Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[CH:3]1.S(Cl)([Cl:37])(=O)=O>C(#N)C>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@:9]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[N:22]=2)([CH3:20])[CH2:8][N:7]4[CH3:33])=[C:3]1[Cl:37]
Reactant: O=S(=O)(Cl)Cl
Reactant: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Solvent: CC#N
Product: CO[C@]12C[C@](C)(c3nc(-c4cncc(Br)c4)no3)CN(C)[C@@H]1Cc1c(Cl)n(C)c3cccc2c13

Procedure:
To a stirred solution of 2 g of 1,6-dimethyl-8β-methyl[3-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-10α-methoxy-ergoline in ml 50 of acetonitrile and ml 0.5 of BF3-2 Et2O was added dropwise a solution of 0.6 g of sulphuryichloride (SO2Cl2) in ml 15 of acetonitrile at -5° C.
Reaction SMILES: [C:1]([NH:4][C:5]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([NH:4][C:5]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@@H]1CCNC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-[(3R)-pyrrolidin-3-yl]hex-5-enamide (315 mg, 1.07 mmol), 4-fluorobenzaldehyde (140 uL, 1.3 mmol) and acetic acid (60 uL, 1 mmol) in methylene chloride (10 mL, 200 mmol) was stirred for 10 minutes prior to the addition of sodium triacetoxyborohydride (377 mg, 1.78 mmol) in a single portion. After stirring at room temperature overnight, the reaction was quenched with 1 N NaOH (10 mL). The organic layer thus obtained was separated and the aqueous layer further extracted with DCM (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)hex-5-enamide (0.387 g, 89.9%) as an oil. The oil was used in the next step without purification. ESI MS found for C23H34FN3O2 m/z 404.3 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:28][NH2:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[CH3:25]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH2:28][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[CH3:25])=[C:16]([Cl:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(F)(F)COc1ncc(CN)cc1Cl
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Product: CC(F)(F)COc1ncc(CN2Cc3c(ccnc3Cl)C2=O)cc1Cl
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (925 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (945 mg, 3.39 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine (730 mg, 3.08 mmol, Amine-86) in a similar manner to Intermediate-2.
Reaction SMILES: [OH-].[Li+].O.[CH:4]([C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:5]>O1CCCC1.CO>[CH:4]([C:6]1[CH:7]=[CH:8][C:9]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]([CH:21]=1)[C:11]([OH:13])=[O:12])=[O:5]
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
Lithium hydroxide (207 mg, 8.66 mmol) and water (2.5 ml) were added to a solution of phenylmethyl 5-formyl-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in description 96) (1 g, 2.89 mmol) in tetrahydrofuran (10 ml) and methanol (2.5 ml). The mixture was stirred overnight. The tetrahydrofuran/methanol was removed in vacuo and the remaining aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×20 ml). The solvent was removed in vacuo to yield the title compound as a white solid. 1.1 g.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>CN(C=O)C.C(OCC)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3]([C:2]([S:19][C:17](=[O:20])[CH3:18])([CH3:16])[CH3:15])=[O:4])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 200 mg (0.69 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in Method B, step 2) in DMF (3 mL) were added 157 mg (1.4 mmol) of potassium thioacetate. The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether (5 mL) and washed with 2M aqueous HCl solution (5 mL). The organic layer was dried over Na2SO4. Filtration and concentration under reduced pressure afforded 151 mg of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]4[S:20][C:21]5[C:22](=[O:30])[NH:23][C:24]([CH3:29])([CH3:28])[CH2:25][C:26]=5[N:27]=4)[C:14]=3[CH:31]=2)[CH:3]=1.C(N(CC)CC)C>CO.[Pd]>[CH3:28][C:24]1([CH3:29])[NH:23][C:22](=[O:30])[C:21]2[S:20][C:19]([N:15]3[C:14]4[CH:31]=[C:10]([O:9][C:4]5[CH:3]=[CH:2][N:7]=[C:6]([CH3:8])[N:5]=5)[CH:11]=[CH:12][C:13]=4[O:18][CH2:17][CH2:16]3)=[N:27][C:26]=2[CH2:25]1
Reactant: Cc1nc(Cl)cc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nccc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a suspension of Example 394 (40 mg, 0.088 mmol) in MeOH (15 mL) was added triethylamine (0.040 mL, 0.263 mmol) and 5% Pd/C (10 mg, 25% wt). The reaction mixture was stirred under an atmosphere of hydrogen for 24 h, then the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the title compound (24 mg, 65%) as an off-white solid. δH (CDCl3) 8.45 (1H, d, J 5.8 Hz), 7.97 (1H, d, J 2.6 Hz), 6.98 (1H, d, J 8.9 Hz), 6.84 (1H, dd, J 8.9 and 2.6 Hz), 6.63 (1H, d, J 5.8 Hz), 5.58 (1H, s), 4.41-4.26 (2H, m), 4.16-4.05 (2H, m), 2.84 (2H, s), 2.62 (3H, s), 1.37 (6H, s). LCMS (ES+) 424.0 (M+H)+, RT 2.75 minutes (Method 1).
Reaction SMILES: [H-].[Na+].I[CH:4]([CH3:6])[CH3:5].[N+:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]2[CH2:22][CH2:23][NH:24][C:25](=[O:26])[CH:18]2[CH2:17]1)([O-:9])=[O:8]>C1COCC1>[CH:4]([N:24]1[CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N+:7]([O-:9])=[O:8])[CH2:17][CH:18]2[C:25]1=[O:26])([CH3:6])[CH3:5]
Reactant: O=C1NCCN2CCN(c3ccncc3[N+](=O)[O-])CC12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCN2CCN(c3ccncc3[N+](=O)[O-])CC2C1=O

Procedure:
NaH (15.87 mg, 0.3967 mmol) then 2-iodopropane (73.56 mg, 43.19 μL, 0.4327 mmol) were added to a solution of 2-(3-nitro-4-pyridyl)-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-9-one (100 mg, 0.3606 mmol) (prepared according to a procedure similar to Step 1 of Preparation N-1) in THF (5 mL) under N2. The reaction mixture was stirred at reflux for 24 h then it was partitioned between EtOAc and a saturated bicarbonate aqueous solution. Combined organic extract was washed with brine, dried over MgSO4 and concentrated in vacuo to produce an oil that was used in next step without further purification. MS (ES+) 320.1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:8][N:7]=2)[CH2:2]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:21]3[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=3)[CH2:2]2)[CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reactant: c1ccc(COc2ccnc(OC3CNC3)c2)cc1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3cc(OCc4ccccc4)ccn3)C2)cc1

Procedure:
Example 8.7 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-4-benzyloxy-pyridine (IX.3) and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6](Cl)[CH:5]=[C:4]([CH3:11])[N:3]=1.O.[NH2:13][NH2:14]>ClCCCl>[Cl:1][C:2]1[C:7]2[CH:8]=[N:13][NH:14][C:6]=2[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(Cl)c(C=O)c(Cl)n1
Reactant: NN
Solvent: ClCCCl
Solvent: O
Product: Cc1cc2[nH]ncc2c(Cl)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-6-methylpyridine-3-carbaldehyde (12 g, 63 mmol) in 1,2-dichloroethane (200 mL) was added hydrazine monohydrate (9.52 g, 0.190 mol), and the reaction mixture was heated at 80° C. for 18 hours. After removal of solvents in vacuo, the residue was suspended in water (150 mL) and stirred for 30 minutes. The resulting precipitate was collected by filtration and washed with petroleum ether (2×250 mL), then was suspended in chloroform (150 mL), stirred for 30 minutes and filtered. The chloroform suspension was repeated twice to afford the product as a white solid. Yield: 6.7 g, 40 mmol, 63%. LCMS m/z 168.1 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 13.70 (br s, 1H), 8.21 (s, 1H), 7.38 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].O.Cl.Cl[CH2:16][C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Nc1cc(O)nc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine hydrate (16.1 g) and powdered sodium hydroxide, (8.0 g) was stirred in dry DMF (100 ml) for 20 mins. 4-Chloromethyl-2-methylthiazole hydrochloride monohydrate (20 g) was added portionwise and the resulting suspension stirred 18 hrs. The mixture was poured onto water and the solid collected, washed with water and dried to afford the sub-title compound (24.3 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:27][C@H:26]([CH3:25])[O:30][C:29]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3F)CC2)c(C)c1
Yield: 81.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (498 mg) described in Preparation Example 65 and (S)-5-methyloxazolidin-2-one (197 mg) described in Preparation Example 42, the title compound (429 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH-].[K+].[CH2:11]([N:13]([CH2:19][CH3:20])[C:14](=[O:18])[CH2:15][N+:16]#[C-:17])[CH3:12]>CO>[CH2:11]([N:13]([CH2:19][CH3:20])[C:14]([C@H:15]1[C@H:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[O:8][CH:17]=[N:16]1)=[O:18])[CH3:12]
Reactant: [C-]#[N+]CC(=O)N(CC)CC
Reactant: O=Cc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(=O)[C@@H]1N=CO[C@H]1c1ccncc1

Procedure:
SLA 07194A was prepared in accordance with method D using pyridine-4-carbaldehyde (1.14 mL, 9.52 mmol), KOH (0.54 g, 9.60 mmol) in methanol (5 mL) and N,N-diethyl-2-isocyanoacetamide SLA 07184A (1.21 g, 8.65 mmol). After work-up and column chromatography on florisil (ethyl acetate) trans-N,N-diethyl-4,5-dihydro-5-(pyridin-4-yl)oxazole-4-carboxamide SLA 07194A was obtained as a brown oil (0.25 g, 12% yield).
Reaction SMILES: [O:1]([C@@H:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][C@@H:11]1[O:14][C:13](=[O:15])[C@H:12]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[Si](C(C)(C)C)(C)C.C(C1C=CC=CC=1C=C)=C>CO>[CH2:16]([C@H:12]1[C@H:11]([CH2:10][C@@H:9]([OH:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:14][C:13]1=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)O[Si](C)(C)C(C)(C)C
Agent: C=Cc1ccccc1C=C
Solvent: CO
Product: CCCCCCCCCCC[C@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC

Procedure:
1.23 g of (3S,4S)-4-[(S)-2-(tert-butyldimethylsiloxy)tridecyl]-3-hexyl-2-oxetanone are dissolved in 6 ml of methanol and heated to reflux with the addition of 1.05 g of DOWEX 50W-X8 (acidic cation exchanger based on polymeric divinylbenzene containing sulphonic acid residues). The ion exchanger is filtered off and the filtrate is evaporated. The residue is chromatographed on silica gel. After recrystallization from hexane there is obtained (3S,4S)-3-hexyl-4-[(S)-2-hydroxytridecyl]-2-oxetanone of melting point 63°-64° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]=[C:29]=[O:30]>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[NH:28][C:29](=[O:30])[N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of N-methyl-N′-(3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine (536.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 1 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between ethyl acetate and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue recrystallized from CH2Cl2/CH3OH. The solid residue is dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:24][C:25]([CH:27]=[CH2:28])=[O:26].Cl>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:28][CH2:27][C:25](=[O:26])[CH3:24])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 20 h

Procedure:
The title compound of Example 2 (2.0 g) was dissolved in methanol (20 ml) and triethylamine (0.5 ml) added followed by methylvinylketone (0.0084 mole). The reaction was stirred under nitrogen for about 20 hours. 0.1 N Hydrochloric acid (80 ml) was added and the aqueous phase extracted with ethyl ether. The organic extracts were dried over sodium sulfate, filtered, the solvent removed in vacuo and the residue chromatographed on silica to give the title compound, m.p. ca. 79-81° C.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:34])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CC(O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:34])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nnc(CC(C)C)o2)cc1-c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: NC1CCOCC1
Solvent: CC(C)O
Product: Cc1ccc(-c2nnc(CC(C)C)o2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C2CCCC2)c1=O
Temperature: 120 °C
Yield: 37.8 %

Procedure:
A mixture of 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methane-sulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.04 g, 0.08 mmol) and 4-aminotetrahydropyran (0.041 g, 0.40 mmol) in 2-propanol (2 mL) was heated in a microwave reactor at 120° C. for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 50-70% ethyl acetate in hexanes to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (Yield: 16.0 mg, 38%). HRMS (ES+) m/z Calcd for C30H36N6O3. +H [(M+H)+]: 529.2922. Found: 529.2917.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[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.[CH3:35][C@@H:36](O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C@@H:36]([CH3:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To an argon-flushed flask containing a solution of 3.01 g (15 mmol) of p-benzyloxy-phenol and 1.25 eq of triphenylphosphine in 220 ml in dry dichloromethane, was added a solution of 4.91 g (15.14 mmol) of (R)-2-octanol in 30 ml of dry dichloromethane via syringe. Then 1.20 eq of diethyl azodicarboxylate dissolved in 60 ml of dry dichloromethane was added dropwise for 30 min. The reaction mixture was stirred at room temperature for 19 h, Then 5 drops of water were added and the mixture was stirred for 1 h. The solvent was then evaporated and the residual crude product was triturated in a mixture of hexanes/ethyl acetate [70/30] for 1 h and filtered through a short silica gel pad. The filtrate was evaporated and the product was purified by flash chromatography on silica gel using dichloromethane/hexanes [10/90 ] as eluent, affording 3.32 g (71%) of (S)-p-Benzyloxy-(1-methylheptyloxy)benzene (Compound 18, Scheme III, R2 =(S)-OCH(CH3) C6H13) as a colorless liquid: Rf [dichloromethane/hexanes 10/90]: 0.13; 1H NMR (300 MHz, CDCl3): δ0.87(t, 3H, J=6.6 Hz), 1.20-1.60(m, 12H), 1.70(m, 1H), 4.21(m, 1H), 5.00(s, 2H), Distorted AA'BB' System [6.82(d, 2H) 6.88(d, 2H)], 7.30-7.46(m, 5H); 13C NMR (300 MHz, CDCl3): δ14.02, 19.77, 22.55, 25.52, 29.26, 31.77, 36.51, 70.63, 74.95, 115.77, 117.35, 127.49, 127.87, 128.55, 137.39, 152.53, 153.01; IR (CHCl3): 3010, 2940, 2850, 1600, 1500, 1475, 1450, 1375; 1230, 1200, 1125, 1025, 925, 825 cm-1 ; Mass spectrum, m/z (rel. Intensity): 312(M+ 7), 212(15), 91(100), 71(5), 57(8), 43(10).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1ccc(Cl)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCCN(Cc4ccc(Cl)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-chlorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-chlorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][NH:38][S:39]([NH:42]C(OC(C)(C)C)=O)(=[O:41])=[O:40])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:51]=[CH:50][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:14][C@H:13]2[CH2:37][NH:38][S:39](=[O:40])(=[O:41])[NH2:42])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
To a solution of (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-t-butoxycarbonylaminosulfonylaminomethyl-4-tritylthiopyrrolidine (1.46 g: 2 mmole) in dichloromethane (5 ml) under ice cooling, anisole (2.4 ml) and trifluoroacetic acid (3.9 ml) are added. The mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with ethyl acetate and ice water and extracted with ethyl acetate. The extract is successively washed with water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from n-hexane to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-sulfamoylaminomethyl-4-tritylthiopyrrolidine (1.4 g). Yield: Nearly quantitative.
Reaction SMILES: ClC1N(CC2C=CC=CC=2C#N)C(=O)NC(=O)C=1.[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]2[N:40](CC3C=CC=CC=3C#N)[C:39](=[O:50])[N:38](C)[C:37](=[O:52])[CH:36]=2)[CH2:30]1>>[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]2[N:40]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[Br:19])[C:39](=[O:50])[NH:38][C:37](=[O:52])[CH:36]=2)[CH2:30]1
Reactant: BrCc1ccccc1Br
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Agent: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Product: N[C@@H]1CCCN(c2cc(=O)[nH]c(=O)n2Cc2ccccc2Br)C1

Procedure:
The title compound was prepared in two steps. The first step was accomplished using the procedure for the preparation of compound 2, except that 2-bromobenzylbromide was used in the place of α-Bromo-o-tolunitrile. The crude product was then converted to the title compound by the method used in the preparation of compound 4. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.52 (d, J=8.1 Hz, 1 H), 7.24 (t, J=7.8 Hz, 1 H), 7.10 (t, J=7.8 Hz, 1 H), 6.89 (d, J=7.579 Hz, 1 H), 5.27 (s, 1 H), 4.92-5.04 (ABq, J=34.1, 15.0 Hz, 2 H), 3.27 (bd, J=10.4 Hz, 1 H), 3.09-3.18 (m, 1 H), 2.89 (m, 1 H), 2.70 (t, J=10.9 Hz, 1 H), 2.48 (t, J=12.0 Hz, 1 H), 2.03 (m, 1 H), 1.60-1.71 (m, 1 H), 1.42-1.53 (m, 2 H). MS (ES) [m+H] calc'd for C16H20BrN4O2, 379.1; found, 379.1.