Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([Cl:28])[C:17]=1[F:29].CCN(CC)CC.CC(=O)OCC>CN(C=O)C.CC(=O)OCC.CO>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2([C:24]([F:27])([F:26])[F:25])[O:14][N:13]=[C:2]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=3)[CH2:23]2)[CH:19]=[C:18]([Cl:28])[C:17]=1[F:29]
Reactant: Cc1cc(C(Cl)=NO)ccc1C(=O)O
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
To a solution of 4-(chloro(hydroxyimino)methyl)-2-methylbenzoic acid (5.1 g, 23.8 mmol) in DMF (30 mL) at 0° C. was added 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (7.4 g, 28.6 mmol) followed by Et3N (4.8 g, 47.6 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water (30 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (1:1) to EA: MeOH (10:1) to give 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (6 g; yield 58% over 3 steps) as a white solid. MS: m/z=435.8 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.Cl[C:31]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32]>>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][O:33][C:31]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)=[O:32]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(C(=O)OCC(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Ex 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one and neopentyl chloroformate.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[C:28]([F:45])[C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[C:28]([F:45])[C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Yield: 80 %

Procedure:
Prepared in 80% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S,24Z)-16,17-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 690.25.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[CH2:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([C:16](=[CH2:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=2)=[O:18])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: C=C(C(=O)Nc1ccc(O)c([N+](=O)[O-])c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C(=O)Nc1ccc(O)c(N)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 70 °C
Yield: 53 %

Procedure:
In a 100 ml flask equipped with a refrigerant, 0.9 g (2.18 mmoles) of 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide is dissolved in 20 ml of ethyl acetate, 2.46 g (10.9 mmoles) of tin chloride (dihydrate) is added and the mixture is heated at 70° C. for three hours. After returning to ambient temperature, the reaction medium is poured onto an agitated solution of sodium bicarbonate (0.1 M), a precipitate forms, which is eliminated by filtration on celite. The filtrate is decanted and the aqueous phase is extracted with 20 ml of ethyl acetate. The organic phases are collected together and washed with 20 ml of water followed by 20 ml of a saturated solution of sodium chloride. After drying over sodium sulphate and filtration, the organic solution is concentrated to dryness, under partial vacuum. The evaporation residue is suspended in a heptane/ethyl acetate mixture (1/1) and filtered to produce a yellowish powder with a yield of 53%. The product is used as it is in the following stage.
Reaction SMILES: C([O:7][C:8]1[CH:9]=[C:10]([N:14]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)[CH:11]=[CH:12][CH:13]=1)(=O)C(C)(C)C.[OH-].[Na+]>CO>[OH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)Oc1cccc(N2c3ccccc3Cc3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cccc(N2c3ccccc3Cc3ccccc32)c1
Yield: 66.4 %

Procedure:
A solution of 621.9 mg of N-(3′-pivaloyloxyphenyl)acridan in 20 mL of methanol containing 2.61 g of 1 M NaOH (2.6 mmol) was refluxed until TLC analysis showed the starting material had been consumed. The solvent was concentrated and the residue was dissolved in water and acidified with 1 M hydrochloric acid. The resulting precipitate was collected via suction filtration, taken up with methy.ene chloride, dried over sodium sulfate and concentrated to a crude oil. The oil was chromatographed on silica gel in 5% ethyl acetate in hexanes. The purified product was treated with hexanes and the resultant solid was collected by filtration to afford 315.8 mg of N-(3′-hydroxyphenyl)acridan (67%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10].C(O)=O>>[OH:22][C:21]1[N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:5]3[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:25][N:24]=2)[N:19]=[CH:18][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=1[CH3:32]
Reactant: CN1CCCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methyl-1,4-diazepane and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (67 mg, 0.145 mmol, 77%) as an off-white solid. MS: 417 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 (br. s., 2 H) 2.35 (s, 3 H) 2.54 (br. s., 2 H) 2.86 (d, J=17.7 Hz, 3 H) 3.01 (br. s., 1 H) 3.39-3.76 (m, 5 H) 7.45 (d, J=8.1 Hz, 1 H) 7.50 (s, 1 H) 7.78-7.91 (m, 2 H) 8.04 (d, J=7.6 Hz, 1 H) 8.42 (br. s., 2 H) 11.65 (br. s., 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:39])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].[ClH:45]>O1CCOCC1>[ClH:45].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:39])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(OC(F)(F)F)ccc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(OC(F)(F)F)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 6-tert-butyloxy-8-oxo-9-[5-(5-trifluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b][1,7]naphthyridine-3-carboxylic acid ethyl ester (0.65 g, 0.98 mmol) in dioxane (20 ml) is combined with 4N HCl in dioxane (3.57 ml). The reaction mixture is stirred at room temperature for 16 hours. The formed insoluble material is collected by filtration, washed with dioxane (100 ml), pentane (50 ml) and dried under vacuum to yield 350 mg of 8-oxo-9-[5-(5-trifluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b][1,7]naphthyridine-3-carboxylic acid ethyl ester hydrochloride as a light brown powder. Yield=64%. Analytical LC/MS (method C): m/z=558 (negative ion mode [M−H]−), m/z=560 (positive ion mode [M+H]+).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:13][C:14]1([CH3:30])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[O:15]1>>[CH:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:30])([CH3:13])[O:15]3)=[CH:29][CH:28]=2)=[O:26])[CH2:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CC(C)N1CCCNCC1
Agent: Cl
Product: CC(C)N1CCCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1

Procedure:
The tile compound (D12) was prepared in a similar manner to Description 7 from 1-(isopropyl)-hexahydro-1H-1,4-diazepine (free base of D2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and isolated as a brown oil. LCMS electrospray (+ve) 373 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH3:16])[CH3:9])=[CH:4][CH:3]=1.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([N:13]2[CH2:14][CH2:15][N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH3:9])[C@H:11]([CH3:16])[CH2:12]2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC1CNCCN1C(C)c1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C2CCN(C(=O)OC(C)(C)C)CC2)CCN1[C@@H](C)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
The product of step 4 was stirred for 20 h. at RT with N-Boc-4-piperidinone (4.32 g), HOAC (1.15 ml), CH2Cl2 (80 ml) and sodium triacetoxy-borohydride (NaBH(OAc)3) (8.3 g). Thereafter the reaction was quenched with excess aqueous Na2CO3 solution slowly and stirred for 0.5 h. The organic layer was separated and filtered through a pad of silca gel, washing with 10:1 CH2Cl2-Et2O to elute all of the product. The filtate was evaporated and dissolved in Et2O (100 ml). To this was added dropwise a 4M solution of HCl in 1,4-dioxane (10 ml). The solids were collected, washed with Et2O, and stirred with CH2Cl2 and excess aqueous NaOH. The organic phase was dried over K2CO3 and evaporated to obtain 1-tert-butoxycarbonyl-4-{4-[1 (S)-(4-bromophenyl)-ethyl]-3(R)-methylpiperazin-1-yl}-piperidine (5.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][S:8]([NH:11][C:12](OC(C)(C)C)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.OC[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][S:8]([NH:11][CH2:12][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:9])=[O:10])=[CH:19][CH:20]=1
Reactant: OCCN1CCCC1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NCCN1CCCC1)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To an ice-cooled solution of of the product from Example 109 step b (321 mg, 1.00 mmol), 1-(2-hydroxyethyl)pyrrolidine (0.152 ml, 1.30 mmol) and triphenylphosphine (393 mg, 1.50 mmol) in THF (2 ml) was added in a single portion diethylazodicarboxylate (0.257 ml, 1.50 mmol). The coolant was removed and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate (25 ml) and washed sequentially with water (20 ml), twice with aqueous hydrochloric acid (2M, 25 ml) and brine (25 ml). The organic phase was dried over anhydrous sodium sulfate and the filtrate was evaporated at reduced pressure. The residue was dissolved in 1,4-dioxan (5 ml) and treated with aqueous hydrochloric acid (2M, 5 ml). The resultant mixture was heated at reflux for 1 h and then diluted with further aqueous hydrochloric acid (30 ml). The aqueous was washed twice with diethyl ether (30 ml) and then the pH was adjusted to 11 with ammonia (880). The now basic phase was extracted twice with chloroform (50 ml) and then dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue was purified by flash column chromatography (200:10:1 DCM:methanol:ammonia) to afford the title compound as a white solid (95 mg, 30%). 1H NMR 7.35-7.28 (4H, m), 6.04.5 (2H, br s), 4.20 (2H, s), 3.19 (2H, t, 5.7), 2.59 (2H, t, 5.7), 2.50-2.46 (4H, m), 1.73-1.67 (4H, m). Microanalysis found C 49.05 H 6.36 N 13.09 C13H20ClN3O2S requires C 49.13 H 6.34 N 13.22.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:50][CH:49]=3)[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:52][CH:53]=3)[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.3 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 25g (2.26 g, 2.56 mmol) in anhydrous tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (5.12 mL, 5.12 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at room temperature for 12 hours, then quenched with water (60 mL) and partitioned. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (100 mL×2) and saturated aqueous sodium chloride (100 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 25h as a light yellow solid (0.54 g, 27.4%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, DMSO-d6) δ (ppm): 7.46 (m, 2H), 7.42 (m, 2H), 7.35-7.24 (m, 17H), 7.01 (m, 4H), 6.84 (m, 2H), 5.02 (s, 2H), 4.82-4.75 (m, 3H), 4.69 (d, 1H), 4.41 (d, 1H), 4.04 (m, 1H), 3.97 (t, 1H), 3.88 (d, 1H), 3.77 (d, 1H), 3.70 (m, 3H), 3.53 (m, 1H), 3.23 (d, 1H), 2.97 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[N:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:30][CH2:29]1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/N1CCN(CCN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.709 mmol), 2-morpholinylethylpiperazine (141.3 mg, 0.709 mmol) in 1 mL of N,N-dimethylformamide is stirred at room temperature for 15 min. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 64 mg (20%) of yellow solid mp 156-156.5° C.; HRMS (ESI) m/z 449 (M+H)+1.
Reaction SMILES: [N+:1](=[CH:3][C:4](=[O:7])[CH2:5][CH3:6])=[N-:2].[CH2:8]([O:10][P:11]([C:16]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH2:17])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]>CCOCC>[CH2:20]([O:19][P:18]([C:16]1([P:11](=[O:15])([O:10][CH2:8][CH3:9])[O:12][CH2:13][CH3:14])[CH2:17][C:3]([C:4](=[O:7])[CH2:5][CH3:6])=[N:1][NH:2]1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: CCC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)CC)=NN1
Reaction time: 8 h

Procedure:
1-Diazo-2-butanone (I, PREPARATION 4, 3.1 g) in ether (50 ml) is treated with ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 9.5 g), stirred at 20°-25° overnight, and concentrated. The concentrate is crystallized twice from methylene chloride/SSB to give the title compound, mp 96°-98°; MS (m/e) 398, 261, 233 and 205; IR (mineral oil mull) 3210, 0664, 1265, 1245, 1046, 1024, 997 and 983 cm-1 ; NMR (CDCl3) 6.92, 4.14-4.33, 3.48, 2.82, 1.30-1.36 and 1.12 δ; CMR (CDCl3) 196, 149, 66, 64, 36, 31, 16 and 8 δ.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[N:6]([CH3:8])[CH:7]=1.C[O:12][CH:13](O)[C:14]([F:17])([F:16])[F:15].C([O-])([O-])=O.[K+].[K+]>>[OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[N:6]([CH3:8])[C:7]=1[CH:13]([OH:12])[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc(=O)c(O)cn1C
Reactant: COC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)c(O)c(C(O)C(F)(F)F)n1C
Temperature: 130 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A mixture of 5-hydroxy-1,2-dimethyl-1H-pyridin-4-one (9.40 g, 67.6 mmol), trifluoroacetaldehyde methyl hemiacetal (28 mL) and K2CO3 (1.40 g, 10.0 mmol) was sealed in a parallel reactor and stirred overnight at 130° C. The reaction mixture was evaporated to dryness, and the residue was purified by flash column chromatography using a mixture of i-PrOH and a 28-30% conc. NH4OH solution (70/30, v/v) as eluant. Fractions containing pure product were pooled together, and evaporated to give the title compound as a light orange powder (6.3 g, 39% yield). HPLC purity (peak area percent) of this compound is 99.8% at λ=254 nm using HPLC Method 2 as described above. 1H NMR (400 MHz, DMSO-D6) δ: 6.83 (br s, 2H, 20H), 6.21 (s, 1H), 5.88 (q, J=8.7 Hz, 1H), 3.73 (s, 3H, NCH3), 2.31 (s, 3H, CH3); MS m/z 238.1 [M+1]+, 220.2, 192.3, 172.3 (100%). A second less pure fraction of the title compound (7.0 g) was also obtained, and was used without further purification in step 1 of Example 14 below.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:19])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Cl)nc2)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A mixture of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic acid (2.0 g, 0.010 mol) and sulfuric acid (0.42 mL, 0.0079 mol) in methanol (30 mL) was stirred at 80° C. for 6 h. The mixture was cooled to RT and concentrated. The residue was dissolved in saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a crude product (2.0 g, 93%). Analytical LCMS: (M+H)+=212.0.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][CH2:12][C:13]([CH3:16])([NH2:15])[CH3:14])[CH2:8]2.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].O>C1COCC1>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[N:11]1[CH2:12][C:13]([CH3:16])([CH3:14])[NH:15][C:17]1=[O:18])[CH2:4]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(N)CNC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN(C2C3CC4CC(C3)CC2C4)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.8 %

Procedure:
N1-Adamantan-2-yl-2-methyl-propane-1,2-diamine (250 mg) was dissolved in dry THF (6 mL) under argon and carbonyldiimidazole (182 mg) was added. The resulting mixture was allowed to stir at RT for 48 hours. The mixture was poured into water/0.5 M HCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography using (a gradient of 10 to 70% ethyl acetate in heptane as an eluent. The fractions containing the desired material were combined and evaporated to leave 1-adamantan-2-yl-4,4-dimethyl-imidazolidin-2-one as a white solid (256 mg). MS (EI): 248.3 (M+).