Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.C(O)(C)(C)C.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2([F:30])[F:29].C(N(CC)CC)C>C(O)(C)(C)C.ClCCCl.[Cl-].[Zn+2].[Cl-].C(OCC)C.ClCCCl>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[C:22]3([F:30])[F:29])[N:5]=1
Reactant: Nc1ccc2c(c1)C(F)(F)C(=O)N2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2C1(F)F
Temperature: 25 °C
Yield: 31 %

Procedure:
316 mg (1.46 mmol) 5-trifluoromethyl-2,4-dichloropyrimidine was taken into 2.30 mL of a 1:1 mix of tert-butanol and 1,2-dichloroethane. To this solution was added 1.46 mL (1.46 mmol) zinc chloride solution (1.0 M in ether). The reaction solution was allowed to stir at ambient temperature for thirty minutes. 1.31 mmol 5-Amino-3,3-difluoro-1,3-dihydro-indol-2-one was added drop-wise as a suspension in 500 □L tert-butanol/1,2-dichloroethane solvent mixture. 202 □L (1.46 mmol) triethylamine was slowly added to the slurry. A slight exotherm and severe clumping was noted (Too much diethyl ether to allow for solution). Allowed the reaction mixture to stir at ambient temperature overnight (16 hours). A complete solution had been achieved over the period. All volatiles were removed under reduced pressure to reveal a brown foam. Triteration from methanol gave the titled compound as a tan solid upon filtration in 31% yield (164 mg, 0.450 mmol). APCI m/z 365.2/367.2 (MH+); 1H NMR (D6-DMSO) δ 11.17 (s, 1 exchangeable H), 10.73 (s, 1 exchangeable H), 8.80 (bs, 1 H), 8.00 (bs, 1 H), 7.69 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1 H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[CH3:24]O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(N)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.4 %

Procedure:
To a solution of 2.5 g (7.8 mmol) of (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of methanol was added 0.125 g (0.66 mmol) of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 2 days and then concentrated to a small volume. The residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to a solid. Recrystallization of this solid from hexane-ethyl acetate gave 2.48 g of methyl (E)-6-(4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 91°-93° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([C:37]([OH:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([F:41])[C:32]=1[C:42]1[N:47]=[C:46]([C:48](O)=[O:49])[CH:45]=[CH:44][C:43]=1[F:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:48]([C:46]3[CH:45]=[CH:44][C:43]([F:51])=[C:42]([C:32]4[C:31]([F:30])=[CH:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:34][C:33]=4[F:41])[N:47]=3)=[O:49])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (299 mg, 0.739 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (230 mg, 0.739 mmol) and HATU (562 mg, 1.48 mmol) in DMF (0.7 mL) and DIPEA (0.386 mL, 2.22 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water, the mixture was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give an amide intermediate, 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25][NH2:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: COc1cc(CN)cc(OC)c1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cc(OC)cc(OC)c1
Yield: 87 %

Procedure:
The compound prepared in Example 3 was reacted with 3,5-dimethoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:21](=[O:22])[C@H:20]3[N:11]([CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH2:19]3)[C:10]2=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][C:20]23[C:21](=[O:22])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:10](=[O:23])[N:11]2[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:19]3)=[CH:27][CH:26]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1[C@@H]2Cc3ccccc3CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)Cc3ccccc3CN12
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of (S)-2-(3,5-dichloro-phenyl)-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione (100 mg) (0.1 mmol) (Prep. 22) in 2.5 mL of dry THF at −40° C. was added a 1 M solution of LIHMDS (0.5 mL) in THF. The reaction mixture was stirred for 15 min. at −40° C. and a solution of 4-bromobenzyl bromide (70 mg) in 1 mL of dry THF was added. The reaction mixture was stirred at −50 C. for 30 min., allowed to warm to RT, stirred overnight, then partitioned between brine and t-Bu methyl ether. The organic layer was dried over MgSO4, concentrated in vacuo, and the residue purified by HPLC to afford the above compound (34.5 mg). NMR (CDCl3, 200 MHz): 7.45 (2H, d), 7.25-7.35 (5H, m), 6.95-7.0 (4H, d+d), 5.15 (1H, d), 4.55 (1H, d), 3.25 (2H, s), 3.20 (1H, d), 2.95 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2
Reactant: C#Cc1ccccc1
Reactant: COc1ccc2c(=O)[nH]ncc2c1OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture under N2 of trifluoro-methanesulfonic acid 6-methoxy-1-oxo-1,2-dihydrophthalazin-5-yl ester (1 g, 3.08 mmoles), prepared as described in example 59, phenylacetylene (0.507 ml, 4.62 mmoles), bis(triphenylphosphine)PdCl2 (108 mg, 0.154 mmole), triethylamine (1.71 ml, 12.32 mmoles) in DMF (20 ml) was heated at 90° C. under stirring for 3 hours, then cooled, poured into water and extracted with CH2Cl2. The extract was washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was taken up in ethyl ether and filtered to give 680 mg of the title compound (yield: 80%).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:39][CH2:40][O:41][CH3:42])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][NH:15][C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][CH:32]=[C:31]4[CH3:37])=[O:25])[C:19]([CH3:38])=[CH:18][N:17]=2)[CH:8]=1)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH3:42][O:41][CH2:40][CH2:39][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][CH2:14][NH:15][C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[C:31]3[CH3:37])=[O:25])[C:19]([CH3:38])=[CH:18][N:17]=1
Reactant: COCCN(Cc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCNCc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Temperature: 50 °C
Reaction time: 56 h

Procedure:
2,2,2-Trifluoro-N-(2-methoxyethyl)N-[3-(2-{[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2 pyrazinyl]amino}ethyl)benzyl]acetamide (preperation 45) (110 mg, 0.18 mmol) was dissolved in methanol(15 ml) and sodium carbonate solution in water (1.5 ml, 0.765 m, 1.15 mmol) was added. The reaction mixture was stirred for 56 hrs, after which time the reaction was heated to 50° C. and sodium carbonate (1.5 ml, 1.15 mmol) was added. The mixture was heated for 18 hrs and then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The crude product was triturated with diethyl ether:methanol (1:1) to afford the title compound, 23 mg, (25%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:28])([F:27])[F:29])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
To 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 14B, 0.18 g, 0.451 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.093 mL, 0.451 mmol) followed by osmium tetroxide (0.071 mL, 9.01 μmol) in one portion at room temperature. The contents were stirred at room temperature for 14 h. LCMS indicated formation of a major peak corresponding to the diol intermediate. Sodium periodate (0.145 g, 0.676 mmol) dissolved in 2 mL of water was added in one portion at room temperature. The milky heterogeneous solution was stirred at room temperature for 45 min. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.06 g, 0.149 mmol, 33.2% yield) as a white solid. LC/MS M+1=402.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]=[C:55]=[O:56])=[CH:50][N:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:47][C:48]1[N:49]=[CH:50][C:51]([NH:54][C:55]([N:43]2[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]3[CH:30]=[CH:31][C:32]4[NH:33][C:34]5[N:35]=[C:19]([NH:20][C:21]6[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=6)[CH2:26][CH2:27][C:28]=3[CH:36]=4)[N:18]=[CH:17][C:16]=5[Cl:15])=[O:39])[CH2:41][CH2:42]2)=[O:56])=[CH:52][CH:53]=1
Reactant: O=C=Nc1ccc(Cl)nc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)Nc2ccc(Cl)nc2)CC1
Yield: 23 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2-chloro-5-isocyanatopyridine as starting materials in 23% yield. LCMS for C30H29Cl2N8O2 (M+H)+: m/z=603.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:28][Si:29]([CH3:69])([CH3:68])[CH2:30][CH2:31][O:32][CH2:33][N:34]([CH2:60][O:61][CH2:62][CH2:63][Si:64]([CH3:67])([CH3:66])[CH3:65])[C:35]1[N:40]2[N:41]=[CH:42][C:43](I)=[C:39]2[N:38]=[C:37]([CH:45]2[CH2:51][CH:50]3[N:52]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH:47]([CH2:48][CH2:49]3)[CH2:46]2)[CH:36]=1>O1CCOCC1.O.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]>[CH3:67][Si:64]([CH3:65])([CH3:66])[CH2:63][CH2:62][O:61][CH2:60][N:34]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:28])([CH3:69])[CH3:68])[C:35]1[N:40]2[N:41]=[CH:42][C:43]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:39]2[N:38]=[C:37]([CH:45]2[CH2:51][CH:50]3[N:52]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH:47]([CH2:48][CH2:49]3)[CH2:46]2)[CH:36]=1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n1)C2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.55 mmol, 1327 mg), K3PO4 (14.48 mmol, 3070 mg), and PdCl2(dppf).CH2Cl2 (0.48 mmol, 394 mg) were added to a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (prepared as described in Example 1, Step 9) (1.98 mmol, 1101 mg) in dioxane (40 mL) and H2O (4 mL). The resulting solution was stirred at 70° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=3.29 Min (5 min run, UV254nm). Mass calculated for M+H 715.35, observed LC/MS m/z 715.02 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: NCCOc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCOc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-phenoxyethylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([NH2:25])=[N:21][C:22]=1[O:23][CH3:24])([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:25][C:20]2[CH:19]=[CH:18][C:17]([CH:14]([CH3:16])[CH3:15])=[C:22]([O:23][CH3:24])[N:21]=2)[CH:7]=1
Reactant: COc1nc(N)ccc1C(C)C
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C(C)C)c(OC)n1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (1.47 g, 6.64 mmol) in acetonitrile (7.6 mL) was added 5-isopropyl-6-methoxypyridin-2-amine (830 mg, 4.99 mmol) and the mixture heated at 100° C. in a sealed tube for 18 h. Upon completion, the mixture was concentrated onto silica gel and purified by chromatography (silica, 10% to 80% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (500 mg, 28.5%). MS (EI/CI) m/z: 351.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH2:10]C)[N:3]=1.CCO[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[NH2:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCSc1nc(N)cc(N)n1
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(N)nc(SC)n1)C(=O)OCC
Temperature: 135 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4,6-diamino-2-ethylmercaptopyrimidine (9.95 g) and diethyl ethoxymethylene malonate (13.77 g) at 165° C. was stirred for 40 minutes, cooled to 135° C., stirred for 60 minutes, cooled to 25° C., and added to refluxing ethanol (700 mL). This mixture was treated with decolorizing carbon (NORIT®) stirred for 30 minutes, cooled, filtered, concentrated to 300 mL, heated until homogeneous, cooled, treated with water until cloudy, stored at 0° C. for 18 hours, and filtered. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (d, 1H), 8.96 (d, 1H), 6.98 (s, 2H), 5.97 (s, 1H), 4.21 (q, 2H), 4.12 (q, 2H), 2.43 (s, 3H), 1.26 (t, 3H), 1.23 (t, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[C:7]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.C[C@H]1CC2C(C3C=CN=CC=3)=C(C)C=C(N)C=2O1>>[CH3:1][C@H:2]1[CH2:6][C:5]2[C:7]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:8]([CH3:12])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1
Reactant: Cc1cc(N)c2c(c1C1CCNCC1)C[C@@H](C)O2
Agent: Cc1cc(N)c2c(c1-c1ccncc1)C[C@H](C)O2
Product: Cc1cc(N)c2c(c1C1CCNCC1)C[C@H](C)O2

Procedure:
The title compound 5h was prepared according to the method for preparation of compound 3i of Example 3 by replacing 3h with 5g. MS-ESI (m/z): 247 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.I([O-])(=O)(=O)=[O:38].[Na+]>CO.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][S:34](=[O:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCSCC4)c3)cc2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCS(=O)CC4)c3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) and sodium periodate (43 mg, 0.2 mmol) in MeOH/water (3:1, 4 mL) was stirred overnight at rt. The reaction was partitioned between EtOAc and brine and the organic phase dried, filtered and concentrated in vacuo to give 1-oxo-thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (30 mg, 58%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.37 (1H, s), 8.25 (1H, s), 8.17 (1H, d), 8.10 (1H, s), 7.96 (1H, t), 7.82 (1H, s), 7.71-7.74 (1H, m), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.96-6.98 (1H, m), 6.67 (1H, t), 6.54 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 3.99-4.04 (2H, m), 3.66-3.74 (2H, m), 2.84-2.93 (2H, m), 2.65-2.70 (2H, m); m/z (LC-ES+) 518 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29]C(=O)CC3SC=CC=3)[C:27](=[O:38])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.CO.O>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH2:29])[C:27](=[O:38])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: c1ccccc1
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of diphenylmethyl 3-methoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (887 mg) in benzene (48 ml) are added pyridine (0.26 ml) and phosphorous pentachloride (676 mg) in benzene (48 ml), and the mixture is stirred for 90 minutes. The mixture is diluted with methanol (96 ml), stirred for 2.5 hours, diluted with water (9.6 ml), stirred for 20 minutes, and evaporated at a temperature lower than 40° C. The residue is dissolved in ethyl acetate, washed with water, aqueous sodium hydrogen carbonate and water, dried and evaporated. The residue crystallizes from a mixture of ether and petroleum ether to give diphenylmethyl 3-methoxyiminomethyl-7-amino-3-cephem-4-carboxylate (639 mg; 94.2 %). m.p. 135°-145° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][CH:9]=2)[N:4]([OH:13])[C:3]1=[O:14].Cl.NC(CC1C=CC(Br)=CC=1[N+]([O-])=O)C(O)=O.O.O.[Sn](Cl)Cl>CCO>[NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][CH:9]=2)[N:4]([OH:13])[C:3]1=[O:14]
Reactant: NC1Cc2ccc(Br)cc2N(O)C1=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: NC(Cc1ccc(Br)cc1[N+](=O)[O-])C(=O)O
Solvent: CCO
Solvent: O
Product: N[C@@H]1Cc2ccc(Br)cc2N(O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
3-Amino-7-bromo-1-hydroxy-3,4-dihydroquinolin-2(1H)-one (26) To a solution of 2-amino-3-(4-bromo-2-nitrophenyl)propanoic acid, hydrochloride salt (25) (343 mg, 1.06 mmol) in EtOH (10 mL) was added tin(II) chloride dihydrate (541 mg, 2.40 mmol), and the reaction was stirred at RT overnight. It was then quenched with aqueous ammonium hydroxide (1.5 mL), and the resulting precipitate was removed via filtration and washed with MeOH. The combined filtrates were concentrated in vacuo, and the residue was purified by chromatography on silica gel to provide the title product as a white powder (161 mg, 58%). LCMS m/z 258.9 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 2.71 (dd, J=15.4, 12.9 Hz, 1H) 2.99 (dd, J=15.6, 6.1 Hz, 1H), 3.56 (dd, J=12.8, 6.0 Hz, 1H) 7.17-7.21 (m, 2H), 7.28 (d, J=1.7 Hz, 1H).