Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][C:19]1[C:24]([CH2:25]O)=[CH:23][CH:22]=[C:21]([CH3:27])[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:61]CCl>>[ClH:61].[CH3:18][C:19]1[C:24]([CH2:25][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:23][CH:22]=[C:21]([CH3:27])[N:20]=1
Reactant: ClCCl
Reactant: Cc1ccc(CO)c(C)n1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(COc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c(C)n1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (149 mg, 0.583 mmol, Description 3) and (2,6-dimethyl-3-pyridinyl)methanol (80 mg, 0.583 mmol) in dichloromethane (10 ml) was stirred under argon at room temperature. Triphenylphosphine (153 mg, 0.583 mmol) and DIAD (0.113 ml, 0.583 mmol) were then successively added. The resulting mixture was stirred at room temperature under argon for 16 hours. Then the reaction mixture was washed with water, dried over sodium sulphate, filtered and evaporated. The desired product was isolated by MDAP, concentrated to a small volume, and partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, filtered and evaporated in vacuo to afford the desired compound as a free base. This was treated with ethereal hydrochloride/methanol to give the title compound as a white solid (92 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:20]=[C:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](I)[CH3:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:41][CH3:42])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:20]=[C:21]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(NS(C)(=O)=O)c(OCc3ccccc3)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CC)S(C)(=O)=O)c(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ethyl 5-(benzyloxy)-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (0.2 g, 0.41 mmol, 1 eq) was dissolved in DMF and cooled to 0° C. Potassium carbonate (0.171 g, 1.6 mmol, 3 eq) was then added and the reaction mixture stirred for 15 minutes. Ethyl iodide (0.037 ml, 0.45 mmol, 1.1 eq) was added slowly dropwise and the resulting mixture was stirred at room temperature for 4 h. The solution was concentrated completely and diluted with water and the product was extracted with dichloromethane twice. The combined organic extracts were washed with water and concentrated yielding the desired product. Yield: 0.16 g (76%). 1HNMR (400 MHz, DMSO-d6): δ 1.07-1.10 (t, J=7.16 Hz, 3H), 1.21-1.24 (t, 3H), 3.04 (s, 3H), 3.64 (m, 2H), 4.19-4.24 (q, J=7.04 Hz, 2H), 5.38 (s, 2H), 7.28 (t, J=8.8 Hz, 2H), 7.42-7.54 (m, 3H), 7.57-7.65 (m, 3H), 7.77-7.95 (m, 2H), 9.02 (s, 1H). LCMS: (ES+) m/z=512.0 (M+H).
Reaction SMILES: [Mg:1].[Br:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21].[Cl-].[NH4+]>CCOCC.C1COCC1>[CH:13]1([CH2:14][Mg:1][Br:2])[CH2:17][CH2:18][CH2:19][CH2:11][CH2:12]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[OH:21]
Reactant: [Mg]
Reactant: BrCC1CCCCC1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Br[Mg]CC1CCCCC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of cyclohexylmethylmagnesium bromide is prepared from 5.37 g of magnesium and 30.8 ml of bromomethylcyclohexane in 15 ml of ether. This solution is added dropwise at +4° C., under an argon atmosphere, to a mixture of 10 g of 5-chloroisatin and 25 ml of THF. After stirring for 3 hours at RT, 500 ml of a saturated solution of ammonium chloride are added, extraction is carried out with AcOEt, the organic phase is washed with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 12 g of the expected product after crystallization from AcOEt and recrystallization from a THF/AcOEt mixture. M.p.=252°-253° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22](C2CCCCO2)[CH:21]=[CH:20]3)[S:13][C:14]=1[CH3:15].[H-].[Na+].[CH2:34](Br)[CH2:35][CH3:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:34][CH2:35][CH3:36])[S:13][C:14]=1[CH3:15]
Reactant: CCCBr
Reactant: COc1ccc(-c2nc(Nc3ccc4c(ccn4C4CCCCO4)c3)sc2C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
10.9 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(1-(tetrahydropyran-2-yl)indol-5-yl)amino]-thiazole are dissolved in 110 ml of dimethylformamide. 1.06 g of 60% sodium hydride in oil and then 3.2 ml of propyl bromide are added at 0° C. After stirring for 16 hours at room temperature, the reaction mixture is poured onto 500 ml of water and extracted 3 times with 250 ml ethyl acetate. The organic phase is washed with 3 times 200 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography on silica gel eluted with a 3/1 (v/v) cyclohexane/ethyl acetate mixture. 10.17 g of the expected product (85%) are obtained. 1H NMR (CDCl3): 0.90 (m, 3H), 1.57-1.75 (m, 6H), 2.02 (s, 3H), 1.95-2.25 (m, 2H), 3.70-4.17 (m, 7H), 5.50 (dd, J=2.6, 10.0, 1H), 6.54-7.61 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1)#[CH:20]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:20]=[CH:19]\[C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]1[CH2:11][C@H:12]3[N:17]([CH3:18])[C@@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@@H]2CCC[C@H]1N2C

Procedure:
The coupling of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107 mg, 0.915 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to give the racemic mixture of the title compound as the major of two alkene isomers. The individual enantiomers from this racemic mixture were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.18-1.41 (m, 2H), 1.48 (dd, J=13, 2 Hz, 1H), 1.65-1.75 (m, 1H), 1.83-2.08 (m, 2H), 2.26 (d, J=17 Hz, 1H), 2.28 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.90 (dd, J=18, 7 Hz, 1H), 3.17 (t, J=5 Hz, 1H), 4.13 (s, 1H), 6.64 (d, J=8 Hz, 1H), 6.84-6.91 (m, 1H), 6.92-7.10 (m, 3H), 7.15-7.23 (m, 2H), 7.96 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[Br:21]N1C(=O)CCC1=O>C1COCC1.C(#N)C>[Br:21][C:14]1[CH:13]=[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]2([C:7]([F:8])([F:10])[F:9])[CH2:6][O:5]2)[C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCO2
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Br)cc2c1OCO2
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a solution of 0.1 g (0.35 mmol) of 4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]dioxole in 5 mL of THF was added 0.06 g (0.35 mmol) of N-bromosuccinimide. The reaction was monitored by TLC. After stirring overnight, TLC showed starting material and a new slightly more polar spot. The reaction was concentrated in vacuo and the residue was diluted with hexanes. The resulting suspension was filtered to remove insoluble material and the filtrate was purified by chromatography over silica gel eluting with ethyl acetate-hexanes (0-10%) to afford an oil as a mixture of starting material and product (3.5:1) by proton NMR. The residue was dissolved in 3 mL of acetonitrile and 0.06 g (0.35 mmol) of N-bromosuccinimide was added. After 3 hours, a TLC indicated the reaction was complete and it was worked up as above to afford 0.07 g (54%) of 6-bromo-4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]dioxole as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][CH2:29][O:28][CH3:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: COCCO
Product: COCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.19 mmol), intermediate 42.1, and 2-methoxyethanol (42 μl; 0.515 mmol), example 50 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:23])=[C:11]3[N:21]=[CH:20][N:19]([CH3:22])[C:12]3=[N:13][C:14]=2[C:15]([NH:17][NH2:18])=[O:16])=[C:4]([F:24])[CH:3]=1.Br[C:26]#[N:27].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:27][C:26]1[O:16][C:15]([C:14]2[N:13]=[C:12]3[N:19]([CH3:22])[CH:20]=[N:21][C:11]3=[C:10]([F:23])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:24])=[N:17][N:18]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NN)nc21
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(-c3nnc(N)o3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3 -methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid hydrazide (1.00 equivalent) in 1,4-dioxane at room temperature is added BrCN (2.0 equivalents) followed by a solution of NaHCO3 (1.0 equivalents) in H2O. After stirring for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford [5-(5-amino-[1,3,4]oxadiazol-2-yl)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-(4-bromo-2-fluorophenyl)-amine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c1
Yield: 44.5 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0314 g, 0.0680 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-methoxybenzenesulfonyl chloride (0.0403 g, 0.195 mmol) to obtain 4-(3-methoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 44%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=1.ClCC1C=NC(OC)=NC=1>>[F:51][C:50]([F:53])([F:52])[C:47]1[O:46][C:45]([CH2:44][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:49][CH:48]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, (3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 64-65° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 1H), 7.20 (d, J=7.4 Hz, 1H), 7.10-7.05 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.75-6.74 (m, 1H), 6.45 (s, 1H), 6.42 (s, 2H), 5.12 (d, J=16.2 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.85 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H), 3.07-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 161.8, 161.1, 151.9, 141.9, 141.2, 132.5, 128.8, 123.9, 123.7, 120.5, 120.0 (2C), 118.7, 112.6, 112.5, 109.2, 108.7, 93.1, 80.3, 72.3, 57.6, 36.8, 28.9; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([Br:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1.[BrH:27]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)C(=O)O
Solvent: CC#N
Product: Br
Product: CC(C)(C)OC(=O)N[C@H](CC1=CN(Cc2ccccc2)CC=C1)C(=O)O
Temperature: 50 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Boc-D-Pal (1.36 g, 6.0 mmol) was suspended in 60 ml of acetonitrile. Benzyl bromide (about 50 mmol) was added and the mixture was warmed to 50° C. on a water bath. A clear solution resulted, and was stirred at room temperature for 16 hours. A white precipitate formed; TLC after 17 hours showed some starting remaining starting material; stirring continued for a total of 5 days, when the reaction was complete. The solvent was evaporated under reduced pressure, and the residue recrystallized from EtOH/ethyl acetate. Yield: 85%; m.p. 166°-170° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][OH:13])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=2)[CH2:7][CH2:8]1)(=[O:24])=[O:23]
Reactant: N#Cc1ccc2c(c1)C(CO)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-cyano-1-indanylmethanol 2a (3 g) and triethylamine (2.8 ml) in dichloromethane (50 ml) was added drop-wise a solution of methansulfonylchloride (1.5 ml) in dichloromethane (25 ml) at 0° C. The mixture was stirred at room temperature for 1 hour. Water was added (200 ml) and the organic phase was subsequently separated and worked-up according to the standard procedure above. The remaining crystalline product was stirred with diethyl ether and filtered off. Yield 2.7 g Mp 62-63° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[CH:22]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH2:42])[CH2:35]2)[N:20]=1>C1COCC1>[NH2:18][C:19]1[N:20]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH:42][S:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:16])=[O:15])[CH2:35]2)[CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[N:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (0.05 mL, 0.36 mmol) and benzenesulfonyl chloride (0.04 mL, 0.31 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (99 mg, 0.29 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow oil. LC-MS (ES) m/z=483 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20]([NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9])=[O:21]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C(Br)CCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (S)-1-(4-fluorophenyl)ethanamine (3.2 g, 23 mmol) in diethyl ether (50 mL) and triethylamine (9.6 mL, 69 mmol) at 0° C. was added 2,4-dibromobutanoyl chloride (7.3 g, 27.6 mmole) and the mixture was allowed to warm to rt and stirred for 12 h. A solid formed which was removed by filtration, washed with ethyl acetate, and then discarded. The combined filtrates were evaporated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 20-30% ethyl acetate/petroleum ether yielding 4.5 g of 2,4-dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide as a brown solid. LCMS (method O) RT=0.99 min, m/z 366, 368, 370 (M+H+, M+H++2, M+H++4); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.44 (m, 3H) 2.27-2.46 (m, 2H) 3.46-3.58 (m, 2H) 4.55-4.66 (m, 1H) 4.81-5.00 (m, 1H) 7.03-7.24 (m, 2H) 7.30-7.45 (m, 2H) 8.89 (d, J=8.03 Hz, 1H).
Reaction SMILES: [N:1]1([S:6]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][C@@H:29]([CH2:33][NH:34][C:35](=O)[O:36]C2C=CC([N+]([O-])=O)=CC=2)[CH2:28]1>CN(C)C=O.ClCCl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][C@@H:29]([CH2:33][NH:34][C:35]([NH:12][CH2:11][CH2:10][CH2:9][S:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:7])=[O:8])=[O:36])[CH2:28]1
Reactant: NCCCS(=O)(=O)N1CCCC1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCCS(=O)(=O)N1CCCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 63 %

Procedure:
A solution of Intermediate 28 (0.027 g) in N,N-dimethylformamide (1 ml) and dichloromethane (2 ml) containing N,N-diisopropylethylamine (0.041 ml) was added to a stirred solution of Intermediate 13 (0.051 g) in dry dichloromethane (2 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 21 h. The mixture was applied directly to a sulphonic acid ion exchange cartridge (2 g Isolute SCX) and eluted with methanol (6 column volumes) followed by 10% 880 ammonia in methanol (3 column volumes); evaporation of the methanol/ammonia fractions gave the crude product (0.063 g). Purification by chromatography on silica gel (2 g Varian Bond Elut cartridge), eluting with chloroform, ether, ethyl acetate, acetone, and methanol, gave the title compound as a gum (0.036 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.O[N:15]=[C:16]([CH:18]1[CH2:20][CH2:19]1)[NH2:17].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2([C:11]3[O:13][N:17]=[C:16]([CH:18]4[CH2:20][CH2:19]4)[N:15]=3)[CH2:9][CH2:10]2)[CH:3]=1
Reactant: O=C(O)C1(c2cncc(Br)c2)CC1
Reactant: NC(=NO)C1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1cncc(C2(c3nc(C4CC4)no3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound from Example 72 Step A (45 mg, 0.19 mmol), N′-hydroxycyclopropanecarboximidamide (22 mg, 0.22 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (116 mg, 0.223 mmol) in N,N-dimethylformamide (0.93 mL) was added triethylamine (26 μl, 0.19 mmol). The reaction stirred at room temperature overnight. It was then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was then diluted with toluene and heated to reflux overnight. Purification by flash chromatography on silica gel (10-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 307.85 [M+2+H]+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:23](=[O:24])[N:14]2[C@@H:15]([C:20]([OH:22])=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)C)=O.[C:31]1([CH:37](N)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:23](=[O:24])[N:14]2[C@@H:15]([C:20]([O:22][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)ON=O
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
6β-Phenoxyacetamido-2,2-dimethylpenam-3α-carboxylic acid (3.50 g, 10 m.moles) was added to a mixture of isopropyl nitrite (2.40 g, 27 m.moles) and diphenylmethylamine (2.21 g, 12 m.moles) in tetrahydrofuran (50 ml) at 35° and stirred for 3 hours. The solvent was removed in vacuo and the gum dissolved in chloroform (50 ml), which solution was washed with 5% sodium bicarbonate solution (50 ml) and then water (50 ml) to leave a gum of the title ester. Yield 2.11 g (40.8% based on the input penicillin acid).