Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[Si:8]([O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][C@:29]([CH2:33][OH:34])([CH3:32])[C:28]1([CH3:36])[CH3:35])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:8]([O:25][CH2:26][C@H:27]1[CH2:31][CH2:30][C@@:29]([CH3:32])([CH:33]=[O:34])[C:28]1([CH3:36])[CH3:35])([C:21]([CH3:23])([CH3:24])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@@]1(C)CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1(C)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@@]1(C)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of 4-methylmorpholine (17.33 g, 148 mmol) in CH2Cl2 (400 mL) was dried over Mg2SO4 for 15 min and filtered into a round bottom flask containing ((1R,3S)-3-((tert-butyldiphenylsilyloxy)methyl)-1,2,2-trimethylcyclopentyl)methanol (40.5 g, 99 mmol). To the resulting clear solution was added 4 A° powdered molecular sieves (20 g), tetrapropylammonium perruthenate (TPAP) (0.693 g, 1.972 mmol) and stirred for 4 h at room temperature. The reaction was concentrated to ˜100 mL, diluted with hexane/Et2O (9:1, 500 mL) and filtered through a plug of silica gel. The plug was washed with 500 mL of hexane/Et2O (9:1). The filtrate was concentrated to afford (1R,3S)-3-((tert-butyldiphenylsilyloxy)methyl)-1,2,2-trimethylcyclopentanecarbaldehyde (32.61 g, 80 mmol, 81% yield) as a viscous pale yellow oil. 1H NMR (500 MHz, CDCl3) δ: 9.63 (1 H, s), 7.66 (4 H, dd, J=7.9, 1.5 Hz), 7.35-7.45 (6 H, m), 3.66-3.71 (1 H, dd, J=10.2, 6.9 Hz), 3.56 (1 H, dd, J=10.4, 7.0 Hz), 2.29 (1 H, ddd, J=13.7, 11.4, 6.0 Hz), 2.09-2.18 (1 H, m), 1.87-1.96 (1 H, m), 1.28-1.44 (2 H, m), 1.06 (3 H, s), 1.02-1.05 (12 H, s), 0.81 (3 H, s). LCMS (M+Na) calcd for C26H36NaO2Si: 431.25; found: 431.52.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[N:7][CH:8]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[N:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-pyridin-2-yl)-amide (12 mg, 0.02 mmol) prepared in Example 199 in DMSO (0.2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.04 g, 0.3 mmol), then aqueous solution (1N) of NaOH (0.1 mL, 0.1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-carbamoyl-pyridin-2-yl)-amide as a light yellow solid (Yield 5 mg, 40%)
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([CH2:14][N+:15]([O-:17])=[O:16])[C@H:2]([CH3:3])[CH:1]=[O:4])=[CH:11][CH:12]=1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Reactant: CCC=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1ccc([C@H](C[N+](=O)[O-])[C@H](C)C=O)cc1

Procedure:
The title compound was prepared from propionaldehyde and (E)-1-methoxy-4-(2-nitrovinyl)benzene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AS-H column at 230 nm (2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer tmajor=42.10 min, minor enantiomer tminor=60.77 min. [α]D20=−4.6 (c=1.3, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:15][CH2:14][C:13]([F:17])([F:16])[C@@H:12]1[CH2:11][N:10]([C@@H](C1C=CC=CC=1)C)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:1]([O:5][C:6]([C@@:8]12[CH2:15][CH2:14][C:13]([F:16])([F:17])[C@@H:12]1[CH2:11][N:10]([C:34]([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1C[C@H]2C(F)(F)CC[C@@]2(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@]12CCC(F)(F)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 40 °C
Reaction time: 17 h
Yield: 84.4 %

Procedure:
{(1S,5S)-6,6-Difluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octan-1-yl}carboxylic acid tert-butyl ester (370.0 mg, 1.05 mmol) was dissolved in dichloromethane (3 mL). Benzyloxycarbonyl chloride (898 mg, 5.26 mmol) was added, and the mixture was stirred at 40° C. for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give 338 mg of the title compound as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]([NH2:24])=[NH:23])[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.[F:25][CH2:26][CH:27]([O:30][CH2:31][C:32]([CH:34]1[C:39](=O)[CH2:38][CH2:37][O:36][CH2:35]1)=O)[CH2:28][F:29]>CN(C=O)C>[F:25][CH2:26][CH:27]([O:30][CH2:31][C:32]1[C:34]2[CH2:35][O:36][CH2:37][CH2:38][C:39]=2[N:23]=[C:22]([NH:21][C:11]2[CH:12]=[CH:13][C:14]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:9]([O:8][CH3:7])[CH:10]=2)[N:24]=1)[CH2:28][F:29]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C1CCOCC1C(=O)COC(CF)CF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(c(COC(CF)CF)n2)COCC3)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Potassium carbonate (222 mg, 1.61 mmol) was added to 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (149 mg, 0.40 mmol) in DMF (1 mL) and set under N2 atmosphere. The DMF (1 mL) solution of 3-(2-(1,3-difluoropropan-2-yloxy)acetyl)dihydro-2H-pyran-4(3H)-one (95 mg, 0.40 mmol) was added dropwise to the reaction mixture and stirred for 16 hours at 50° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by silica flash chromatography using a gradient of methanol in dichloromethane (0 to 4%) affording the title compound (120 mg, 67% yield).
Reaction SMILES: CNC(NC1SC(C2C=CN=CC=2)=C(C)N=1)=O.[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2[S:29][C:28]([NH:30][C:31]([N:33]3[CH:37]=[CH:36]N=C3)=[O:32])=[N:27][C:26]=2[CH3:38])[CH:22]=[C:21]([CH3:39])[N:20]=1.[CH2:40]([C:42]1[O:46][C:45](CCN)=[N:44][CH:43]=1)[CH3:41]>>[CH3:39][C:21]1[CH:22]=[C:23]([C:25]2[S:29][C:28]([NH:30][C:31]([NH:33][CH2:37][CH2:36][C:45]3[O:46][C:42]([CH2:40][CH3:41])=[CH:43][N:44]=3)=[O:32])=[N:27][C:26]=2[CH3:38])[CH:24]=[C:19]([CH3:18])[N:20]=1
Reactant: CCc1cnc(CCN)o1
Reactant: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)cc(C)n1
Agent: CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(C)c3)s2)o1

Procedure:
The titled compound is prepared by an analogous procedure to 1-methyl-3-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-urea (example 18b) by replacing imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) with imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide and by replacing methylamine with 2-(5-ethyl-oxazol-2-yl)-ethylamine. The preparation of 2-(5-ethyl-oxazol-2-yl)-ethylamine is described previously.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:28](=[O:30])[C:27]4[CH:26]=[CH:25][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)(=[O:30])[CH:27]([CH3:31])[CH3:26]
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: CC(C)C(=O)Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 386 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:33]([CH3:34])=[C:32]([CH3:35])[C:18]4[C:19]([C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)(O)[C:20]([CH3:23])([CH3:22])[O:21][C:17]=4[C:16]=3[CH3:36])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:33]([CH3:34])=[C:32]([CH3:35])[C:18]4[CH:19]([C:25]5[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[C:20]([CH3:23])([CH3:22])[O:21][C:17]=4[C:16]=3[CH3:36])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)OC(C)(C)C4(O)c3ccc(C)cc3)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)OC(C)(C)C4c3ccc(C)cc3)CC2)cc1
Yield: 85 %

Procedure:
Using 6-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,5,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-3-ol obtained in Example 140, the title compound was synthesized in the same manner as in Example 46. Yield 85% mp. 160–162° C. (ethanol).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:2]1[CH2:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1]1)[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCOc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CC(=O)c2ccccc2O1
Yield: 38 %

Procedure:
A solution of 48 g of 4-chromanone, 67 ml of 3-buten-2-ol and 500 mg of p-toluenesulfonic acid in 67 ml of 2,2-dimethoxypropane and 500 ml of anhydrous toluene was boiled under reflux for 46 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 24.7 g (38%) of (RS)-2-(2-buten-1-yl)-4-chromanone were obtained as a yellow oil.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1NC(C)C(O)=O.COC(OC)CNCCCN1CCC2(CC2)[C@H](O)C1.CO[CH:38](OC)[CH2:39][N:40]([CH2:56][CH2:57][CH2:58][N:59]1[CH2:66][CH2:65][C:62]2([CH2:64][CH2:63]2)[C@H:61]([OH:67])[CH2:60]1)[C:41](=[O:55])[CH:42]([NH:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)[CH3:43]>>[OH:67][C@@H:61]1[CH2:60][N:59]([CH2:58][CH2:57][CH2:56][N:40]2[CH2:39][CH2:38][N:44]([C:45]3[CH:54]=[CH:53][C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:46]=3)[C@@H:42]([CH3:43])[C:41]2=[O:55])[CH2:66][CH2:65][C:62]21[CH2:64][CH2:63]2
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O)C1)C(=O)C(C)Nc1ccc2ccccc2c1)OC
Agent: CC(Nc1ccc2ccccc2c1)C(=O)O
Agent: COC(CNCCCN1CCC2(CC2)[C@H](O)C1)OC
Product: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc2ccccc2c1

Procedure:
The title compound was produced in analogy with examples 74 and 75, steps D-F. Thus, coupling of 2-(naphthalen-2-ylamino)-propionic acid (intermediate 16) with (S)-6-[3-(2,2-dimethoxy-ethylamino)-propyl]-6-aza-spiro[2.5]octan-4-ol (examples 74/75C) in step D led to N-(2,2-dimethoxy-ethyl)-N-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-(naphthalen-2-ylamino)-propionamide, which was cyclized in step E. Finally, HPLC purification of the epimeric mixture, 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-4-naphthalen-2-yl-piperazin-2-one, in step F afforded the title compound. Light yellow gum, MS: 408.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32](SCC)=[N+:31]([CH2:37][CH3:38])[C:30]=2[CH:39]=1.C(N(CC)CC)C>CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:32][N:31]([CH2:37][CH3:38])[C:30]=2[CH:39]=1
Reactant: CCSc1sc2ccc(Cl)cc2[n+]1CC
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1CS(=C2C(=O)N(c3ccccc3)NC2C)c2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01) was mixed with 4.3 g (0.01 mol) 5-chloro-2-ethylthio-3-ethylbenzothiazolium tosylate in 15 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 1 hour, then filtered and washed with methanol. After drying the yield was 2.20 g (59%), mp 161°-162.5° C., λmax=382 (ε=21,000).
Reaction SMILES: ClC1C=C(NCC(N2CCC3CCN(C4C5C=CNC=5N=CN=4)C3C2)=O)C=C(Cl)C=1.[CH:31]1([C@:34]([NH:58][C:59]2[CH:64]=[C:63]([Cl:65])[CH:62]=[C:61]([Cl:66])[CH:60]=2)(CCC)[C:35]([N:37]2[CH2:42][CH2:41][CH:40]3[CH2:43][CH2:44][N:45]([C:46]4[C:47]5[CH:54]=[CH:53][NH:52][C:48]=5[N:49]=[CH:50][N:51]=4)[CH:39]3[CH2:38]2)=[O:36])[CH2:33][CH2:32]1>>[N:49]1[C:48]2[NH:52][CH:53]=[CH:54][C:47]=2[C:46]([N:45]2[CH:39]3[CH2:38][N:37]([C:35](=[O:36])[C@H:34]([NH:58][C:59]4[CH:60]=[C:61]([Cl:66])[CH:62]=[C:63]([Cl:65])[CH:64]=4)[CH:31]4[CH2:32][CH2:33]4)[CH2:42][CH2:41][CH:40]3[CH2:43][CH2:44]2)=[N:51][CH:50]=1
Reactant: CCC[C@](Nc1cc(Cl)cc(Cl)c1)(C(=O)N1CCC2CCN(c3ncnc4[nH]ccc34)C2C1)C1CC1
Agent: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCC2CCN(c3ncnc4[nH]ccc34)C2C1
Product: O=C([C@H](Nc1cc(Cl)cc(Cl)c1)C1CC1)N1CCC2CCN(c3ncnc4[nH]ccc34)C2C1

Procedure:
A similar procedure was used as described for the synthesis 2-(3,5-dichloro-phenylamino)-1-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-octahydro-pyrrolo[2,3-c]pyridin-6-yl]-ethanone using (2R)-2-cyclopropyl-(3,5-dichlorophenylamino)-1-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-octahydro-pyrrolo[2,3-c]pyridin-6-yl]pentan-1-one in place of 2-(3,5-dichloro-phenylamino)-1-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-octahydro-pyrrolo[2,3-c]pyridin-6-yl]-ethanone. 1H NMR (400 MHz, DMSO-d6) δ=11.37 (br. s., 1H), 7.98-7.75 (m, 1H), 6.89 (br. s., 1H), 6.59-6.14 (m, 3H), 5.52 (s, 1H), 4.56-4.27 (m, 1H), 4.03 (br. s., 2H), 3.83-3.37 (m, 3H), 2.13-1.91 (m, 2H), 1.91-1.38 (m, 3H), 1.04-0.80 (m, 2H), 0.35-−0.25 (m, 4H). LC/MS (m/z): calcd. For C24H26Cl2N6O (M+1H) 485. found 485.
Reaction SMILES: C(O[C:6]([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C>O1CCCC1.CNC>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]([CH3:6])[CH3:40])=[O:39])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=1)[CH3:38]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CNC
Solvent: C1CCOC1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C)C)CC2)c(C)c1
Yield: 52.9 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 809 and 2 mol/L dimethylamine tetrahydrofuran solution (220 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (27 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][C:23](=O)[C:24](F)(F)F)=[O:7].C(Br)[C:36]1[CH:41]=[CH:40]C=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([NH:22][C:11]1[CH:12]=[C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[CH:29]=1)[C:24]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)C(F)(F)F)cc(OC)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCc2ccccc2)cc(OC)c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A solution of compound 1h (200 mg, 0.42 mmol), benzyl bromide (0.100 mL, 0.84 mmol), and potassium carbonate (173 mg, 1.25 mmol) in DMF (2 mL) was sealed in a pressure tube and heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried, and concentrated on a rotary evaporator. The residue was dissolved in a mixture of MeOH (10 mL) and water (1 mL), and potassium carbonate (200 mg) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and the precipitated solid was recovered by filtration and dried in vacuo to give compound 23a (163 mg, 82%). ESI-MS m/e 473.1 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([CH2:11][CH2:12][C@@H:13](N)[C:14]([OH:16])=[O:15])=[O:10])=[CH:3][CH:2]=1.[K+].[Br-:19].N([O-])=O.[Na+]>OS(O)(=O)=O>[Br:19][C@H:13]([CH2:12][CH2:11][C:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:10])[C:14]([OH:16])=[O:15]
Reactant: [Br-]
Reactant: N[C@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(CC[C@@H](Br)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.3 %

Procedure:
To a solution of D-glutamic acid γ-benzyl ester (5.00 g, 21 mmol) and KBr (7.5 g, 63 mmol) in 2.5N H2SO4 (35 mL) at 0° C. (ice bath) was added NaNO2 (2.45 g, 35.5 mmol) in small portions over 1.5 hrs keeping the internal temperature below 5° C. The resulting mixture was stirred at 0° C. for 1 hr and at room temperature for 45 min. The mixture was extracted with Et2O, extract washed with water and saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was taken up in CH2Cl2, re-dried over Na2SO4 and evaporated to dryness to give crude (2R)-2-bromo-4-carbobenzyloxy-butyric acid (5.52 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:11]2[N:12]=[C:13]([CH3:22])[N:14]=[C:15]([O:16][CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:10]2=[N:9]1.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:31]#[N:32])[N:9]=[C:10]3[C:15]([O:16][CH2:17][C:18]([F:20])([F:21])[CH3:19])=[N:14][C:13]([CH3:22])=[N:12][C:11]=23)=[CH:25][CH:26]=1
Reactant: Cc1nc(OCC(C)(F)F)c2nn(-c3ccccc3Br)c(-c3ccc(Cl)cc3)c2n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(OCC(C)(F)F)c2nn(-c3ccccc3C#N)c(-c3ccc(Cl)cc3)c2n1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine (10A-7, 50 mg, 0.1 mmol), Zn(CN)2(20 mg, 0.17 mmol), Pd(PPh3)4 (15 mg, 0.01 mmol) in DMF (1 ml) was heated in a microwave apparatus (Emrys Optimizer, Personal Chemistry) at 200° C. for 3 minutes. The reaction mixture was quenched with saturated aqueous NaCl and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated under vacuum. The crude residue was purified via HPLC (Shimadzu) using a solvent gradient of 30% CH3CN/hexanes to 100% CH3CN to give the desired product, 2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile (11A-1), as a colorless solid (25 mg): MS (M+1)+440.0; 1H NMR (400 MHz, CDCl3) δ 7.80-7.64 (m, 4H), 7.40-7.26 (m, 4H), 4.8 (t, J=11.6 Hz, 2H), 2.7 (s, 3H), 1.79 (t, J=18.67 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[N:24]=[N:25][C:26](OC)=[CH:27][CH:28]=1.C(N(CC)CC)C>C(O)CCCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:26]3[N:25]=[N:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1ccc(Cl)nn1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4ccc(Cl)nn4)CC3)nc(N)c2cc1OC

Procedure:
4-Amino-6,7-dimethoxy-2-piperazinoquinazoline (3.0 g, 10.4 mmole), 3-chloro-6-methoxy-pyridazine (3.96 g, 27.4 mmole) and triethylamine (5.0 g, 49.5 mmole) in n-pentanol (210 ml) were heated under reflux for 25 hours. The solvent was evaporated in vacuo and the residue partitioned between chloroform and saturated aqueous sodium carbonate solution. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel (200 g) eluting with chloroform followed by 5% methanol in chloroform. Further purification of the major product by HPLC using a Waters 500 Prep. LC/system, eluting with 6% by volume methanol in methylene chloride at a flow rate of 0.15 liters per minute gave the desired product which was recrystallized from methanol, m.p. 269°-270° C. (0.5 g).
Reaction SMILES: [OH:1][CH2:2][C:3](C)([CH3:6])[CH:4]=O.[CH:8]([O:13][CH3:14])([O:11][CH3:12])OC.Cl.O1CCOCC1.O(C)[Na]>CO>[CH3:14][O:13][CH:8]([O:11][CH3:12])[C:3]([CH3:6])([CH3:4])[CH2:2][OH:1]
Reactant: COC(OC)OC
Reactant: CC(C)(C=O)CO
Agent: CO[Na]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(OC)C(C)(C)CO
Reaction time: 8 h

Procedure:
A solution of 24.4 g (0.24 mol) of 3-hydroxy-2,2-dimethylpropanal (Aldrich), 26 g (0.25 mol) of trimethyl orthoformate, and 0.5 mL of 6.8 N HCl/dioxane in 300 mL of methanol was allowed to stand at room temperature overnight. A slight excess of NaOCH3 was added and the solvent evaporated at reduced pressure. The residue was dissolved in ether and the mixture filtered. After evaporation of solvent and fractionation twice through a 15 cm Vigreux column, the product was obtained as a water white oil, bp 43°-48°/0.2mm, 18.5 g (52%).