Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=O)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[CH3:18][C:17]([NH:21][CH2:6][CH2:7][S:8][CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)OCCSCC#Cc1cccs1
Product: CC(C)(C)NCCSCC#Cc1cccs1

Procedure:
A solution of 400 mg of 9d in 8 ml of tert-butyl amine was stirred for 3 days at RT; conversion was completed after that time. The reaction mixture was concentrated and the residue was treated with 30 ml of water and 30 ml of sat. NaHCO3 and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated to provide 354 mg of 9e as essentially pure material, which was used without further purification in the next step. NMR (CDCl3) δ 1.12 (s, 9, tertC4H9), 2.88 (m, 4, 2×CH2), 3.52 (s, 2, CH2), 6.96, 7.18 and 7.22 (3×m, 3, thiophene-H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH:17]=[CH:16][C:15]=2[N+:25]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.[F:33][C:34]1[CH:44]=[CH:43][C:37]([C:38]([N:40]=[C:41]=S)=[O:39])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CCO>[F:33][C:34]1[CH:35]=[CH:36][C:37]([C:38](/[N:40]=[C:41]2\[NH:25][C:15]3[CH:16]=[CH:17][C:18]([N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)=[CH:19][C:14]=3[N:13]\2[C@H:10]2[CH2:11][CH2:12][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:9]2)=[O:39])=[CH:43][CH:44]=1
Reactant: O=C(N=C=S)c1ccc(F)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(-n3cncn3)ccc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(-n4cncn4)cc32)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
To a solution of cis-N-isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)-cyclohexanecarboxamide (100 mg, 0.269 mmol) in EtOH (3 mL) was added tin(II) chloride dihydrate (242 mg, 1.074 mmol). The reaction was stirred at 80° C. After 3 hours, another four equivalents of tin(II) chloride dihydrate (242 mg, 1.074 mmol) was added, and the reaction was stirred at 80° C. for an additional 3 hours, and then at RT overnight. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and 1 N aqueous sodium hydroxide. The aqueous layer was extracted with EtOAc; the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The diamine was dissolved in THF (3 mL), cooled to 0° C., and 4-fluorobenzoyl isothiocyanate (53.5 mg, 0.296 mmol) was added. The reaction was stirred at 0° C. for 30 minutes, then DIPEA (0.070 mL, 0.403 mmol) and EDC (77 mg, 0.403 mmol) were added, and the reaction was stirred for 1 hour at 60° C. The residual material was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 20-100% EtOAc in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as an off-white powder (44 mg, 33.5% yield). MS, m/z (C26H28FN7O2): Calc'd, 489.2. found, 489.9 [M+H].
Reaction SMILES: [C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:25])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>>[C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([OH:25])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Yield: 64.7 %

Procedure:
1.0 g of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3-one is reacted as described in Example 6 with lithium tri-tert.-butoxyaluminum hydride and worked up. After chromatography on silica gel, 650 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3β-ol is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][C:23](=[O:37])[CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=1)=[O:27])([CH3:21])([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[C:18]([O:22][C:23](=[O:37])[CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:34])=[CH:31][CH:32]=1)=[O:27])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (49 mg, 0.17 mmol) in isopropanol (2.0 mL) was heated with tert-butyl{[5-(hydrazinocarbonyl)thiophene-2-carbonyl]amino}acetate (44 mg, 0.15 mmol) prepared in Reference Synthetic Example 8 and 3 mg of p-toluenesulfonic acid monohydrate at 100° C. for 8 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, methanol and chloroform and dried to give 69 mg of the desired product (yield 83%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH2:13]([N:15](CC)CC)[CH3:14].ClCC#N>C(OCC)(=O)C>[C:13]([CH2:14][O:11][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12])#[N:15]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CCOC(C)=O
Product: N#CCOC(=O)c1cc2ccccc2o1
Yield: 85.5 %

Procedure:
81 g of benzofuran-2-carboxylic acid and 50 g of triethylamine were added to 550 ml of ethyl acetate, and to the mixture were further added 40 g of chloroacetonitrile, and the mixture was refluxed by heating for 3 hours. The deposited crystals were removed and the solvent was distilled off, and the obtained crystals were recrystallized from methanol to thereby obtain 85 g of benzofuran-2-carboxylic acid cyanomethyl ester having a melting point between 74° C. and 76° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29](OCC)=[O:30])[C:11]1=[O:34].[CH2:36]([CH2:38][NH2:39])[OH:37]>>[O:35]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29]([NH:39][CH2:38][CH2:36][OH:37])=[O:30])[C:11]1=[O:34]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.40 (s, 1 H), 8.58 (s, 1 H), 7.88 (s, 1 H), 7.24 (m, 2 H), 7.01 (t, J=8.5 Hz, 2 H), 4.40 (m, 2 H), 4.13 (s, 2 H), 3.87 (m, 2 H), 3.66 (m, 2 H), 3.43-3.36 (m, 4 H), 2.97 (m, 2 H), 2.19 (m, 2 H), 1.60 (m, 2 H); MS m/z 519 (M+H)+.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[CH:41]=[N:40][C:39]([O:42][CH3:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1)(=O)C1C=CC=CC=1.CO.[ClH:46].CON.N1C=CC=CC=1>C1COCC1.C(O)C>[ClH:46].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:33][C:34]([C:36]3[CH:41]=[N:40][C:39]([O:42][CH3:43])=[CH:38][N:37]=3)=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])[N:15]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)cn1
Agent: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(N)=N4)c2)cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-[3-[(4aR,7aS)-2-Benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carboxamide (0.350 g, 0.58 mmol, isomer 1) is dissolved in THF (2 mL) and then methanol (4 mL) and ethanol (4 mL) are added. O-Methylhydroxylamine hydrochloride (495 mg, 5.81 mmol) and pyridine (470 μL, 5.81 mmol) are added to the mixture and the reaction is warmed to 50° C. and stirred overnight. Silica gel (˜10 g) is added to the reaction and the mixture is concentrated. The sample, dried onto silica gel, is loaded onto an empty cartridge and purified eluting with a 0-10% gradient of 7 N ammonia methanol in dichloromethane. The product is purified a second time on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol. The product is purified a final time over silica gel with a 0% to 10% gradient of 7 N ammonia methanol in dichloromethane to give the free base of the title compound. This material is dissolved in dichloromethane (5 mL) and 1 M hydrogen chloride in diethyl ether (0.20 mL, 660 μmol) is added. The solvent is removed in vacuo to give the title compound (71 mg, 23%). ES/MS (m/e): 498 (M+H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Yield: 83.7 %

Procedure:
A mixture of compound (6a) (3 g, 8.4 mmol), 20% Pd(OH)2/C (1.5 g) and ammonium formate (1.6 g) was suspended in 20 mL of methanol. After refluxing the mixture for 10 min, the catalyst was filtered off through celite column and washed by methanol. All the filtrate was combined and concentrated to give a white solid material. The latter was crystallized from 10% ethanol/dichloromethane to yield 1.9 g (84%) of compound (7a) which had the same chromatographic mobility (silica TLC) and H1- and C13-NMR spectra as authentic compound (Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar, R.; Meldgaard, M.; Olsen, C. E.; Wengel, J., Tetrahedron 1998, 54(14), 3607).
Reaction SMILES: [CH3:1][C:2]12[CH2:10][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:11](=[O:22])[CH:12]([NH:13]C(OC(C3CC3)C)=O)[C@H:4]1[S:3]2>C(O)=O>[CH3:1][C:2]12[CH2:10][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:11](=[O:22])[CH:12]([NH2:13])[C@H:4]1[S:3]2
Reactant: CC(OC(=O)NC1C(=O)N2[C@@H]1SC1(C)CC21C(=O)O)C1CC1
Solvent: O=CO
Product: CC12CC1(C(=O)O)N1C(=O)C(N)[C@H]1S2
Yield: 68.9 %

Procedure:
A solution of 2-methyl-2,3-methylene-6-(1-cyclopropylethoxy)carbonylaminopenam-3-carboxylic acid(840 mg.) in formic acid(5 ml.) was stirred for 1.5 hours at room temperature. After the reaction, formic acid was distilled off under reduced pressure. The residue was washed with ether, crystallized by adding acetonitrile containing water and the crystals were collected by filtration to give 2-methyl-2,3-methylene-6-aminopenam-3-carboxylic acid(380 mg.), mp. 200°C (dec.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37].[BH4-].[Li+].C(CN)O.B(Br)(Br)Br>ClCCl.O>[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([NH:39][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:37])[CH3:38]
Reactant: CC(C)(N)Cc1ccc(F)cc1Cl
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: BrB(Br)Br
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: NCCO
Product: CC(C)(Cc1ccc(F)cc1Cl)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: -78 °C

Procedure:
357 mg (1 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 202 mg (1 mmol) of 2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamine are reacted with lithium borohydride analogously to the method for Example 10(d). To debenzylate the ethanolamine thus obtained, it is dissolved in 3 mL of dichloromethane and cooled to −78° C. At this temperature, 2 mL of a 1 molar solution of boron tribromide in dichloromethane is added and the mixture is slowly allowed to come up to ambient temperature. The reaction mixture is combined with 10 mL dichloromethane and 3 mL water and filtered through an EXTRELUT® column. The eluate is freed from solvent and the residue is purified by chromatography. White solid. Yield: 70 mg (13%, trifluoroethyl acetate); mass spectroscopy: [M+H]+=409/11.
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[Cl:50][C:51]1[C:65]([O:66][CH3:67])=[C:64]([NH:68][C:69]2[N:74]=[C:73](Cl)[C:72]([C:76]([F:79])([F:78])[F:77])=[CH:71][N:70]=2)[CH:63]=[CH:62][C:52]=1[CH2:53][P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57].[NH2:80][C:81]1[C:82]([C:88]([NH:90][CH3:91])=[O:89])=[N:83][C:84]([Br:87])=[CH:85][CH:86]=1>>[Br:87][C:84]1[N:83]=[C:82]([C:88](=[O:89])[NH:90][CH3:91])[C:81]([NH:80][C:73]2[C:72]([C:76]([F:79])([F:78])[F:77])=[CH:71][N:70]=[C:69]([NH:68][C:64]3[CH:63]=[CH:62][C:52]([CH2:53][P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])=[C:51]([Cl:50])[C:65]=3[O:66][CH3:67])[N:74]=2)=[CH:86][CH:85]=1
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1Cl)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl)OCC

Procedure:
Prepared analogously to Compound 1B with diethyl (2-chloro-4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 54D) and compound 6D. MS (ESI): m/z 681.34/683.34 [M+H]+. UPLC: tR=1.51 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1)=[O:7])(=O)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: CC(=O)NNC(=O)c1ccc2occc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occc3c2)o1
Yield: 220.8 %

Procedure:
A solution of N′-acetyl-1-benzofuran-5-carbohydrazide (20.7 g, 36.2 mmol) and p-toluenesulfonyl chloride (36.2 g, 190 mmol) in pyridine (200 mL) was stirred under an argon atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed water, 2 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from tetrahydrofuran to give the title compound (16.0 g, yield 84%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>C1COCC1.CO.O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:20][CH:21]=1
Reactant: Clc1ccc(Br)cn1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
To a a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (500 mg, 2.41 mmol) in THF (5 mL) at room temperature was added sodium hydride (55% dispersion in mineral oil, 137 mg, 3.1 mmol) and the reaction mixture stirred at room temperature for 1 h. Then a solution of 2-chloro-5-bromo-pyridine (484 mg, 2.41 mmol) in THF (5 mL) was added at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with methanol and water and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=9:1 to 4:1) afforded the title compound (128 mg, 15%) which was obtained as a colourless oil. MS: m/e=363.1/365.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:17][CH2:15][CH3:16])=[O:12]
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CCO
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@@H](/C=C/C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 12.5 ml of benzene and 1 ml of ethanol were reacted to obtain 1.31 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+93°±1.5° (c=1% in chloroform).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:28])[CH2:16][NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[CH:11][C:10]=1[CH2:29][OH:30])C1C=CC=CC=1>[Pd].CO>[CH3:27][C:18]([NH:17][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:29][OH:30])[CH:11]=1)[OH:28])([CH3:26])[CH2:19][CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: CC(C)(CCn1cncn1)NCC(O)c1ccc(OCc2ccccc2)c(CO)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(CCn1cncn1)NCC(O)c1ccc(O)c(CO)c1

Procedure:
The debenzylation of 6 g of 1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-ethanol is carried out hydrogenolytically with 1 g of palladium on charcoal (5%) in 100 mL methanol. After the catalyst has been removed by suction filtering and the filtrate has been evaporated down the residue is dissolved in 20 mL 90% ethanol, combined with sulphuric acid and seeded. The precipitated product is filtered off and washed. Yield: 3 g (55%, hemisulphate); m.p.=177-180° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([CH2:51][CH3:52])=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:49]([NH:48][CH2:51][CH3:52])=[O:50])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CCN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 77 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 77% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.65 (s, 1H), 9.60 (s, 1H), 9.30 (s, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.24 (d, 1H), 7.12 (m, 1H), 7.04 (d, 1H), 6.87 (d, 1H), 6.80 (d, 1H), 6.40 (s, 1H), 3.92 (d, 2H), 3.01 (m, 2H), 2.90 (m, 4H), 2.62 (m, 2H), 2.28 (d, 2H), 1.92 (m, 1H), 1.61 (m, 2H), 1.12 (m, 2H), 1.00 (t, 3H). LCMS for C28H33ClN7O2 (M+H)+: m/z=534.2.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:44]1[CH:49]=[N:48][CH:47]=[CH:46][N:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:49]=[N:48][CH:47]=[CH:46][N:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH2:14][CH2:13]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Clc1cnccn1
Product: COc1ccc(-c2cnccn2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (201 mg, 0.32 mmol) is coupled to 2-chloropyrazine (50 μL, 0.35 mmol) using Method B to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][C@H:5]1[NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH3:2].Br[CH:33](C)C.BrCC>>[CH:1]([O:3][C@@H:4]1[CH2:8][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][C@H:5]1[NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)([CH3:33])[CH3:2]
Reactant: CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)Br
Solvent: CCBr
Product: CC(C)O[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in similar fashion to rel-N-(2-{[(3R,4R)-4-ethoxy-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, 2-bromopropane was substituted for bromoethane, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.10 (d, J=6.0 Hz, 3H), 1.15 (d, J=6.0 Hz, 3H), 1.40-1.60 (m, 2H), 1.64-1.80 (m, 2H), 2.17-2.26 (m, 1H), 2.20-2.40 (m, 1H), 2.64-2.78 (m, 2H), 3.21-3.43 (m, 3H), 3.75-3.90 (m, 2H), 3.90-4.00 (m, 2H), 4.07-4.17 (m, 2H), 4.18-4.25 (m, 1H), 6.47-6.60 (m, 1H), 7.20-7.30 (m, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 8.08 (s, 1H). MS m/z: 458 (M+1).