Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.C(OC([N:17]1[CH2:22][CH2:21][CH:20]([C@@H:23]2[CH2:25][C@@H:24]2[CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]1)=O)(C)(C)C>>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:25][CH:24]3[CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Reactant: Cc1nc(Cl)ncc1F
Product: Cc1nc(N2CCC(C3CC3CCO)CC2)ncc1F
Temperature: 90 °C

Procedure:
The titled compound was prepared from 2-chloro-5-fluoro-4-methylpyrimidine and rac cis-tert-Butyl-4-[-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate by a procedure analogous to example 6 step 2, with the exception of reaction temperature. The reaction was heated at 90° C. for 2 h.
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([OH:31])=O.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])=[N:25][C:24]=1[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 54 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 54% yield: mp 197-198° C.; 1H NMR (300 MHz, CDCl3) δ 7.36-7.16 (m, 9H), 5.97 (t, J=5.4 Hz, 1H), 4.54 (d, J=5.4 Hz, 2H), 4.44 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.44 (t, J=8.1 Hz, 2H), 2.59 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 162.3, 157.2, 155.4, 152.9, 148.9, 137.9, 134.3, 129.7, 128.7, 127.8, 127.6, 121.4, 120.8, 117.4, 47.2, 44.0, 42.0, 41.7, 17.2: MS (ES+) m/z 491.3 (M+1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].C(N(CC)CC)C>C(O)C>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:10]
Reactant: CCOC(=O)CN
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 37.5 °C

Procedure:
Ethyl acrylate (11.5 g, 0.115 mol) was added to a solution of glycine ethyl ester hydrochloride (187) (20 g, 0.144 mol) and triethylamine (17.6 mL, 0.127 mol) in ethanol (134 mL) and the mixture heated to 35-40° C. for 3.5 hrs. The mixture was concentrated and partitioned between water (100 mL) and ethyl acetate (1×300 mL). The organics were washed with 1×100 mL half saturated sodium bicarbonate, 1×50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to 20.94 g of clear colorless oil that was used in the next step without further purification. MS (ESI) m/z 204 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:28])[N:4]([CH3:29])[C:3]1=[O:30])[CH2:12][CH2:11][CH:10]=[C:9]3[C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1.[H][H].C(OCC)C>C(OCC)(=O)C.[Pt]>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:28])[N:4]([CH3:29])[C:3]1=[O:30])[CH2:12][CH2:11][CH2:10][CH:9]3[C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: [H][H]
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(C)cs2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3c2nc(C)cs2)c1

Procedure:
1,3-Dimethyl-10-(4-methylthiazol-2-yl)-5-m-tolyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate M) (100 mg, 0.24 mmol) was dissolved in ethyl acetate (20 mL) and the resulting solution was hydrogenated using the H-Cube® (10% platinum on carbon CatCart®), at atmospheric pressure of hydrogen and 20° C., for 6.5 hours. The solvent was removed under vacuum. The crude material was purified by chromatography on silica, eluting with 1-2% MeOH/DCM to obtain a gum. Diethyl ether was added and removed under vacuum to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]1([CH:41]=O)[CH2:40][O:39][CH2:38]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:36][C:37]3([CH3:41])[CH2:40][O:39][CH2:38]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC1(C=O)COC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1(C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)COC1
Reaction time: 3 h

Procedure:
To a slurry of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (74 mg, 0.16 mmol) in ethanol (3 mL) was added 3-methyloxetane-3-carbaldehyde (78.54 mg, 0.78 mmol) and then piperidine (0.02 mL, 0.16 mmol) and the mixture heated to 80° C. with stirring. After 3 h, the mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and the filtered. Solvents were removed to afford an oil which was purified by column chromatography (gradient from neat methylene chloride to 95-5 methylene chloride:MeOH). The pure fractions were concentrated, then taken up in acetonitrile/water, frozen and lyophilized to afford 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile as a colorless solid weighing 14 mg.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2].[CH3:34][Mg]Cl>C1COCC1>[CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:24]([C:31]([OH:33])([CH3:34])[CH3:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1cnc(N2CCn3c(cc4ccc(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H]1c2cc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of (R)-1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (5 mg, 0.01 mmol) in THF (1 mL) was added LaCl3-2LiCl (0.2 mL, 0.12 mmol, 0.6M) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h. MeMgCl (0.3 mL, 0.9 mmol, 3M) was added to the formed mixture and then the reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with sat. NH4Cl (5 mL) at 0° C. and then extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated, purified by preparative TLC eluting with PE/EtOAc 1:1 and then by SFC separation to afford (R)-2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (1.20 mg, 24.68% yield, Isomer 1) as a colorless oil. Analytical chiral HPLC: tR=6.394 min in 15 min chromatography (Method: OJ-H—3—5—40—2.35 ML). LC-MS m/z 497.3 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.75 (s, 1H), 7.93 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.62 (d, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.48 (s, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.16-5.12 (m, 1H), 4.32-4.28 (m, 1H), 4.14-4.07 (m, 1H), 3.86-3.77 (m, 1H), 3.07 (s, 3H), 2.34-2.25 (m, 1H), 1.92 (s, 1H), 1.68 (s, 6H), 1.18 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H)
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]5[CH2:54][CH2:53][CH2:52][CH2:51]5)=[O:11])[CH:24]=4)=[CH:27][C:28]=3[F:48])=[O:34])[CH2:37][CH2:36]2)=[O:47])=[CH:45][CH:44]=1
Reactant: C1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCCC1
Reaction time: 8 h

Procedure:
To a solution of roughly purified [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (150 mg) in N,N-dimethylformamide (1.5 ml) was added pyrrolidine (0.100 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white powder (17.4 mg).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl.N1C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:20])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C2(N)CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)NC1(c2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 0 °C

Procedure:
3 g of tert-butyl 4-(1-aminocyclopropyl)benzoate was placed in 30 mL of dichloromethane and 1.8 mL of pyridine. The solution was cooled to 0° C. and 1.2 mL of allyl chloroformate (dissolved in 5 mL of dichloromethane) was added dropwise at 0° C.-5° C. The mixture was left to react for 30 minutes at 0° C. and 2 hours at RT. The solution was combined with silica gel and evaporated down to the residue. This was chromatographed with dichloromethane on silica gel 70. Yield: 1.46 g of oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[C:19]([CH3:20])=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH3:20][C:19]1[C:11]([CH2:10][CH2:9][OH:8])=[CH:12][C:13]2[O:17][CH2:16][O:15][C:14]=2[CH:18]=1
Reactant: Cc1cc2c(cc1CCOCc1ccccc1)OCO2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2c(cc1CCO)OCO2
Reaction time: 1 h
Yield: 79 %

Procedure:
1.9 g of 5-(2-benzyloxyethyl)-6-methyl-1,3-benzodioxole was dissolved in 80 ml of ethanol. 0.2 g of 10% palladium/carbon (containing 50% water) and 4 ml of acetic acid were added thereto and the catalytic reduction was conducted under 3 atm/cm2 for 1 h. After removing palladium/carbon, ethanol was distilled off and the product was purified according to silica gel column chromatography (ethyl acetate/hexane=2:3) to obtain 1.0 g of the intended compound in the form of a faint yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-chloro-pyrimidine (3.0 g, 15.51 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.42 g, 17.06 mmol, 1.1 equiv; commercially available) in DMAc (50 mL) was added anhydrous K2CO3 (5.36 g, 38.78 mmol, 2.5 equiv) and the reaction mixture stirred at rt for 18 h. The reaction mixture was heated for an additional time period of 2 h to 60° C. and then extracted with ethyl acetate (3×100 mL) and the combined organic phases washed with a sat. solution of sodium chloride (2×50 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 2.22 g (40%) of the title compound. MS (ISP): 357.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](Cl)(Cl)=[S:25]>>[Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:24]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:9]=1)=[S:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline (80 mg, 0.308 mmol) and NaHCO3 in CHCH3:H2O (2.5:1, 7 mL) with thiophosgene at 0° C. The solution was allowed to warm to 23° C. and the reaction was continued overnight. The CHCH3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.C[Sn](C)(C)[C:31]1[CH2:37][CH:36]2[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]([CH2:34][CH2:35]2)[CH:32]=1>>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([C:31]2[CH2:32][CH:33]3[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:36]([CH2:35][CH2:34]3)[CH:37]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1C2C=C([Sn](C)(C)C)CC1CC2
Reactant: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Product: CC(C)(C)OC(=O)N1C2C=C(c3cc4c(ccc(=O)n4-c4c(Cl)cccc4Cl)c(-c4ccc(F)cc4Cl)n3)CC1CC2

Procedure:
The tert-butyl 3-[5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate was prepared from 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND CCC1) and tert-butyl 3-(trimethylstannyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (COMPOUND PPA-3) by a procedure analogous to that described in EXAMPLE CZC1, except that the eluting solvents in the purification step were 20:80 acetone-hexanes. Mass spectrum (ESI) 626 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-Methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C:6](=[O:8])[CH3:7].C(O)(C)C.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CC(C)=O>[CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 102.7 %

Procedure:
A flame-dried 1 L 3-necked flask, fitted with a 30 cm Vigreux column topped with a distillation head, an argon inlet tube and a magnetic stirring bar, was charged with 36.8 g (0.189 mol) of (3E,6R)-6,10-dimethyl-3,9- undecadien-2-one (GC purity 93.6%). 500 mL of isopropanol and 40.0 g (0.196 mol) of aluminum isopropoxide. The reaction mixture was stirred and heated to gentle reflux under argon. Acetone was allowed to distill off at a rate of about 30 drops/min. while maintaining a head temperature of ca. 80° C. After 3.5 hours the reaction was shown by GC to be almost complete with 5% of starting material remaining. The reaction was cooled in an ice bath and the pressure was reduced to ca. 54 mmHg. Isopropanol was distilled off at a head temperature of 30° C.-31° C. until the reaction mixture was concentrated to a volume of about 200 mL. The residual oil was cooled in an ice bath, 200 mL of 2N HCl were carefully added with stirring and the mixture was poured into a separatory funnel containing 200 mL of ether. An additional 200 mL of 2N HCl were added to dissolve some remaining white solid material. The layers were separated and the aqueous phase was extracted with 2×200 mL of ether. The combined organic layers were washed successively with 200 mL of sat. NaHCO3 -solution and 200 mL of brine, dried over MgSO4, filtered and concentrated on the rotovapor. The residue was dried at 0.1 mm for 30 minutes to afford 38.1 g (102.6%) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol as a light yellow liquid. GC analysis indicated a purity of 94.6%. This material was used as is in Example 2.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=O)=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)(=[O:20])=[O:22])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Reactant: CN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added N-methylpiperazine (13.7 g, 0.137 moles) in one portion, the mixture is stirred until a clear solution is obtained, and concentrated on a rotary evaporator. The residue is taken up in water, filtered, recrystallized from ethanol, and dried at 48° to yield 5.12 grams of 1-[[4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)phenyl]sulfonyl]4-methylpiperazine, mp 305°-307° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][CH3:14])[CH2:9][C@H:8]2[NH:15][C:16](=[O:18])[CH3:17])[C:3]1=[O:19].C(N(CC)CC)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1>ClCCl>[CH3:14][NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:15][C:16](=[O:18])[CH3:17])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[C:3]2=[O:19])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CN[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC(C)=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(methylamino)cyclohexyl)acetamide (12.5 g, 46.6 mmol) in dichloromethane was added triethylamine (12.98 mL, 93 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (10.83 g, 46.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (350 mL) and extracted with a solution of aqueous acetic acid (1×200 mL, 1×100 mL; made from 300 mL of H2O and 16 mL of acetic acid. The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 mL), basified with Na2CO3 to pH 10-11, and then extracted with dichloromethane (2×350 mL; maintained pH of aqueous layer at 10-11 with Na2CO3 as necessary). The organic phase was washed with saturated NaCl solution (1×200 mL); the NaCl layer was back-extracted with dichloromethane (1×100 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (19.4 g, 90%). LC/MS found [M+H]+=465. HPLC shows the purity as 99.4%, with the largest single impurity as 0.5%. 1H-NMR (500 MHz, CD3OD), δ ppm: 8.77 (1H, s), 8.56 (1H, s), 8.02 (1H, dd, J=8.80, 1.37 Hz), 7.87 (1H, d, J=8.52 Hz), 5.25 (1H, t, J=8.52 Hz), 4.53 (1H, q, J=3.94 Hz), 4.01 (1H, dt, J=11.96, 3.85, 3.71 Hz), 3.46-3.64 (2H, m), 2.77-2.86 (1H, m), 2.47-2.57 (1H, m), 2.41 (3H, s), 2.22 (1H, dq, J=12.51, 12.44, 3.57 Hz), 1.98 (3H, s), 1.95-1.98 (1H, m), 1.92-1.98 (1H, m), 1.84-1.91 (1H, m), 1.78 (1H, t, J=3.44 Hz), 1.71-1.76 (1H, m), 1.62-1.69 (1H, m).