Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:5][C:4]([CH3:15])([CH3:14])[NH:3]1.[CH2:17](Br)[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[CH2:19]([CH:7]1[C:2]([CH3:16])([CH3:1])[NH:3][C:4]([CH3:15])([CH3:14])[CH:5]=[C:6]1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC1(C)C=C(N2CCCCC2)CC(C)(C)N1
Solvent: ClC(Cl)Cl
Product: C=CCC1C(N2CCCCC2)=CC(C)(C)NC1(C)C
Reaction time: 24 h
Yield: 50.1 %

Procedure:
2.2 g of the 1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine and 1.2 g of allyl bromide were dissolved in 3 ml of chloroform and the solution was then allowed to stand at room temperature for 24 hours. The crystals which precipitated were filtered off, washed with hexane and dissolved in 4 ml of concentrated aqueous ammonia; the resulting solution was extracted with hexane. The hexane extract was dried over potassium carbonate and, after removal of the hexane, 1.3 g of 5-allyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine were obtained. On thin layer chromatography using a 0.25 mm thick layer of alumina ("60F 254", available from Merck & Co.) and a mixture of benzene, hexane, ethyl acetate and triethylamine (2 : 2 : 1 : 0.5 by volume) as developing solvent, the compound showed a single spot with an Rf value of 0.80.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH2:38][CH2:36][OH:37])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNCCO)no1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (489 mg, 0.97 mmol) and ethanolamine (250 μl, 3.87 mmol) as starting materials.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Product: CN(C)CCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.35) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 59%). MS (ISP) 564.3 [(M+H)+]; mp 160-162° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.Cl>ClCCCl.CCCCO>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH:11]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CCCCO
Product: CCC(C(c1ccc2nc(Nc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C

Procedure:
A solution of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine (30 mg, 0.079 mmol), methyl-4-aminobenzoate (24 mg, 0.16 mmol) in 300 μL DCE and 300 μL n-BuOH was treated with 4N HCl (40 μL, 0.16 mmol) and refluxed overnight. The mixture was then partitioned between DCM and saturated NaHCO3 and the aqueous phase was extracted with DCM. The combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified by PTLC using two 1 mm silica plates eluting with 5% MeOH (2N NH3)/DCM to provide methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate. MS (ESI+) nil 450.19 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[N:30]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[N:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:36][C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: O=Cc1cncnc1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5cncnc5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (45 mg, 0.1 mmol) and pyrimidine-5-carbaldehyde (32 mg, 0.3 mmol) in DCM (1.5 mL) was added NaBH(OAc)3 (64 mg, 0.3 mmol), followed by addition of AcOH (12 uL). After stirring at room temperature in a sealed vial for 16 h, the reaction was quenched with EtOAc (50 mL). The reaction mixture was sequentially washed with water (10 mL), brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica chromatography (0-10% MeOH in EtOAc gradient with 1% NH3 in MeOH additive) to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(pyrimidin-5-ylmethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; 1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.81 (s, 2H), 8.00 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H), 6.23 (br s, 1H), 3.65 (s, 2H), 3.03 (m, 2H), 2.76 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.25 (m, 2H), 1.80-1.68 (m, 4H); ESMS m/z 508.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[O:20][CH3:21])[NH:16][C:15](=[O:22])[CH2:14][CH2:13]3)=[CH:6][CH:5]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[O:20][CH3:21])[N:16]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15](=[O:22])[CH2:14][CH2:13]3)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a mixture of 95% dry sodium hydride (24 mg, 1.00 mmol) in anhydrous N,N-dimethylformamide (8 mL) at room temperature was added a solution of 6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (7) (110 mg, 0.38 mmol) in N,N-dimethylformamide. The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl bromoacetate (390 mg, 2.00 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature until majority of the starting material was converted (as shown by LCMS), then it was quenched by addition of methanol (10 mL). The mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added to the residue, and the solvent removed under reduced pressure, to afford crude (tert-butyl 2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetate).
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9]CC)=O.[CH3:28][N:29]=[C:30]=[O:31]>>[CH2:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[N:5]([CH2:4][CH2:3][C:2](=[O:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:30](=[O:31])[N:29]([CH3:28])[C:7]1=[O:9])=[O:19])[CH3:22]
Reactant: CN=C=O
Reactant: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Product: CCCCCC(=O)CCN1C(=O)N(C)C(=O)C1CCCCCCC(=O)OCC

Procedure:
Diethyl 2-((3-oxooctyl)amino)nonanedioate was allowed to react with methyl isocyanate as described in Example 89 to give 5-(6-ethoxycarbonylhexyl)-3-methyl-1-(3-oxooctyl)hydantoin, which was hydrolysed to 5-(6-carboxyhexyl)-3-methyl-1-(3-oxooctyl)hydantoin, a colourless oil.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.C([NH:16][C:17]1[C:26]([CH:27](O)[CH2:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[C:41]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:42])[CH:23]=2)[N:18]=1)(C)(C)C>C1(C)C=CC=CC=1>[NH2:16][C:17]1[C:26]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:32]2)=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[C:41]([N:43]3[CH2:44][CH2:45][CH2:46][CH2:47]3)=[O:42])[CH:23]=2)[N:18]=1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(NC(C)(C)C)c(C(O)CCCCO)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(C3CCCCO3)cc2c1

Procedure:
TsOH (0.109 g, 0.572 mmol) was added to a solution of (2-(2-(tert-butylamino)-3-(1,5-dihydroxypentyl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.070 g, 0.143 mmol) in toluene (2.0 mL) and the reaction was refluxed for 1.5 h. The reaction was concentrated and diluted with 10% sodium carbonate and extracted with dichloromethane. The combined organic extracts were washed with saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography by eluting with 100% EtOAc followed by 1:20 2M NH3 in MeOH/dichloromethane, to provide (2-(2-amino-3-(tetrahydro-2H-pyran-2-yl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: C([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:19])=[CH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:19][C:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:8][C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[CH:11]=1
Reactant: FC1=Cc2ccccc2N(Cc2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: FC1=Cc2ccccc2Nc2ccccc21

Procedure:
A solution of 6.03 g (0.02 mole) of 5-benzyl-10-fluoro-5H-dibenz[b,f]azepine in 100 ml of methanol is hydrogenated at 25° C in the presence of 0.6 of palladium on charcoal catalyst (5% Pd) until the uptake of hydrogen has ceased (app. 15 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo. The residual colourless oil is chromatographed over 50 times the amount of silica gel (particle size: 0.063-0.2 mm) with benzene/petroleum ether (1:1) as eluant. The homogeneous fractions are combined, concentrated by rotary evaporation and the residue is crystallised from ether/hexane to yield 10-fluoro-5H-dibenz[b,f]azepine of m.p. 69°-72° C.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C@@:15]([C:30]1[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=1)([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13].[C:44]([O-])([O-])=O.[K+].[K+].CI>CC#N>[F:43][C:32]1[CH:31]=[C:30]([C@:15]([NH:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:44])[N:1]=2)=[O:13])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCCCCCc1nn[nH]n1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1nnc(CCCCCNC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
To a solution of (R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (12 mg, 0.019 mmol) in MeCN (115 μl) at rt was added K2CO3 (3.2 mg, 0.023 mmol) followed by MeI (1.5 μL, 0.023 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was quenched by addition of H2O and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-(2-methyl-2H-tetrazol-5-yl)pentyl)urea (Example 260, 2 mg, 18% yield) as white solid. 1H NMR (500 MHz, CDCl3) ppm 7.17-7.08 (m, 5H), 6.99-6.85 (m, 5H), 6.67 (d, J=5 Hz, 2 H), 5.98-5.75 (m, 1H), 4.23 (s, 3H), 3.82 (d, J=15 Hz, 1H), 3.68 (d, J=15 Hz, 1H), 3.10-3.07 (m, 2H), 2.85-2.82 (m, 2H), 1.77-1.71 (m, 2H), 1.46-1.40 (m, 2H), 1.32-1.26 (m, 2H); LC/MS: RT=3.218 min [M+H] 621.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[N:15]=[CH:16][C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1cnn2-c1c(F)cccc1Cl
Product: Fc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Phosphorus oxychloride (17.54 mL, 188.18 mmol) was added to 1-(2-chloro-6-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate BH2) (2.49 g, 9.41 mmol). The resulting solution was stirred at 100° C. for 1 hour. The reaction mixture was evaporated. Ice/water (100 mL) and then EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with water (100 mL), dried (MgSO4) and concentrated to give the crude product (2.48 g) which was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:16])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[I:15])[CH3:2].[CH:17]1(N)CC1>>[CH:1]1([NH:3][C:4](=[O:16])[C:5]2[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[I:15])[CH2:17][CH2:2]1
Reactant: NC1CC1
Reactant: CCNC(=O)c1c(I)cccc1[Si](C)(C)C
Product: C[Si](C)(C)c1cccc(I)c1C(=O)NC1CC1
Yield: 87 %

Procedure:
The acid chloride prepared in Example 207 was reacted with cyclopropylamine (3 eq) using General Method E1 to afford the title compound. Purification by recrystallization from hexanes gave 0.49 g of the title compound as white needles in 87% yield. m.p. 162-164° C.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH3:40][C:41]([CH3:43])=[O:42]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH2:17][C:41]([OH:42])([CH3:43])[CH3:40])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-ethan-1-one (Example 2) (1.07 g, 4.3 mmol) in CH2Cl2 (65 mL) is cooled to -78° C., and diisopropylethylamine (0.97 mL, 5.6 mmol) and trimethylsilyltriflate (1.08 mL, 5.6 mmol) are added sequentially via syringe. The reaction is stirred at -78° C. for 10 min and then is allowed to warm to 24° C. and is stirred at that temperature for 45 min. The solution is once again cooled to -78° C., and acetone (0.54 mL, 4.3 mmol) is added, followed by TiCl4 (1M solution in CH2Cl2, 4.3 mL, 4.3 mmol). After 1 h at -78° C., the reaction mixture is allowed to warm to 24° C. and evaporated. The residue is partioned between MeOH/1N HCl and CH2Cl2. The CH2Cl2 layer is dried (MgSO4), filtered, evaporated, and chromatographed over SiO2 using EtOAc/hexane (1:6), to yield 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-hydroxy-3-methylbutan-1 -one.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:22])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([CH:20]=[CH2:21])[O:14]1>>[F:10][C:8]1[CH:9]=[C:2](/[CH:21]=[CH:20]/[B:15]2[O:16][C:17]([CH3:19])([CH3:18])[C:13]([CH3:22])([CH3:12])[O:14]2)[CH:3]=[C:4]([F:11])[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Product: CC1(C)OB(/C=C/c2cc(F)c(C=O)c(F)c2)OC1(C)C
Yield: 75.1 %

Procedure:
According to procedure for the synthesis of example A51A, by using 4-bromo-2,6-difluorobenzaldehyde (1.10 g, 4.98 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.97 mL, 5.72 mmol) to give the title compound as a colorless oil (1.10 g, 76%). 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.05 (d, J=9.6 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 6.28 (d, J=18.8 Hz, 1H), 1.33 (s, 12H); MS ESI 295.1 [M+H]+, calcd for [C15H7BF2O3+H]+ 295.13.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH2:51])[C@H:47]3[S:46][CH2:45][C:44]=2[CH:53]([S:55][C:56]2[NH:60][N:59]=[N:58][N:57]=2)[CH3:54])=[O:42])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN1CCOCC1>[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH:51][C:16](=[O:18])[CH2:15][C:13]4[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=4)[C@H:47]3[S:46][CH2:45][C:44]=2[CH:53]([S:55][C:56]2[NH:60][N:59]=[N:58][N:57]=2)[CH3:54])=[O:42])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
5.43 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 200 ml of methylene chloride containing 2.20 ml of 4-methyl-morpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 2.86 ml of chloroformic acid isobutyl ester are added dropwise. After 30 minutes, a solution of 9.35 g of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of methylene chloride is added, after which stirring is continued for one hour at -20° C. and for 16 hours whilst slowly warming to room temperature. The mixture is poured out onto ice-cold water, the organic solution is separated off and the aqueous phase is again extracted with 100 ml of methylene chloride. The organic extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Crystallisation of the residue from a mixture of methyl acetate and diethyl ether gives 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel): Rf= 0.38 (system: chloroform/ethyl acetate/acetic acid, 80:19:1); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): shoulders at 242 mμ (ε=16,400) and 274 mμ (ε=9,200); infrared absorption spectrum (in mineral oil): characteristic bands at 3.03μ, 5.58μ, 5.79μ, 6.12μ and 6.51μ.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([CH:20]([C:33](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:34])[C:21](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH2:13]([C:20]1[C:21](=[O:22])[NH:1][C:2]2[C:3]([C:33]=1[OH:34])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Oc1c(Cl)cc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCOCC
Product: CCOC(=O)c1ccc2[nH]c(=O)c(Cc3ccccc3)c(O)c2c1
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-aminobenzoate (2.85 g, 17.2 mmol) and bis(2,4,6-trichlorophenyl) 2-benzylmalonate (11.4 g, 20.7 mmol, Intermediate 33: step a) was microwaved at 250° C. for 15 minutes (Biotage Initiator). The reaction was then allowed to cool to room temperature, and the resulting tan semisolid was dispersed in ether (15 mL) and filtered. The beige filter cake was washed with ether (1×15 mL) and dried at 100° C. to provide the title compound as a light beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)(=[O:11])=[O:10].[CH2:24]1[NH:29][CH2:28][CH2:27][N:26]2[CH2:30][CH2:31][CH2:32][C@@H:25]12.CCN(C(C)C)C(C)C>C(#N)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C@H:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([N:29]3[CH2:28][CH2:27][N:26]4[CH2:30][CH2:31][CH2:32][C@H:25]4[CH2:24]3)=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](S(=O)(=O)c2ccc(F)cc2Cl)C1
Reactant: C1C[C@H]2CNCCN2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](S(=O)(=O)c2ccc(N3CCN4CCC[C@H]4C3)cc2Cl)C1
Temperature: 60 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
In a 50 mL round-bottomed flask, (S)-tert-butyl 3-(2-chloro-4-fluorophenylsulfonyl)-pyrrolidine-1-carboxylate, example 52D) (2 g, 5.5 mmol, 1 eq) was combined with acetonitrile (20 mL) to give a light yellow solution. (S)-octahydropyrrolo[1,2-a]pyrazine (1.04 g, 8.25 mmol, 1.5 eq) and DIEA (1.42 g, 1.92 mL, 11.0 mmol, 2 eq) were added. The reaction mixture was stirred for 15 h. The reaction mixture was heated to 60° C. and stirred for 5 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (25 mL) and extracted with aqueous 10% Na2CO3 (2×20 mL) and brine. The organic layers were dried over Na2SO4 and concentrated in vacuo to yield a colorless viscous oil (2.48 g, 96%).