Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C>C(O)C.O>[OH:16][C@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H]3CO3)c2n1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)CN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
In a mixed solvent (16 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2R)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (400 mg, 1.62 mmol) and 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (synthesized using [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536 in the same manner as in Reference Examples 20, 21 and 22; 402 mg, 1.62 mmol) and stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 323 mg (40%) of the title compound in the form of a yellowish solid.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=2)[N:3]=1.[CH:24]1([CH:27]([N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:28][C:29]#[N:30])[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O.CCOCC.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>[CH:24]1([CH:27]([N:31]2[CH:35]=[C:34]([C:2]3[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=[C:4]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=4)[N:3]=3)[CH:33]=[N:32]2)[CH2:28][C:29]#[N:30])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 75.1 %

Procedure:
A flask was charged with 5-chloro-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Step C, 150 mg, 0.429 mmol), 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (Preparation P; 185 mg, 0.643 mmol) and K3PO4 (273 mg, 1.29 mmol). DME (2.5 mL) and H2O (1.5 mL) were added and the resulting solution was purged with N2 for 15 minutes. Pd(PPh3)4 (49.5 mg, 0.0429 mmol) was added, the flask sealed, and the mixture stirred at 80° C. for 3.5 hours. The mixture was cooled to ambient temperature and was diluted with H2O (5 mL). The mixture was extracted with 50% EtOAc/hexanes and the combined extracts were washed with saturated NaCl and dried over MgSO4/activated carbon. The dried solution was eluted through a SiO2 column eluting with 50% EtOAc/hexanes, EtOAc and 10% MeOH/EtOAc. The EtOAc and 10% MeOH/EtOAc pools were combined and concentrated to give a gold syrup. The syrup was dissolved in Et2O and concentrated to give the title compound (153 mg, 75.0% yield) as a brittle, light beige foam. MS (apci) m/z=475.3 (M+H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CO.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([Cl:1])=[C:12]([Cl:17])[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: O
Solvent: CO
Product: Nc1nc(N)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
50 g of N-chlorosuccinimide are added in portions at 23° C. to a solution of 45 g of 2,4-diamino-6-chloropyrimidine in methanol (1030 ml). On completion of addition, the reaction mixture is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the crude product obtained is taken up under reflux in 850 ml of water for 1 hour. After filtering, the crude product is recrystallized two times from an EtOH:H2O (80:20) mixture to give 44.5 g of 2,4-diamino-5,6-dichloropyrimidine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][CH2:9][CH2:10][C:11]([NH2:13])=O)=[CH:6][CH:5]=1>S(=O)(=O)(O)O>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][CH2:9][CH2:10][C:11]#[N:13])=[CH:6][CH:5]=1
Reactant: NC(=O)CCNc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: N#CCCNc1ccc(OC(F)(F)F)cc1

Procedure:
3-(4-Trifluoromethoxyanilino)propionamide may be prepared in the following manner: 3-(4-trifluoromethoxyanilino)propionitrile (5.4 g), obtained in Example 1, and concentrated sulphuric acid (20 cc) are heated to 90° C. for 2 hours. After cooling to a temperature of 20° C., this solution is added to ice (250 g) and the pH is brought to 9-10 with concentrated sodium hydroxide (10N). 3-(4-Trifluoromethoxyanilino)propionamide (4.2 g), m.p. 76° C., is thereby isolated directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)[S:5][CH:6]=1.[Br:14]Br>C(Cl)Cl>[Br:14][C:6]1[S:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: Cc1cccc(-c2cc(Cl)cs2)n1
Solvent: ClCCl
Product: Cc1cccc(-c2cc(Cl)c(Br)s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 141 %

Procedure:
To a 0° C. solution of 2-(4-chloro-thiophen-2-yl)-6-methyl-pyridine (example Rupp-96) (0.45 g, 1.45 mmol) and CH2Cl2 (10 mL) is added Br2 (0.15 mL, 2.91 mmol). The solution is warmed to ambient temperature and stirred for 1 hour. The solution is washed with sat. NaHCO3 (10 mL), sat. Na2S2O3 (10 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.59 g, 2.04, 95%). 1H NMR (CDCl3), δ 2.55 (s, 3H), 7.05 (d, 7.9 Hz, 1H), 7.29 (s, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.9, 7.9, 1H). LC/MS (m/z): calcd. for C10H7BrClNS (M+H)+: 288.0; found: 287.9.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:3]=1.CN1CCOCC1.ClC(OC(C)=C)=O.[CH2:44]([NH2:47])[CH:45]=[CH2:46]>C1COCC1>[CH2:44]([NH:47][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:8]=1)[CH:45]=[CH2:46]
Reactant: C=CCN
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)O)c3)ccnc2n1
Agent: C=C(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CCNC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 208d (60 mg, 0.147 mmol) was dissolved in THF to which was added N-methyl morpholine (49 mg, 0.162 mmol), and isopropenyl chloroformate (36 mg, 0.295 mmol). This was stirred at room temperature for 1 hr at which time the allylamine (42 mg, 0.739 mmol) was added and the reaction mixture stirred at room temperature for another 1 hr. THF was then removed under a stream of N2 and then crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid. (8.0 mg, 9.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.92 (s, 3H), 2.74 (s, 2H), 3.86 (d, J=5.15 Hz, 2H), 5.04-5.16 (m, 2H), 5.73-5.98 (m, 1H), 6.73 (d, J=6.99 Hz, 1H), 7.10 (dd, J=7.72, 2.21 Hz, 1H), 7.27-7.43 (m, 3H), 7.51-7.65 (m, 2H), 7.69-7.82 (m, 2H), 8.54 (d, J=7.35 Hz, 1H), 8.82 (d, J=8.46 Hz, 1H); MS (ESI+) m/z 445 (M+TFA+H)+; (ESI−) m/z 443 (M+TFA−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([SH:9])[N:3]=1.[Cl:10][CH2:11][C:12]1[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH:15]=[CH:14][N:13]=1>CC(O)C>[ClH:10].[CH3:18][C:17]1[C:12]([CH2:11][S:9][C:4]2[N:5]=[C:6]([NH2:8])[CH:7]=[C:2]([NH2:1])[N:3]=2)=[N:13][CH:14]=[CH:15][C:16]=1[S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=2)[N:29]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Nc1cc(N)nc(S)n1
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CSc1nc(N)cc(N)n1
Product: Cl
Temperature: 4 °C

Procedure:
A suspension of 4,6-diamino-pyrimidine-2-thiol (0.36 g, 2.5 mmol) and 6-[3-(2-chloromethyl-3-methyl-pyridin-4-ylsulfanyl)-propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.03 g, 2.5 mmol) in 2-propanol (50 ml) is heated under reflux for 6 h under a nitrogen atmosphere. After cooling to 4° C., the precipitate is filtered, washed with cold 2-propanol and dried in vacuo. The crude product is triturated with hot acetonitrile (15 ml), filtered and dried again in vacuo to give the title compound as an off-white solid, 1.25 g (90%). M.p. 215-224° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11]C(C)(C)C)=[O:10])=[CH:7][C:6]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5]1)[CH3:3].Cl>O1CCOCC1.O>[CH3:3][CH:2]([N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([CH2:16][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:5]1)[CH3:1]
Reactant: CC(C)n1nc(CN2CCOCC2)cc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nc(CN2CCOCC2)cc1C(=O)O
Temperature: 25 °C
Yield: 99.8 %

Procedure:
1,1-Dimethylethyl 1-(1-methylethyl)-3-(4-morpholinylmethyl)-1H-pyrazole-5-carboxylate (628 mg) was dissolved in 1,4-dioxane (2 ml). 4M Hydrogen chloride in 1,4 dioxane (5 ml) was added and the mixture was stirred at RT under nitrogen. After 24 h further 4M hydrogen chloride in 1,4 dioxane (3 ml) was added and the mixture was stirred at RT for 72 h. One drop of water was added and the mixture was stirred at RT for 24 h. The solvent was removed in vacuo, toluene (20 ml) was added and removed in vacuo to give a white solid. The solid was dried in a vacuum oven over-night to give the title compound (513 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-])=O)([CH3:9])[CH3:8]>CO.[Ni]>[NH2:20][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
A mixture of N-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5 g, 16 mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under H2 (1 atm) at room temperature 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give N-{3-amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1.6 g, 35%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[N:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cn1nnc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1nnc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc21
Yield: 65 %

Procedure:
The title compound is prepared from 1-methyl-1H-benzotriazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 65% of theory; LC (method 4): tR=1.88 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)O1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:29]1[C:30]2[C:26](=[C:25]([C:7]3[CH:16]=[N:15][C:10]4[O:11][CH2:12][CH2:13][NH:14][C:9]=4[CH:8]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc(-c2cnc3c(c2)NCCO3)c2cc[nH]c2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 139.8 %

Procedure:
To 3 ml of tetrahydrofuran (THF)/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-indole (109 mg, 0.45 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (172 mg, 0.15 mmol) were added and stirred at 80° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain 7-(1H-indol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (130 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][Cl:11])[N:7]=[C:6](Cl)[N:5]=1)[CH3:2].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][Cl:11])[N:7]=[C:6]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[N:5]=1)[CH3:2]
Reactant: CCOc1cc(CCl)nc(Cl)n1
Reactant: CCNCC
Product: CCOc1cc(CCl)nc(N(CC)CC)n1

Procedure:
4-Ethoxy-2-chloro-6-chloromethyl-pyrimidine (see Example 97) is reacted with diethylamine analogously to the process described in Example 98 in order to produce 4-ethoxy-6-chloromethyl-2-diethylamino-pyrimidine which is required as the starting material in Example 42. This product is obtained in the form of a yellow oil, 1H-NMR (CDCl3): 1.20 (t, N(CH2CH3)2), 1.37 (t, OCH2CH3), 3.60 (q, N(CH2CH3)2), 4.33 (s, CH2Cl), 4.35 (q, OCH2CH3), 6.06 (s, CH).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:41])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][C:16]([CH2:35][CH2:36][O:37]C(=O)C)([S:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:26]([C:24]1[CH:25]=[C:20]([S:19][C:16]2([CH2:35][CH2:36][OH:37])[CH2:17][CH2:18][N:13]([S:10]([C:7]3[N:6]([CH3:41])[C:5]([CH2:3][OH:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:21]=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]=1[OH:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(CCOC(C)=O)(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)ccc1S(=O)(=O)N1CCC(CCO)(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To 5-[4-(2-acetoxy-ethyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 1d, 460 mg, 0.75 mmol) in 4 mL of THF was added dropwise 3 mL of a 1 M LiAlH4 in THF. The mixture was stirred for 2 h and then quenched with saturated aqueous NaH2PO4 (20 mL). It was diluted with Ethyl acetate (30 mL), stirred for 10 min, and then let sit for 1 h. The layers were separated and the aqueous layer was extracted with Ethyl acetate (20 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was chromatographed with 10-85% Ethyl acetate/hexanes to afford the title compound as a white solid (305 mg, 75%), mp 126-127° C. 1H NMR (400 MHz, CD3OD): δ 7.26 (d, J=2.0 Hz, 1H), 7.15 (s, 2H), 6.34 (d, J=2.0 Hz, 1H), 4.57 (s, 2H), 3.88 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.26 (1H), 3.02 (td, J=7.2, 2.4 Hz, 2H), 1.75-1.68 (m, 2H), 1.64-1.58 (m, 4H), 1.39 (s, 3H); ESI/CI-MS m/z 539 ([M+H]+), 537 ([M−H]−). Anal. calcd for C27H42N2O5S2: C, 60.19; H, 7.86; N, 5.20. Found: C, 60.28, H, 7.93; N, 5.13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2([CH3:13])[CH3:12].[CH:14](O)=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:14]=[O:15])[CH2:7][CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: O=CO
Reactant: CC1(C)CCNc2ccc(Br)cc21
Product: CC1(C)CCN(C=O)c2ccc(Br)cc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline, available in accordance with U.S. Pat. No. 5,089,509, the specification of which is incorporated herein by reference (1.8 g, 7.5 mmol) in 10 mL of formic acid was refluxed for 3 h. The reaction mixture was then cooled to ambient temperature and poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 15-25% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow solid (1.8 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([CH2:15][CH:14]=[CH2:13])[CH:3]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1cc(C(=O)OC)ccc1C
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 101.8 %

Procedure:
Argon was bubbled into a solution of methyl 3-bromo-4-methylbenzoate (11.45 g, 50 mmol), allyltributyl-stannane (16.72 g, 50.5 mmol) and lithium chloride (5.30 g, 125 mmol) in DMF (100 mL) with magnetic stirring for 20 minutes. Dichlorobis(triphenyl-phosphine)palladium (0.81 g, 1.16 mmol) was then added and mixture heated at 95° C. for 1.5 hours. After cooling to room temperature, the mixture was partitioned between ether-hexanes (1:1 V/V) and water. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Isco RediSep 330 g silica gel, 5% then 35% dichloromethane in hexanes) to give 3-allyl-4-methyl-benzoic acid methyl ester (9.68 g, 100%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][N:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[CH:14]=[C:13]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd].C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[CH:14]=[C:13]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOCc3ccccc3)n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(CNNc2cc(N3CCOCC3)nc(CCOCc3ccccc3)n2)c1
Yield: 9600 %

Procedure:
Compound 91, N-[2-(2-benzyloxy-ethyl)-6-morpholin-4-yl-pyrimidin-4-yl]-N′-(3-methyl-benzylidene)-hydrazine (109 mg., 0.25 mmol) was dissolved in ethanol (20 mL) and to the solution was added 10% palladium on carbon (200 mg.), three drops of glacial acetic acid, and the reaction was stirred at room temperature under 1 atmosphere of hydrogen for 4 hours. The reaction was passed through celite, evaporated and purified by column chromatography to give Compound 92, N-[2-(2-benzyloxy-ethyl)-6-morpholin-4-yl-pyrimidin-4-yl]-N′-(3-methyl-benzyl)-hydrazine (106 mg., 24 mmol).
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of crude (133) (6.0 g) and benzyl alcohol (4.1 mL, 39.2 mmol) in dichloromethane at 0° C. was added dicyclohexylcarbodiimide (6.07 g, 29.4 mmol) and DMAP (120 mg, 0.98 mmol), and the resulting reaction mixture was stirred at room temperature for 2 h, then filtered through a pad of Celite. The filtrate was washed with brine and dried over Na2SO4. After filtration and evaporation, the crude product was purified by flash chromatography on silica gel, eluting with 10% ethyl acetate in hexane, to afford 5.8 g of the desired ester (134). (CDCl3, 400 MHz): δ 0.95 (t, J=7.4 Hz, 3H), 1.72-1.20 (m, 14H), 2.34 (s, 2H), 3.19 (m, 2H), 5.10 (s, 2H), 5.47 (t, J=6.2 Hz, 1H), 6.42 (t, J=5.8 Hz, 1H), 7.33 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:12]=2[CH:26]=[O:27])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2coc(-c3ccccc3)n2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-phenyloxazole (14.43 g), phosphorus oxychloride (12.97 g), N,N-dimethylformamide (100 mL) was stirred at 90° C. for 1.5 hrs. The reaction mixture was poured into iced water, and the precipitated solid was collected by filtration, washed successively with aqueous sodium hydrogen carbonate solution and water and dried. The obtained crystals were recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-2-phenyl-5-oxazolecarbaldehyde (7.90 g, 49%) as yellow prism crystals.