Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][S:27][CH3:28])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.[OH2:35].[OH:36]OS([O-])=O.[K+]>C(#N)C>[CH3:28][S:27]([CH2:26][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[C:3]([O:2][CH3:1])[CH:8]=1)(=[O:36])=[O:35]
Reactant: O=S([O-])OO
Reactant: O
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CSC)ccc1-c1noc(=O)[nH]1
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 35 mg of 3-{2-methoxy-4-[4-methylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one in 4 mL of acetonitrile was added 1 mL of water and 84 mg of Oxone®. The resulting mixture was stirred overnight at room temperature, then poured into water and extracted with dichloromethane. The organic extracts were washed with a saturated aqueous solution if sodium bicarbonate and concentrated under reduced pressure. The crude product was triturated with dichloromethane/methanol/tetrahydrofuran/acetone to give 26 mg of 3-{4-[4-methanesulfonylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-1,2,4-oxadiazol-5-one as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][O:14][P:15]([CH:21]([OH:42])[C:22]1[CH:41]=[CH:40][C:25]([CH2:26][CH:27]([C:36]([O:38][CH3:39])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:24][CH:23]=1)([O:17][O:18][CH2:19][CH3:20])=[O:16])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH2:19]([O:18][O:17][P:15]([C:21](=[O:42])[C:22]1[CH:41]=[CH:40][C:25]([CH2:26][CH:27]([C:36]([O:38][CH3:39])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[CH:24][CH:23]=1)([O:14][O:13][CH2:11][CH3:12])=[O:16])[CH3:20]
Reactant: CCOOP(=O)(OOCC)C(O)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOOP(=O)(OOCC)C(=O)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
To a solution of oxalyl chloride (371 μL, 548 mg, 4.32 mmol, 2 equivalents) in anhydrous CH2Cl2 (8 mL) at -78° C. under argon was added anhydrous DMSO (612 μL, 674 mg, 8.64 mmol, 4 equivalents) in anhydrous CH2Cl2 (8 mL) dropwise over 17 minutes. To the resulting clear, colorless solution was added 40 (961 mg, 2.16 mmol) in anhydrous CH2Cl2 (8 mL) dropwise at -78° C. over 15 minutes. The reaction was stirred at -78° C. (45 minutes) then NEt3 (3.00 mL, 2.18 g, 21.6 mmol, 10 equivalents) in anhydrous CH2Cl2 (8 mL) was added dropwise at -78° C. over 10 minutes. The resulting clear, light yellow solution was stirred at 0° C. (50 minutes), then shaken well with ice-cold 0.2 N HCl/brine (100 mL); extracted with EtOAc (3×75 mL); washed with ice-cold 0.2 N HCl/brine (2×50 mL); brine (2×100 mL); dried (MgSO4) and rotovapped (20° C.) once from CHCl3, then twice from CH2Cl2 and placed under high vacuum, yielding 41 as an oil (962 mg, 100%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[C:27]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:34]Br)([CH3:30])([CH3:29])[CH3:28].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:1]=[C:2]1[C@H:7]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([O:39][Si:40]([C:43]([CH3:45])([CH3:44])[CH3:46])([CH3:42])[CH3:41])=[C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:32]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: CC(C)(C)c1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Yield: 71.3 %

Procedure:
According to example 142, 3.82 g of tert-butyl (2R, 3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate was alkylated with 3.86 g of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl bromide in 80 mL of anhydrous THF using 11.34 mL of 1 M sodium bis(trimethylsilyl)amide in THF. The crude product was subjected to flash chromatography on silica gel (85:15 hexane:EtOAc) to afford 4.85 g (71%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl)-4-morpholinecarboxylate as a white foam, m.p. 75-83° C.
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH:56]4[CH2:58][CH2:57]4)[C:50]=3[C:49](=[O:59])[N:48]2[C:60]2[CH:61]=[C:62]([NH:70][CH3:71])[C:63]3[N:64]([C:66]([CH3:69])=[N:67][N:68]=3)[N:65]=2)=[CH:43][CH:42]=1>CCCCCCC.C(Cl)Cl.CCO>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH:56]4[CH2:57][CH2:58]4)[C:50]=3[C:49](=[O:59])[N:48]2[C:60]2[CH:61]=[C:62]([NH:70][CH3:71])[C:63]3[N:64]([C:66]([CH3:69])=[N:67][N:68]=3)[N:65]=2)=[CH:43][CH:42]=1
Reactant: CNc1cc(N2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)nn2c(C)nnc12
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CCO
Solvent: CCCCCCC
Solvent: ClCCl
Product: CNc1cc(N2C(=O)c3c(c(C)nn3C3CC3)[C@H]2c2ccc(Cl)cc2)nn2c(C)nnc12

Procedure:
The title compound (38 mg, 34% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: Gilson PLC 2020; column: Chiralpak ID 5 μm, 20×250 mm; mobile phase: heptane/CH2Cl2/EtOH 70:25:5; flow: 10 mL/min; detection UV: 275 nm) of the racemic mixture of 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-5-(3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 113).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.[Na]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1CCC(O)CC1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: OC1CCC(N2C[C@@H]3COCCN3c3nc(Cl)ncc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
To (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol) and 4-hydroxycyclohexanone (126 mg, 1.103 mmol) in CH2Cl2 (8 mL) was added titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) dropwise to give an orange suspension. The reaction mixture was stirred at ambient temperature for 4 hours and then cooled to 0° C. Sodium triacetoxyhydroborate (514 mg, 2.427 mmol) was added in two portions. The reaction mixture was stirred for 1 hour and then quenched with aqueous saturated NH4Cl (1 mL). The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a colorless foam (30 mg, 8%). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O2, 325.14. found 325.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=O)[N:12]=2)=[O:9])[CH:3]=1.C[N:22]([CH3:26])[C:23](=O)[CH3:24].[CH:27]1(N)CC1.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:22]([CH:23]4[CH2:27][CH2:24]4)[CH:26]=[N:20][N:19]=3)[N:12]=2)=[O:9])[CH:3]=1
Reactant: NNC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Reactant: CC(=O)N(C)C
Reactant: NC1CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)c1cc(Cl)ccn1
Temperature: 150 °C
Yield: 72 %

Procedure:
To a suspension of 4-chloro-N-(6-(hydrazinecarbonyl)pyridin-2-yl)picolinamide (1.00 g, 3.43 mmol) in toluene (0.20 M) was added a mixture of N,N-dimethylforinamide.N,N-dimethylacetamide (1.14 mL, 8.56 mmol), cyclopropylamine (873 μL, 13.7 mmol), and acetic acid (194 μL, 3.43 mmol). The reaction mixture was heated to 150° C. for 30 minutes in a microwave reactor. The reaction product was concentrated under reduced pressure, and the residue was suspended in acetonitrile/diethyl ether (15 mL, 1:1 ratio), filtered, and the solid washed with acetonitrile/diethylether (2×10 mL). The filtrate was concentrated and the solid thus obtained was purified as above. The combined solids were dried under reduced pressure to afford 842 mg (72% yield) of 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)picolinamide as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: NC(=O)CCC(=O)O
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CCC(=O)OCc1ccccc1

Procedure:
A mixture of 23.4 g. (0.20 mole) of succinamic acid, 25.4 g. (0.20 mole) of benzyl chloride, 20.2 g. (0.20 mole) triethylamine and 250 ml. dimethylformamide is stirred at 95°C. for 20 hours. The reaction mixture is diluted with 500 ml. water and the product extracted into two 200 ml. portions of ethyl ether. The combined ether extracts are washed with two 50 ml. portions of saturated sodium bicarbonate solution, then two 50 ml. portions of water and dried over anhydrous magnesium sulfate. After filtering, the solution is concentrated at 15 - 20 mm. and 40°C. to give benzyl succinamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([Br:19])=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccnc(N)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 2-amino-isonicotinic acid methyl ester (5.58 g, 36.7 mmol) in DMF (56 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (7.21 g, 38.5 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and washed with water (2×250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (3.0 g, 13.0 mmol, 35%) as a yellow solid, which was used in the next step without further purification. MS: 231 [M+1]+; HPLC: AtRet=0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([OH:28])[C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[CH2:10][C:11](=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([OH:28])[C:7]3[CH2:8][CH:9]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[CH2:10][C:11](=[N:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Reactant: CN(C)CCCN
Solvent: CCO
Product: CN(C)CCCN=C1CC(c2ccc(C(F)(F)F)cc2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Temperature: 25 °C

Procedure:
To 2.3 g of 7-chloro-3,4-dihydro-10-hydroxy-3-[4-(trifluoromethyl)phenyl]-1,9(2H,10H)-acridinedione in 55 ml of ethanol is added 0.70 g of N,N-dimethyl-1,3-propanediamine in 5 ml of ethanol. The solution is heated to reflux and then allowed to cool to room temperature. The solvent is removed in vacuo and the residue is recrystallized from a mixture of benzene and cyclohexane to give 7-chloro-1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro-10-hydroxy-3-[4-(trifluoromethyl)phenyl]9(2H)-acridinone; mp 130°-135° C.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:16][C:17]1[N:32]=[CH:31][CH:30]=[CH:29][C:18]=1[C:19](NC1C=CC=CC=1C)=[O:20]>>[F:16][C:17]1[N:32]=[CH:31][CH:30]=[CH:29][C:18]=1[C:19]([NH:15][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:20]
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Reactant: NC(CN1CCOCC1)c1ccccc1
Product: O=C(NC(CN1CCOCC1)c1ccccc1)c1cccnc1F
Yield: 87 %

Procedure:
2-Morpholin-4-yl-1-phenylethylamine (Array Biopharma, Inc., 0.33 g, 1.6 mmol) was converted to the desired compound (0.12 g, 87%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). HRMS(ESI+), 330.1618 (M+H)+ calc, 330.1620 (M+H)+ found.
Reaction SMILES: C([Li])CCC.BrC1[C:8]([F:17])=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13].CN(C=O)C1C=CC=CC=1.Cl.C([O:31][CH2:32][CH3:33])C>CCCCCC>[CH3:16][C:9]1[C:8]([F:17])=[C:33]([C:12]([F:13])=[C:11]([F:14])[C:10]=1[F:15])[CH:32]=[O:31]
Reactant: Cc1c(F)c(F)c(F)c(Br)c1F
Reactant: CCOCC
Agent: CN(C=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1c(F)c(F)c(F)c(C=O)c1F

Procedure:
n-Butyl lithium (12.9 ml of a 1.6 M solution in hexane) was added dropwise to a solution of 3-bromo-2,4,5,6-tetrafluorotoluene (5.0 g) in diethyl ether (40 ml) under an argon atmosphere whilst maintaining the mixture temperature within the range -60° to -70° C. When the addition was complete the mixture was stirred for a period of 1.5 hours at -70° C. after which a solution of N-methylformanilide (2.8 g) in diethyl ether (15 ml) was added and the resultant mixture allowed to attain the ambient temperature (ca. 25° C.). Dilute hydrochloric acid (25 ml) of a 2 N solution) was added to the well-stirred mixture after which the ethereal layer was separated, washed with water and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation under reduced pressure the residual oil was distilled to yield 3-methyl-2,4,5,6-tetrafluorobenzaldehyde (1.6 g) b.p. 78°-80° C./14 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:27][N:28]([CH2:29][C:30]([O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[O:31])[CH3:33]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Reactant: CN(C)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(OC(=O)CN(C)C)CC3)s2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Compound 6 (3.70 g) was dissolved in pyridine (100 mL), and N,N-dimethylglycin (5.15 g) was added to the solution, followed by stirring at room temperature for 1 hour. Subsequently, p-toluenesulfonyl chloride (9.43 g) was added to the mixture, followed by stirring under reflux for 12 hours. After completion of reaction, the solvent was evaporated to dryness. Chloroform (800 mL) was added to the residue, and the mixture was washed with water three times. The pH of the aqueous layer was checked by use of a pH testpaper, and adjusted to 4 to 5 with 1N aqueous hydrochloric acid. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (CHCl3-Hexane), to thereby yield the target product (yield: 3.48 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][OH:15])=[O:4].ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][O:15][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][O:36]1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(CO)c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]nc(COC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-hydroxymethyl-1H-indazole-5-carboxylic acid methyl ester (0.32 g, 1.55 mmol) in a mixture of anhydrous dichloromethane and THF (2:1, 60 mL) was added pyridinium p-toluene sulfonate (0.08 g, 0.31 mmol) and then 3,4-dihydro-2H-pyran (0.19 g, 2.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated; water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carboxylic acid methyl ester as a yellow gummy material. Yield: 0.55 g (crude). This product was used in next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3]1.C1C=CC=CC=1.[CH2:25](O)[CH2:26][OH:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[C:13]1([S:10]([CH:4]2[CH:5]([C:8]#[N:9])[CH2:6][CH2:7][C:2]3([O:27][CH2:26][CH2:25][O:1]3)[CH2:3]2)(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CC1CCC(=O)CC1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: N#CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a pressure vessel was added (1R,2S and 1S,2R)-4-oxo-2-(phenylsulfonyl)cyclohexanecarbonitrile (100 mg, 0.380 mmol), benzene (19.0 mL), ethylene glycol (0.9 mL, 15.6 mmol), and p-toluenesulfonic acid monohydrate (14 mg, 0.076 mmol). The vessel was capped and the reaction mixture was heated to reflux and allowed to stir for 16 hours. The reaction mixture was allowed to cool to ambient temperature before it was diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford (7S,8R and 7R,8S)-7-(phenylsulfonyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a crude residue. To the crude residue (110 mg, 0.358 mmol) was added THF (7.1 mL) and potassium tert-butoxide (137 mg, 1.22 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes before it was diluted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1>C1(C)C=CC=CC=1>[ClH:3].[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:3])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(Cl)n1
Solvent: Cc1ccccc1
Product: COc1cc(CCl)cc(Cl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Thionyl chloride (1.0 ml) was added to a solution of 2-chloro-4-hydroxymethyl-6-methoxypyridine (0.9 g, 5.2 mmol) in toluene (10 ml) and the mixture stirred at ambient temperature for 1 hour. The volatiles were removed by evaporation, the residue was azeotroped with toluene and dried under vacuum to give 2-chloro-4-chloromethyl-6-methoxypyridine hydrochloride (0.88 g, 74%).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OCC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1(b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a brownish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 42.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (99 mg, 0.21 mmol) obtained in step 2 and ethanesulfonamide (110 mg, 1.05 mmol), the title compound (50 mg, 42%) was obtained.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]#[C:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1)(C)C.[H][H].O>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[OH:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([O:50][CH2:51][O:52][CH3:53])[CH:25]1[O:29][CH:28]([CH:30]2[CH2:34][CH2:33][CH:32]([CH:35]([O:46][CH2:47][O:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[O:31]2)[CH2:27][CH2:26]1)[CH2:8][C:9]1[C:10](=[O:15])[O:11][CH:12]([CH3:14])[CH:13]=1
Reactant: [H][H]
Reactant: CCCCCCCC#CCC(OCOC)C1CCC(C2CCC(C(CC#CC=CCCCC(CC3=CC(C)OC3=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OCOC)O2)O1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCC(OCOC)C1CCC(C2CCC(C(CCCCCCCCC(O)CC3=CC(C)OC3=O)OCOC)O2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of {2R-[2α[2′R*, 5′R*(R*)], 5β[1(S*),2R*,11R*]}-3-{2-[(1,1-dimethylethyl)diphenylsilyloxy]-11-methoxymethyloxy-11-[octahydro-5′-(1-(methoxymethyloxy)undec-3-ynyl)[2.2′-bifuran]-5-yl]-6-undecen-8-ynyl}-5-methyl-2-(5H)-furanone(64 mg, 70 umole) in benzene (0.5 mL) is stirred at room temperature under a flow of nitrogen while tris(triphenylphosphine)rhodium chloride (14 mg, 15 umole) is added. The mixture is charged with hydrogen gas and stirred at room temperature for two days. Water is added, and the layers are separated. The aqueous extracted with ethyl acetate (3×2 mL) and the combined organic fractions are washed (1×20 mL water) dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) affords the desired product.