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[S:32][C:31]2C(I)=[N:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]=2[CH:26]=1)=[O:24].ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(N1C2C(=CC(CO)=CC=2)C=C1C1C2SC=CC=2N(C(OC(C)(C)C)=O)N=1)=O)(C)(C)C.N#N.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:21][O:22][C:23]([C:25]1[S:32][C:31]2[C:20]([C:9]3[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]4[C:11]([CH:10]=3)=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=4)=[N:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]=2[CH:26]=1)=[O:24]
Reactant: COC(=O)c1cc2c(s1)c(I)nn2C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)OC(=O)n1nc(-c2cc3cc(CO)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)c(-c1cc3cc(C(C)=O)ccc3n1C(=O)OC(C)(C)C)nn2C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
In a Smith process vial (10-20 mL capacity) is placed 5-acetyl-2-methyl-indole-1-carboxylic acid tert-butyl ester (436 mg, 1.44 mmol, Intermediate (20)], 3-iodo-thieno[3,2-c]pyrazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester [392 mg, 0.960 mmol, Intermediate (21)], [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium with dichloromethane adduct (78 mg, 0.0955 mmol), cesium carbonate (938 mg, 2.88 mmol) and a mixture of 1,4-dioxane/water (10:2 mL). The reaction tube is filled with N2 and sealed using capping device. The reaction mixture is heated at 90° C. via microwave (Personal chemistry optimizer) for 10 minutes. Water is pipetted out and added solid sodium sulfate. The organic phase is directly loaded onto 10 g silica gel cartridge and chromatographed on 35 g silica gel cartridge (20-30% ethyl acetate gradient in heptane) to afford 3-(5-acetyl-1-tert-butoxycarbonyl-1H-indol-2-yl)-thieno[3,2-c]pyrazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester (230 mg, Example 35) as white solid; 1H NMR [(CD3)2SO)]: δ 8.388 (1H, s), 8.199 (1H), 8.055 (1H), 7.901 (1H, s), 7.339 (1H, s), 3.914 (3H, s), 2.662 (3H, s), 1.671 (9H, s), 1.365 (9H, s); LC/MS: 540 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:41]([C:38]3[CH:37]=[CH:36][C:35]([C:32]4[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=4)=[CH:40][CH:39]=3)(=[O:43])=[O:42])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CCCc4c(OCC(=O)OC(C)(C)C)cccc43)cc2)cc1

Procedure:
Starting from (R)-(5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (28 mg, 0.1 mmol), triethylamine (0.02 mL, 0.11 mmol) and 4′-methyl-biphenyl-4-sulfonyl chloride (29 mg, 0.11 mmol), using the method analogous to the one for example 1-1, method A, 4th step, crude [(R)-5-(4′-methyl-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was obtained, which was used in the next step without further purification. MS cald. for C29H33NO5S 507, obsd. 508 [(M+H)+].
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH3:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][NH:16][C:15]([NH:14][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:3])[CH:13]=2)=[O:28])[CH2:20][CH2:21]1)=[O:27]
Reactant: Cc1cc(NC(=O)NCCN2CCC(C(=O)O)CC2)c2ccccc2n1
Reactant: CNc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)NCCN2CCC(C(=O)N(C)c3ccccc3)CC2)c2ccccc2n1
Reaction time: 15 h

Procedure:
To a suspension of 1-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-piperidine-4-carboxylic acid dihydrochloride (64.25 mg, 0.15 mmol), TEA (0.07 mL, 0.5 mmol) and N-methylaniline (11 mg, 0.1 mmol) in DMF (0.6 mL) is is added T3P (50% in EtOAc, 0.07 mL, 0.12 mmol) at room temperature. The mixture is stirred for 15 h, quenched with sat. Na2CO3 (5 mL) and extracted with CH2Cl2 (3×10 mL). The organic phases are dried (Na2SO4), filtered, evaporated and the residue purified by preparative HPLC to provide the title compound.
Reaction SMILES: C(O[CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[NH:29]1[CH:36]=[CH:35][C:33]([NH2:34])=[N:32][C:30]1=[O:31].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S([O-])(=O)=O.[K+].C[Si](N[Si](C)(C)C)(C)C.[Si](Cl)(C)(C)C.C([O-])(O)=O.[Na+]>C(#N)C.ClCCl>[Si:12]([O:11][CH2:10][C@H:8]1[S:9][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33]([NH2:34])=[N:32][C:30]2=[O:31])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Reactant: Nc1cc[nH]c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CC[C@H](n2ccc(N)nc2=O)S1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 10 (0.26 g, 0.63 mmol), cytosine (0.105 g, 0.95 mmol), and potassium nonafluorobutanesulfonate (0.77 g, 2.3 mmol) was suspended in 12 mL dry acetonitrile under nitrogen. HMDS (0.135 mL, 0.63 mmol) and TMS-Cl (0.37 mL, 2.9 mmol) were added sequentially via syringe and the reaction stirred at 25° C. overnight. The reaction was poured into a mixture of 20 mL dichloromethane and 15 mL saturated NaHCO3 and shaken. The organic phase was dried (MgSO4) and concentrated in vacuo. The anomeric mixture was separated by preparative TLC with 7.5% MeOH/CHCl3 with an ammonia atmosphere: yield of β-anomer, 78 mg and 117 mg of the α-anomer to afford total yield of 195 mg (66.5%); FAB MS 466 (M+H)+ ; 1H NMR (CDCl3) of α/β anomer, δ 8.12 (d, 1, 6-H), 7.7 (m, 4, ArH), 7.4 (m, 6, ArH), 6.32 (m, 1, 1'-H), 5.9-5.3 (hump, 1, NH2), 5.75 (d, 1, 5-H), 5.45 (d, 1, 5-H), 3.75 (m, 3, 4'-Hα,β 's, 3'-Hα,β 's).
Reaction SMILES: BrCCBr.[Si](Cl)(C)(C)C.Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.Br[Zn]CC1C=CC(C(OC)=O)=CC=1.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1>C1COCC1.[NH4+].[Cl-].O.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:37]1[CH:38]=[CH:39][N:40]=[C:36]1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: Brc1nccs1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(=O)c1ccc(C[Zn]Br)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: BrCCBr
Product: COC(=O)c1ccc(Cc2nccs2)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Zinc dust, <10 micron (2.227 g, 34.1 mmol) was suspended in THF (5 ml), and 1,2-dibromoethane (0.090 ml, 1.048 mmol) was added. The mixture was stirred for 10 min at 70° C. It was then cooled to room temperature, and TMS-Cl (0.100 ml, 0.786 mmol) was added. After 30 min at room temperature, the activated zinc was cooled to 0° C., and methyl 4-(bromomethyl)benzoate) (6.00 g, 26.2 mmol) in THF (20 ml) was added drop-wise over 75 min (˜2 mL every ˜5-7 min). After stirring for another 1 h at 0° C., another portion of THF (25 ml) was added to dilute to ˜0.5 M. The gray suspension was allowed to stand so the remaining zinc solid would settle, and the supernatant was used as bromo[4-(methoxycarbonyl)benzyl]zinc (0.5 M in THF). Palladium(II) acetate (103 mg, 0.457 mmol), and 2-dicylochexylphosphino-2′,6′-dimethoxy-1′,1′,biphenyl (375 mg, 0.915 mmol) were combined in a flask, sealed, and flushed with nitrogen (2×). Degassed THF (15 ml), 2-bromothiazole (0.408 ml, 4.57 mmol), and the freshly prepared 0.5 M bromo[4-(methoxycarbonyl)benzyl]zinc in THF (27.4 ml, 13.72 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NH4Cl and water before being extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-(1,3-thiazol-2-ylmethyl)benzoate (1.06 g, 4.54 mmol, 99%) as a yellow oil that crystallized upon standing. MS ESI: [M+H]+ m/z 234.0.
Reaction SMILES: [Cl:1]Cl.[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18]([O:25]C(=O)C)=[CH:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:29][CH3:30])[CH:8]=1)(=[O:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@H:17]([Cl:1])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:29][CH3:30])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(OC(C)=O)=CC[C@H]3[C@@H]1CC2
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@H](Cl)C[C@H]3[C@@H]1CC2

Procedure:
A solution of Cl2 (0.162 g, 2.3 mM) in 5 ml of carbon tetrachloride is added over a period of 30 min to a stirred suspension of 1,17-diacetoxy-3-methoxyestra-1,3,5(10),16-tetraene (0.77 g, 2 mM), K2CO3 (5 g) and 25 ml of CCl4 at 0°. Dilute aqueous sodium thiosulfate is then added, the layers are separated and the aqueous layer is extracted with 2 × 50 ml chloroform. The organic layers are combined, dried over MgSO4 and evaporated in vacuo. The residue is triturated with ether to give a white solid. Recrystallization from methanol gives 1-acetoxy-16α-chloro-3-methoxyestra-1,3,5(10)-trien-17-one, yield 0.64 g (76%); m.p. 194.5°-196°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(OB(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.C1(C)C=CC=CC=1>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccn1
Reactant: OB(O)Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Into a reactor were introduced 0.79 g (5.0 mmol) of 2-bromo-pyridine, 0.73 g (6.0 mmol) of phenylboric acid, 1.38 g (10.0 mmol) of potassium carbonate, 11.2 mg (0.05 mmol) of palladium acetate, 39.1 mg (0.1 mmol) of the 1,1-diphenyl-2-(dicyclohexylphosphine)propene obtained in Example 2, 5.0 ml of water, and 15.0 ml of toluene under a nitrogen atmosphere. The resultant reaction mixture was stirred at 80° C. for 4 hours and then cooled. Thereafter, the solvent was removed under pressure. The concentrate was purified by column clromatography to obtain 0.66 g (85%) of 2-phenylpyridine as the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.O.C(#N)C>CN(C=O)C>[CH:27]1([NH:31][C:2]2[N:7]=[C:6]3[CH:8]=[N:9][CH:10]=[CH:11][C:5]3=[N:4][C:3]=2[N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:14][CH2:13]2)[CH2:30][CH2:29][CH2:28]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: NC1CCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
To a solution of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (10 g, 26.5 mmol) in DMF (150 mL) was added cyclobutanamine (15.10 g, 212 mmol) at rt. Then the mixture was stirred at 70° C. for 15 h. After the reaction was done, the reaction mixture was poured into water/ACN (200 mL, 7:3). The suspension was filtered and rinsed with ACN to give the title compound (8.5 g, 78%). ESI-MS m/z [M+H]+ 412.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([CH:17]=[O:18])[NH:15][CH:16]=[C:10]2[C:9]1=[O:19])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[O:19]=[C:9]1[C:10]2=[CH:16][NH:15][C:14]([CH:17]=[O:18])=[C:11]2[CH2:12][CH2:13][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c[nH]c2C=O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1[nH]cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A mixture of 1-formyl-4-oxo-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (1.2 g, 4.54 mmol) in 50% of trifluoroacetic acid in dichloromethane was stirred at room temperature for 30 minutes. The reaction was concentrated and the residue was recrystallized from dichloromethane to give 400 mg (75%) of 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH:26][C:27](=[O:41])[C:28]4[CH:33]=[CH:32][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:30][CH:29]=4)[N:25]=3)[CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9]CC1C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:9][C:8]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH:26][C:27](=[O:41])[C:28]4[CH:29]=[CH:30][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:32][CH:33]=4)[N:25]=3)[CH:22]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(-c2ccc3nc(NC(=O)c4ccc(CN5CCCCC5)cc4)nn3c2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3nc(NC(=O)c4ccc(CN5CCCCC5)cc4)nn3c2)ccc1O
Temperature: 75 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
N-(6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4-(piperidin-1-ylmethyl)benzamide (14.9 mg, 0.027 mmol) was treated with trifluoroacetic acid (2 mL) and the reaction mixture was stirred for 1 hour at 75° C. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (1.4 mg, 11%). HPLC, Rt: 2.23 min (purity: 99%). LC/MS M+(ESI): 458.2, M−(ESI) 456.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1.[CH3:32]N(C=O)C.[H-].[Na+].IC>O>[NH2:1][C:2]1[C:7]([N:8]([CH3:32])[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1
Reactant: CCOC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
54 mg (0.13 mmol) of ethyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 2 are added to 5 ml of DMF, the mixture is cooled to 0° C., and 7.67 mg (0.19 mmol) of sodium hydride are added. Then 18.14 mg (0.13 mmol) of iodomethane are added dropwise, and the mixture is stirred for one hour. The mixture is mixed with water and extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is purified first by column chromatography (mobile phase: dichloromethane/methanol=10:1) and then by preparative RP-HPLC.
Reaction SMILES: [Na].[Na].[C:3]([CH2:6][CH2:7][C:8]1[N:9]=[N:10][NH:11][C:12]=1[SH:13])([OH:5])=[O:4].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:12]3[NH:11][N:10]=[N:9][C:8]=3[CH2:7][CH2:6][C:3]([OH:5])=[O:4])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CCc1nn[nH]c1S
Agent: [Na]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3[nH]nnc3CCC(=O)O)CS[C@H]12

Procedure:
When an equivalent amount of 4-(2-carboxyethyl)-1,2,3-triazol-5-thiol disodium salt, prepared as in Example 8, is reacted with 7-aminocephalosporanic acid by the procedure of Example 8, 7-amino-3-[4-(2-carboxyethyl)-1,2,3-triazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid is obtained.