Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.C(O)C.CC(N=C=NC(C)C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[NH:30][C:31]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[C:2]([N:1]=1)=[CH:7][N:6]=[C:5]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([OH:15])[CH2:13][CH2:14]1)[N:4]=2
Reactant: Nc1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Reactant: Fc1cccc(F)c1N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H]1CC[C@H](Nc2ncc3nc(Nc4c(F)cccc4F)n(C4CCCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-{[5-Amino-4-(cyclopentylamino)pyrimidin-2-yl]amino}trans-cyclohexan-1-ol (1.13 mmol, 330 mg) was dissolved in DMF (8.5 mL) and 2,6-difluorophenyl-isothiocyanate (1.13 mmol, 0.146 mL) was added. The reaction mixture was stirred at room temperature for about 90 minutes. Ethanol (2.5 mL) was added and the reaction mixture was stirred for about an additional 30 minutes. N,N-Diisopropylcarbodiimide (3.40 mmol, 0.532 mL) was added and the reaction mixture was stirred overnight. Solvent was removed and the residue was purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→ethyl acetate→1% methanol/ethyl acetate) to give the desired product (222.5 mg, 46% yield). ES-MS: 429 (M+1). Tetrahydrofuran can also be used as solvent in this step.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH3:30][C:31]([CH3:37])([CH3:36])[CH2:32][CH2:33]C=O>>[CH3:30][C:31]([CH3:37])([CH3:36])[CH2:32][CH2:33][C:21]1[C:20]2[C:19]([F:22])=[CH:18][C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: CC(C)(C)CCC=O
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC(C)(C)C

Procedure:
The product of Example 100 is treated with 4,4-dimethylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])=[N:10][N:11]3[CH2:15][CH2:14][S:13][C:12]=23)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>S(Cl)(Cl)=O.C(OCC)(=O)C>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([C:9]3[C:8]([C:5]4[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=4)=[C:12]4[S:13][CH2:14][CH2:15][N:11]4[N:10]=3)[CH:17]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(-c3nn4c(c3-c3ccncc3)SCC4)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
3-(7-Pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-benzoic acid hydrochloride (45 mg, 0.125 mmol) was dissolved in thionylchloride (1 mL) and stirred at 60° C. for 1 hour. The solvent was distilled and the residue was taken up with toluene, evaporated to dryness and dried under high vacuum for 1 h. The acid chloride was then dissolved in dry pyridine (1 mL) under nitrogen and 4-tert-butylaniline (0.030 mL, 0.187 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 1 h and then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluant DCM/EtOH 95:5 to give 44 mg of N-(4-tert-butyl-phenyl)-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-benzamide as a white solid (77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:17]=1[CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][C:17]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:16]=4[F:15])[CH2:24][CH2:23]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(F)c(CC2CCNCC2)c1
Reactant: O=C1CCC(c2ccc(F)cc2)CC1
Product: Fc1ccc([C@H]2CC[C@H](N3CCC(Cc4cc(F)ccc4F)CC3)CC2)cc1

Procedure:
4-(4-Fluorophenyl)cyclohexanone and 4-(2,5-difluorobenzyl)piperidine were reacted as described in example 9 to give the product (36%, mp: 80°-81° C.). Calc'd for C24H28F3N: C, 74.40%; H, 7.29%; N, 3.18%. Found: C, 74.25%; H, 7.29%; N, 3.56%.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C(=O)(O)[O-].[Na+].[CH3:17][CH:18](O)[CH3:19]>Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:18]([CH3:19])[CH3:17])=[O:10]
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)OC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a solution of 355 mg of 2-pyridylacetic acid hydrochloride in 5 ml of 2-propanol, hydrogen chloride was saturated at 0° C., and the solution was stirred for 10 hours at room temperature. Sodium bicarbonate was added to the reaction mixture to make alkaline, and the solution was extracted with 50 ml of diethyl ether. The ethereal layer was washed successively with water and a suturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 305 mg of isopropyl 2-pyridylacetate as an oil.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]([CH3:16])[CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[F:34].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:20]2[CH2:19][CH2:18][N:17]([CH:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:23])[CH:14]([CH3:16])[CH3:15])[CH2:22][CH2:21]2)=[O:30])=[CH:27][C:26]=1[F:34]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of N-tert-butyl-3-(2-methyl-1-(piperazin-1-yl)propyl)benzamide (13.6 mg, 0.043 mmol), 4-amino-3-fluorobenzoic acid (10 mg, 0.065 mmol), N-ethyl-N-isopropylpropan-2-amine (11 mg, 0.086 mmol) and 1-propanephosphonic acid cyclic anhydride (55 mg, 0.086 mmol, 50% solution in ethyl acetate) in dichloromethane (2.0 mL) was stirred at room temperature for 2 hours. The mixture was treated with strong cation exchange column chromatography and purified with silica column chromatography (eluting with 33% ethyl acetate in heptane then 66% ethyl acetate in heptane) to afford the title compound (11.8 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20](=[O:21])[NH:19][CH2:18][CH2:17][N:16]3[CH3:22])=[CH:11][CH:10]=2)[C:5](=[O:23])[N:4]([CH3:24])[CH:3]=1.[C:25]([C:29]1[S:36][C:35]2[C:34](=[O:37])[N:33]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40](B4OC(C)(C)C(C)(C)O4)[C:39]=3[CH3:53])[CH2:32][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:25]([C:29]1[S:36][C:35]2[C:34](=[O:37])[N:33]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:2]4[N:7]=[C:6]([NH:8][C:9]5[CH:14]=[CH:13][C:12]([CH:15]6[C:20](=[O:21])[NH:19][CH2:18][CH2:17][N:16]6[CH3:22])=[CH:11][CH:10]=5)[C:5](=[O:23])[N:4]([CH3:24])[CH:3]=4)[C:39]=3[CH3:53])[CH2:32][C:31]=2[CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Reactant: CN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
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
Product: Cc1c(-c2cn(C)c(=O)c(Nc3ccc(C4C(=O)NCCN4C)cc3)n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 110 °C
Yield: 12.6 %

Procedure:
A 5-mL reaction tube equipped with a magnetic stirrer was charged with 104d (65 mg, 0.166 mmol), 102g (68 mg, 0.166 mmol), sodium carbonate (53 mg, 0.498 mmol) dioxane (1.0 mL) and water (0.2 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (19 mg, 0.017 mmol) was added, and the tube was sealed. After heating at 110° C. (bath temperature) for 16 h, the reaction mixture was cooled to room temperature and concentrated to a residue. The resulting residue was purified by flash chromatography on silica gel. This material was further purified using a preparative HPLC to afford a 13% yield (12.5 mg) of 104 as a yellow solid: mp 174-176° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 7.82 (d, 1H, J=4.5 Hz), 7.43 (t, 2H, J=8.0 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.22 (s, 1H), 7.19 (d, 2H, J=8.5 Hz), 7.14 (s, 1H), 4.78 (s, 2H), 3.55 (s, 3H), 3.52 (s, 1H), 3.40 (td, 1H, J=11.0, 3.5 Hz), 3.13 (m, 1H), 2.90 (dd, 1H, J=6.0, 3.0 Hz), 2.47 (m, 1H), 2.24 (s, 3H), 2.05 (s, 3H), 1.42 (s, 9H); MS (ESI+) m/z 597.7 (M+H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]1[O:40][C:39]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=2[O:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:33]1[C:34]2[CH:35]=[CH:36][C:37]([N:18]3[C:19]4[C:15](=[CH:14][C:13]([C:11]([N:8]5[CH2:7][CH2:6][N:5]([CH:1]6[CH2:2][CH2:3][CH2:4]6)[CH2:10][CH2:9]5)=[O:12])=[CH:21][CH:20]=4)[CH:16]=[C:17]3[C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:38][C:39]=2[O:40][CH2:32]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc2c(c1)OCO2)N1CCN(C2CCC2)CC1
Yield: 24 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,4-methylenedioxybenzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (24%).
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]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:24]>>[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][N:28]([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:20])[CH2:27]1)[CH3:24]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CCN(CC)[C@@H]1CCNC1
Product: CCN(CC)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

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 (R)—N,N-diethylpyrrolidin-3-amine (1.2 equiv) to give 202 (M+1 438.0)
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[Cl:21][C:22]1[C:23]([NH2:30])=[N:24][C:25]([NH2:29])=[N:26][C:27]=1Cl.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:21][C:22]1[C:27]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)[CH3:19])=[N:26][C:25]([NH2:29])=[N:24][C:23]=1[NH2:30]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 14.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (95 mg, 0.372 mmol), 5,6-dichloropyrimidine-2,4-diamine (100 mg, 0.559 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.20 mL, 1.1 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then at 160° C. for 1.5 hours. The mixture was concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30% ACN in water. The fractions containing the desired compound were combined and extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (21 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 1.38 (d, J=6.35 Hz, 3 H), 3.65 (s, 3 H), 3.83-3.89 (m, 3 H), 5.38 (q, J=6.67 Hz, 1 H), 6.40-6.46 (m, 1 H), 6.65-6.70 (m, 1 H), 7.58-7.64 (m, 2 H), 7.80 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H20ClN9, 398; found 398.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([NH2:8])=[N:5][CH:4]=1)[CH3:2].[C:9]1([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([C:3]1[O:7][C:6]([NH:8][C:16](=[O:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCc1cnc(N)o1
Product: CCc1cnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 148-149° C. and MS: m/e=307.3 (M+H+) was prepared in accordance with the general method of example 44a from 5-ethyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.S1C2C=CC=CC=2N=C1S[C:37](=[O:46])[C:38]([C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1)=[O:39]>ClCCl>[NH2:45][C:42]1[S:43][CH:44]=[C:40]([C:38](=[O:39])[C:37]([NH:1][CH:2]2[C:13](=[O:14])[N:4]3[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]23)=[O:46])[N:41]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 72 %

Procedure:
4.28 g of 7-amino-3-methylceph-3-em-4-carboxylic acid are suspended under a nitrogen atmosphere in 80 ml of dry dichloromethane, and mixed with 5.4 ml of N,O-bis(trimethylsilyl)acetamide. The preparation is stirred at room temperature until a clear solution is present, and then cooled to -15°. 8.4 g of 2-(2-amino-4-thiazolyl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added, and stirred for one hour at -15°, one hour at 0° and then two hours at +20°. The solvent is carefully drawn off on a rotary evaporator, and the oily residue is rubbed with 50 ml of ethanol. The resultant deposit is filtered, washed with ethanol and ether, and vacuum dried at 40°. 5.3 g of the title compound are obtained as a yellow powder.
Reaction SMILES: C1(COC(=O)[N:10]([CH2:12][C:13]2[N:22](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=[C:19](Br)[CH:20]=[C:15]3[N:14]=2)[CH3:11])C=CC=CC=1.[CH3:32][C:33]1([CH3:57])[CH2:42][CH2:41][C:40]2[N:39]=[CH:38][N:37]=[C:36]([N:43]3[CH2:49][C:48]4[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][C:47]=4[O:46][CH2:45][CH2:44]3)[C:35]=2[CH2:34]1>>[CH3:32][C:33]1([CH3:57])[CH2:42][CH2:41][C:40]2[N:39]=[CH:38][N:37]=[C:36]([N:43]3[CH2:49][C:48]4[CH:50]=[C:51]([C:19]5[CH:20]=[C:15]6[NH:14][C:13]([CH2:12][NH:10][CH3:11])=[N:22][C:16]6=[N:17][CH:18]=5)[CH:52]=[CH:53][C:47]=4[O:46][CH2:45][CH2:44]3)[C:35]=2[CH2:34]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CN(Cc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Product: CNCc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl}methylcarbamate (reagent preparation 19) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.62 (br, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.62 (br, 1H), 7.53 (d, 1H), 7.09 (d, 1H), 4.74 (s, 2H), 4.38 (m, 2H), 4.22 (s, 2H), 3.97 (m, 2H), 2.77 (t, 2H), 2.59 (s, 3H), 2.48 (s, 2H), 1.68 (t, 2H), 0.88 (s, 6H); MS (EI) for C27H31N7O: 470 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=O)[CH:18]=2)[CH:13]=[N:12]1>CO.N1CCCCC1>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)[CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To a mixture of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol) in MeOH (2 mL) was added 1 drop of piperidine via syringe needle. The resulting mixture was refluxed for 2 h (oil temp. 70° C.) and then cooled to rt. The resulting precipitate was collected by suction filtration to give the title compound as a yellow solid (37 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H, NH), 11.25 (s, 1H, NH), 8.16 (s, 1H), 8.10 (d, J=5.2 Hz, 1H), 7.93-7.87 (m, 4H), 7.44 (d, J=8.8 Hz, 1H), 6.90 (dd, J=7.6 Hz, 5.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][C:36]([CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[CH:37][CH:38]=1)CCC>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:34]5[O:35][C:36]([CH:39]6[O:43][CH2:42][CH2:41][O:40]6)=[CH:37][CH:38]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine (4.3 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem. Soc., Chem Commun., (1988), 560) (10 g) and 1,4-bis(diphenylphosphino)palladium(II)chloride (1 g) in dioxane. The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound δH [2H6]-DMSO 10.13 (1H, s), 8.85 (1H, s), 8.54 (1H, s), 8.20 (3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H, d), 6.79 (1H, d), 6.04 (1H, s), 5.71 (2H, s), 4.15 (4H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[CH2:23][C:22](=[O:24])[C:21]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl>[Si:11]([O:18][CH:19]1[CH2:23][C:22](=[O:24])[C:21]([S:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C(SCCCCO)C(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OC1C=C(SCCCC=O)C(=O)C1
Temperature: -30 °C
Reaction time: 0.05 h
Yield: 61 %

Procedure:
Oxalyl chloride (48 microliters; 0.55 mmole) was dissolved in 2 ml of dry dichloromethane, and the solution was cooled to -30° C. Dimethyl sulfoxide (78 microliters; 110 mmoles) was added, and the mixture was stirred for 3 minutes. A solution of 158 mg (0.5 mmole) of 4(R)-t-butyldimethylsilyloxy-2-(4-hydroxybutylthio)-2-cyclopentenone in 1 ml of dry dichloromethane was added over the course of 1 minute, and the mixture was stirred at -30° C. for 30 minutes. Then, 5 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (5/1) to give 96 mg (yield 61%) of 4(RS)-t-butyldimethylsilyloxy-2-(4-oxobutylthio)-2-cyclopentenone.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCCCC2)c2ccccc21

Procedure:
The product obtained from Example 23 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as an oil. Mass. Spec. Calcd. for C22H25N3O4 : 394 (M+H). Found: 394.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][S:10]C)=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].IC1C=CC=C(CC([O-])=O)C=1CC([O-])=O.S(=O)(O)[O-].[Na+]>O>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][SH:10]=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: CSCc1cnc(Cl)c(Cl)c1
Reactant: N#CN
Agent: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: N#CN=[SH]Cc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,3-dichloro-5-methylthiomethylpyridine (3.5 g, 16.8 mmol) and cyanamide (1.43 g, 34 mmol) cooled in an ice-water bath was added iodobenzenediacetate (6.76 g, 21 mmol) in one portion. The resulting mixture was stirred at 0° C. for 30 min and then continued at room temperature for 1 h. A solution of sodium bisulfite (2 g) in water (50 mL) was added and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phase was dried over MgSO4 and the solvent evaporated to give a dark red oily residue which was triturated with boiling ether (2×40 mL) with the ether being discarded each time. After standing at room temperature overnight, the residue solidified, which was triturated with hot ethyl acetate (25 mL). Upon cooling down, the off-white solid product was collected by filtration and dried. Concentration of the filtrate and repeating the trituration process gave additional product. The total yield for the product [1-(5,6-dichloropyridin-3-yl)methyl]-λ4-sulfanylidenecyanamide was 2.45 g (58.8%). LC-MS: calcd for C8H7Cl2N3S [M]+ 247. Found 247.