Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:19]([CH3:21])[CH3:20])[C:15]=1[N:16]([CH3:18])[CH3:17])[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:26]([CH2:33][CH2:34][C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[NH:26]([CH:33]=[C:34]([CH2:6][C:5]1[CH:13]=[C:14]([N:19]([CH3:20])[CH3:21])[C:15]([N:16]([CH3:18])[CH3:17])=[C:3]([N:2]([CH3:1])[CH3:22])[CH:4]=1)[C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N(C)C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1N(C)C

Procedure:
A mixture of 8.96 g. of 3,4,5-tris(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.56 g. of sodium methylate and 6.6 g. of β-anilinopropionitrile in 70 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 50 minutes. The mixture was poured into 500 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethylene)-3,4,5-tris(dimethylamino)hydrocinnamonitrile having a melting point of 179°-181° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>C1COCC1>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:36]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccc(Cl)cc3Cl)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2,4-dichlorophenyl isocyanate: ESMS m/e: 533.2 (M+H)+.
Reaction SMILES: C1([C:7](=[N:14]CCCO)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:52][C:53]1[CH:54]=[C:55]([N:60]2[C:64](=[O:65])[O:63][N:62]=[C:61]2[C:66]2[C:67]([NH:71][C:72](=O)[C:73](F)(F)F)=[N:68][O:69][N:70]=2)[CH:56]=[CH:57][C:58]=1[F:59].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>O1CCCC1>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:14][CH2:7][CH2:73][CH2:72][NH:71][C:67]1[C:66]([C:61]2[N:60]([C:55]3[CH:56]=[CH:57][C:58]([F:59])=[C:53]([Cl:52])[CH:54]=3)[C:64](=[O:65])[O:63][N:62]=2)=[N:70][O:69][N:68]=1
Reactant: OCCCN=C(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
A solution of 3-[(diphenylmethylene)amino]propan-1-ol (80 mg, 0.33 mmol) and triphenylphosphine (93 mg, 0.36 mmol) in tetrahydrofuran (1 mL) at 0° C. was treated with diisopropyl azodicarboxylate (75 μL, 0.38 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (100 mg, 0.25 mmol) in tetrahydrofuran (0.5 mL), and stirred at 25° C. for 16 h. The reaction mixture was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 3 h, and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (18 mg, 15%). LCMS for C13H13ClFN6O3 (M+H)+: m/z=355.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:37][CH2:36][N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:41])([F:42])[F:27])[CH:30]=4)[CH2:40][CH2:39]3)=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with N-(3-trifluoromethylphenyl)-piperazine to give the title compound as a colorless solid. MS: 588.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41]OS(C)(=O)=O)[CH:35]=2)[C:10]1=[O:47].[CH3:48][NH:49][CH3:50]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][N:49]([CH3:50])[CH3:48])[CH:35]=2)[C:10]1=[O:47]
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCOS(C)(=O)=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Reactant: CNC
Solvent: CCO
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN(C)C)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 50 °C
Yield: 22 %

Procedure:
50 mg (0.07 mmol) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one of Example 81(a) was treated with 3 ml of a 33% solution of dimethylamine in ethanol and the mixture heated at 50° C. for 3 hours. The mixture was cooled and evaporated. The product was purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 10 mg (22%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-(dimethylamino)ethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 92° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][CH3:15])[N:13]=1)(C)(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][CH3:15])[N:13]=1
Reactant: O=C(O)c1ccccn1
Reactant: CC[C@@]1(c2cc(N)ccc2F)CCOC(NC(=O)OC(C)(C)C)=N1
Product: CC[C@@]1(c2cc(NC(=O)c3ccccn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-ethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F2 (R3=Et) and pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])Cl)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])[NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: C[Si](C)(Cl)C1=Cc2c(c3ccccc3c3ccccc23)C1
Reactant: CC(C)(C)N
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1=Cc2c(c3ccccc3c3ccccc23)C1

Procedure:
To a 500 ml round bottom flask containing 1.98 g (0.0064 mole) of (1H-cyclopenta[1]phenanthrene-2-yl)dimethylchlorosilane and 250 ml of hexane was added 2.00 ml (0.0160 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™). washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.98 g (88.9 percent).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36]2.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>C(Cl)Cl>[CH2:45]([O:44][C:42]([C:37]1[NH:38][C:39]2[C:35]([CH:36]=1)=[CH:34][C:33]([NH:32][C:28]([C@H:9]1[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30])=[CH:41][CH:40]=2)=[O:43])[CH3:46]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.321 mmol), ethyl 5-amino-1H-indole-2-carboxylate (114 mg, 0.558 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 159 mg, 0.417 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by RP-HPLC chromatography (20-95% acetonitrile/water) to afford 5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carbonyl]-amino}-1H-indole-2-carboxylic acid ethyl ester (37 mg, 17.6%) as an off-white powder. LCMS (ES+) m/z Calcd for C34H32Cl2F2N4O3+H [(M+H)+]: 652.18. found: 6512.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:32])[CH:12](P(OCC)(OCC)=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:9])([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:48])[NH:39][C:40]1[CH:45]=[C:44]([CH:46]=O)[CH:43]=[CH:42][N:41]=1)([CH3:36])([CH3:35])[CH3:34].O>C1COCC1>[C:6]([O:10][C:11](=[O:32])[C:12](=[CH:46][C:44]1[CH:43]=[CH:42][N:41]=[C:40]([NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:48])[CH:45]=1)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:7])([CH3:8])[CH3:9]
Reactant: CCOP(=O)(OCC)C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Butyllithium (1.6 M in hexane, 14.8 ml, 23.7 mmol) was added dropwise to a solution of 2-(diethoxy-phosphoryl)-succinic acid 4-benzyl ester 1-tert-butyl ester (9.50 g, 23.7 mmol in THF (75 mL) at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the solution was transferred to a solution of (4-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3.70 g, 16.6 mmol) in THF (75 mL). The resulting reaction mixture was stirred at 0° C. for 1 h before being allowed to warm to 25° C., and the mixture was stirred overnight. Water (400 mL) was added and the product extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried and concentrated. Flash chromatography (hexane/EtOAc, 4:1) gave 2-(2-tert-Butoxycarbonylamino-pyridin-4-ylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester 4.30 g (55%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1>C(O)C>[CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:24]3\[C:25](=[O:30])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCNCCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCNCCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 90 °C
Yield: 80.9 %

Procedure:
5-(2-Ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 62j (45 mg, 0.118 mmol) was dissolved in 5 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (16 mg, 0.106 mmol) and piperidine (0.15 ml, 1.49 mmol) to the solution. Upon completion of the addition, the reaction mixture was refluxed at 90° C. in an oil bath for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, added with a little ethanol, and filtered to obtain the title compound (Z)-5-(2-ethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 62 (34 mg, yield 76%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:47]4[CH:48]=[CH:49][C:44]([C:43](=[O:50])[NH2:51])=[CH:45][CH:46]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: NC(=O)c1ccncc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a stirred solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in dry DMSO (2 ml) was added isonicotinamide (244 mg, 2 mmoles). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate (200 ml). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40°-50° C. for 1 hour, and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). After filtration of an insoluble material, the filtrate was chromatographed on a reverse phase column (packing of PrepPAK/C18, 100 ml) using water and 5%, 10%, 20% and 30% aqueous CH3OH as eluant. The fractions containing the desired compound were combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. Mp. >180° C. (dec.).
Reaction SMILES: C[Mg]Cl.[CH:4]([C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])([CH2:6][CH3:7])[CH3:5].Cl.[CH:18]#[CH:19]>C1COCC1>[CH:4]([C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]([OH:12])[C:18]#[CH:19])([CH2:6][CH3:7])[CH3:5]
Reactant: CCC(C)c1cccc(C=O)c1C
Reactant: C#C
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(C(C)CC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
50 ml of absolute THF is saturated under a nitrogen blanket at 0° C. with acetylene. While passing in further acetylene, 87 ml of methylmagnesium chloride solution (1.5 molar) is dripped in over a 45-minute period, and the whole is then stirred for 30 minutes at 0° C. At -20° C., a solution of 15.3 g of 3-sec-butyl-2-methylbenzaldehyde in 20 ml of absolute THF is dripped in. The mixture is stirred for 2 hours at -20° C., is allowed to stand overnight at room temperature, and is then poured into 300 ml of ice water. The mixture is acidified with dilute hydrochloric acid and extracted by shaking three times with ether. The combined ether extracts are washed with water, dried over sodium sulfate and concentrated. There is obtained 16.6 g of an oil (70% desired compound), which, after purification by column chromatography over silica gel using toluene as eluant, gives 5.1 g of the pure benzyl alcohol.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH:1]1([N:7]2[C:11]3[N:12]=[C:17]([CH:14]4[CH2:15][CH2:16]4)[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]=3[C:9]([CH3:13])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(N)n(C2CCCCC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCCC1

Procedure:
The title compound was prepared in the same manner as described for intermediate 37 using 1-(1-cyclohexyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79 mmol). The final product was collected as a solid, 0.827 g (91%). LCMS E-S (M+H)=328.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.10 (m, 3H), 1.20-1.30 (m, 1H), 1.37 (t, J=7.07 Hz, 3H), 1.41-1.52 (m, 2H), 1.70 (d, 1H), 1.79-1.98 (m, 6H), 2.30-2.38 (m, 1H), 2.54 (s, 3H), 4.42 (q, J=7.07 Hz, 2H), 4.60-4.74 (m, 1H), 7.44 (s, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH:16][C@@H:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18]O)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][N:14]4[CH2:18][C@H:17]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:16]=[C:15]4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H](Cc1ccccc1)Nc1ncnc2c1cnn2-c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12

Procedure:
Next, 300 mg of the above product (S)-β-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol was dissolved in 15 ml CH2Cl2 followed by addition of 0.44 ml SOCl2. The reaction was heated to reflux for 3.5 hours. The solvent was then removed under a stream of nitrogen. The white solid was recrystallized from about 30% isopropyl alcohol/hexane followed by a second recrystallization from about 5%MeOH/butanone to yield 45 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-3H-imidazo[1,2-c]pyrazolo[4,3-e]-pyrimidine after drying under vacuum at 39° C. for 5 days (m.p. 255° C.).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:15][CH:14]=1.O>O1CCOCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[C:21]([CH2:20][O:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:9][CH2:8][CH:5]4[CH2:7][CH2:6]4)=[O:11])=[CH:14][N:15]=3)=[C:25]([CH3:26])[O:24][N:23]=2)=[CH:32][CH:31]=1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of cyclopropanemethylamine (0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 1 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (56 mg, 70%) which was obtained as a white solid. MS: m/e=398.4 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([NH:10][C@@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:1][N:2]([S:40]([CH3:39])(=[O:42])=[O:41])[C@H:3]([C:8]([NH:10][C@@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N2-methyl-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Example 164 (122 mg, 0.296 mmol) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (78 μL, 0.445 mmol) followed by methanesulfonyl chloride (25.4 μL, 0.326 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 0% to 5% methanol (2 N ammonia)/dichloromethane over 20 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.59 (d, J=6.7, 1H), 7.73 (s, 1H), 7.66 (d, J=7.6, 1H), 7.62 (d, J=7.8, 1H), 7.51 (t, J=7.7, 1H), 4.78 (dd, J=6.2, 9.5, 1H), 4.41-4.33 (m, 1H), 3.67 (d, J=13.3, 1H), 3.16 (s, 3H), 3.15 (s, 3H), 2.90 (qd, J=3.3, 7.9, 1H), 2.75 (dd, J=3.3, 9.6, 1H), 2.53-2.44 (m, 1H), 2.38-2.29 (m, 3H), 1.89-1.70 (m, 4H), 1.70-1.58 (m, 3H), 1.36-1.26 (m, 1H), 0.83 (d, J=6.6, 3H), 0.81 (d, J=6.5, 3H); MS (ESI+) m/z 490 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(Cl)(Cl)(Cl)[Cl:43]>>[CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:11][Cl:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ccccc1[C@@H](CO)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1ccccc1[C@@H](CCl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (2S)-3-benzyloxy-2-(2-methoxyphenyl)propan-1-ol (Description 98, 2 g, 7.4 mmol) and triphenylphosphine (2.12 g, 8.1 mmol) in carbon tetrachloride (10 mL) was heated in an oil bath at 100° C. for 5 h. Methanol (1 mL) was cautiously added and the mixture was cooled to room temperature and stirred for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (100:0 increasing to 95:5) to give the title compound (1.5 g). 1H NMR (250 MHz, CDCl3) δ7.37-7.2 (7 H, m), 6.96-6.86 (2 H, m), 4.54 (2 H, s), 3.92 (2 H, m), and 3.81-3.73 (7 H, m).