Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:13]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
Ethyl pyrazole-4-carboxylate (W. Holtzer, G. Seiringer, J. Heterocyclic Chem., 1993, 30, 865) (1.7 g, 12.1 mmol) and NaH (680 mg, 60% in mineral oil, 16.94 mmol) reacted in dry DMF for 1 h. Then, trityl chloride (3.373 g, 12.1 mmol) was added, and the reaction mixture stirred for 3 days at room temperature. The title compound was recovered as described in example 2a for 3,5-dimethyl-4-ethylacetate-1-tritylpyrazole. Yield: 82% (3.79 g, 4 mmol).
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([CH:10]=[C:11](C(C)(C)C)[C:12]=1OCOCCOC)[C:8]#[N:9])(C)C.C(N(CC)CC)C.N1C=CC=CC=1.[SH2:37]>>[C:7]1([C:8](=[S:37])[NH2:9])[CH:10]=[CH:11][CH:12]=[CH:5][CH:6]=1
Reactant: S
Reactant: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ccccc1
Reaction time: 15 h

Procedure:
Into a solution containing 10.0 g (0.03 mole) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile, 5.7 ml (0.04 mole) of triethylamine and 14.2 ml (0.18 mole) of pyridine, hydrogen sulfide gas is bubbled over 15 hours. The mixture is poured into ice water (110 ml), and an oily precipitate solidifies upon standing at 0° C. for 15 hours. The solid is thoroughly washed with water and filtered. Recrystallization from ethyl acetate and hexane gives 7.9 g (71%) of analytically pure 3,5-bis(1,1-dimethylethyl) -4-[2-methoxyethoxy)methoxy]benzenecarbothioamide, mp 113°-115° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[O:9][N:8]=2)[NH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[O:9][N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 3-(5-methyl-2H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (Example 96, Step 4, 400 mg, 1.3 mmol) and K2CO3 (445 mg, 3.3 mmol) in DMF (5 mL) was added 2-chloro-4-(chloromethyl)pyridine (210 mg, 1.3 mmol). The mixture was stirred at RT for 2 h, then diluted with H2O (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with H2O (20 mL) and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (Petroleum ether:EA=1:3) to give the title compound as a light yellow solid (300 mg, 53.3%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[K+].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH-:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C.O>CS(C)=O>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(Cl)c(-c2ccccc2)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Reaction time: 24 h
Yield: 87.4 %

Procedure:
2.77 g 4,6-dichloro-2-methylthio-5-phenylpyrimidine was dissolved in 50 ml DMSO and 3.42 g 4-tert-butylbenzenesulfonamide potassium salt and 1 ml Hünig's base was added. Stirring was continued for 24 h. The mixture was poured onto 400 ml water, washed with diethylether and acidified with conc. hydrochloric acid. The product precipitated and was filtered off and dried in vacuo to give 4 g of 4-tert.-butyl-N-(6-chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl)-benzenesulfonamide. LC-MS: tR=6.29 min, [M+1]+=448.17; 459.17.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[O:24]1[CH2:28][C:27](=O)[N:26]=[C-:25]1.[H-].[Na+].[O:32]1CCOCC1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[CH2:27][CH2:28][O:24][C:25]2=[O:32])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CBr)c1
Reactant: C1COCCO1
Reactant: O=C1CO[C-]=N1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
[3-(4-Bromo-2-bromomethyl-phenoxy)-5-chloro-phenyl]-acetic acid ethyl ester (0.10 g, 0.25 mmol), 2-oxazolidone (0.044 g, 0.5 mmol), and sodium hydride (60% in mineral oil; 0.02 g, 0.5 mmol) were combined in 1,4-dioxane (4 mL) and stirred at 80° C. for 2 hours. After work-up, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:21](=[O:23])[CH3:22])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 4-(4-bromophenyl)piperidine (400 mg, 1.70 mmol) in dichloromethane (20 mL) was added triethylamine (340 mg, 3.40 mmol) and acetic anhydride (500 mg, 5.10 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. The material was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was washed two additional times with ethyl acetate (30 mL). The combined organics layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (260 mg, 60% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2 H), 6.91 (d, 2 H), 4.63 (d, 1 H), 3.77 (d, 1 H), 3.00 (t, 1 H), 2.57-2.42 (t, 2 H), 1.97 (s, 3 H), 1.75-1.68 (m, 2 H), 1.47-1.40 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:20])[C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]#[C:17][CH2:18][OH:19])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:20])[C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]#[C:17][CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](CC#CCO)CC1
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](CC#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A solution of 1.08 g (3.68 mmol) of trans-4-{4-[(6-Chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-but-2-yn-1-ol in 30 ml CH2Cl2 was treated at 0° C. with 0.31 ml (4.04 mmol) methanesulfonylchloride and 0.64 ml (5.51 mmol) 2,6-lutidine. The reaction was stirred for 46 h at room temperature, water (4 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 1.45 g of crude trans-Methanesulfonic acid 4-{4-[(6-chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-but-2-ynyl ester, MS: 372 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:17][CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([O-])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:15][CH2:16][CH2:17]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)[O-])C1CCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CCCO)C1CCC1

Procedure:
This compound was prepared from N-tertbutoxycarbonyl-3-cyclobutylamino-propanoate (4a, 1.71 9, 6.3 mmol) using the procedure described in Example 2b. Yield: 0.94 g (65%). ESI-MS: 230.2 (M+H)+. 252.3 (M+Na)+, 174.2 (M+H—C4H8)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.37.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]1[C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[S:30][CH:31]=1>>[ClH:24].[CH3:37][O:36][C:35]1[C:28]2[C:27]([CH2:26][CH2:25][N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]4[C:14](=[O:15])[CH2:13][C:12]5[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=5[CH2:10][CH2:9]4)[CH2:2]3)=[CH:31][S:30][C:29]=2[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc2scc(CCCl)c12
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3csc4cccc(OC)c34)C1)CC2
Product: Cl

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 3-(2-chloroethyl)-4-methoxy-benzo[b]thiophene analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[N:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:9][CH:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nnc(NC(C)C)s1
Solvent: c1ccncc1
Product: Cc1nnc(N(C(=O)c2ccccc2)C(C)C)s1

Procedure:
N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-methylethylamine (5 g, 0.032 mole) in pyridine (100 ml) was treated with benzoyl chloride (4.1 ml). The reaction mixture was stirred and heated to reflux for 51/2 hours. The pyridine was removed under reduced pressure and the residue treated with water and extracted with ether (×3). The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ether/petrol ether (40°-60° C.) to give the title compound as a pale yellow crystalline solid m.p. 82.5°-83.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([Cl:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C(O)C.Cl.O1CCOCC1.CCOCC>[Cl:30][C:22]1[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:20]([CH:21]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)c1cc(Cl)cc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 27.9 g (109 mMol) of 1-chloro-4-(4-pyridyl-methyl)-phthalazine (Example 67A.1 in WO 98/35958) and 21.4 g (109 mMol) of 5-amino-3-chloro-benzotrifluoride (Example 5b) in 500 ml of ethanol and 27.4 ml of 4 N HCl/dioxane is stirred during 3 h a 80° C. After cooling down, the reaction mixture is diluted with 0.3 l of ether, filtrated, and washed with ether. The remaining solid is then taken up in water and EtOAc, brought to alkaline pH by means of NH3 solution, stirred for 15 min at room temperature and then filtered and washed with ether (→raw product). The water layer is removed from the filtrate and extracted twice with ethyl acetate. The organic layers are washed with water and brine, dried over Na2SO4 and evaporated. The residue is combined with the raw product mentioned above, and the solid is dissolved in ethyl acetate and methanol. About 100 g SiO2 are added, followed by evaporation, and the powder is applied onto a silica gel column and eluted with ethyl acetate and subsequently with a mixture of ethyl acetate and methanol (98:2→95:5, v/v). Solving the obtained fractions in ethyl acetate/methanol, partial evaporation and crystallization by addition of ether/hexane leads to the title compound: m.p. 231-232° C.; An. calc. (C21H14N4ClF3) C, 60.81%; H, 3.40%; N, 13.51%; Cl, 8.55%; F, 13.74%; An meas. C, 60.8%; H, 3.4%; N, 13.5%; Cl, 8.5%; F, 13.8%; 1H-NMR (DMSO-d6) 9.63 (s, HN), 8.60 (d, 1H), 8.56 (s, 1H), 8.44 (d, 2H), 8.39 (s, 1H), 8.16 (d, 1H), 8.03 (t, 1H), 7.97 (t, 1H), 7.43 (s, 1H), 7.32 (d, 2H), 4.63 (s, 2H); FAB-MS (M+H)+=415.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:13]=[O:20])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
One equivalent of 3,4-dinitrotoluene and 2 equivalents of N-bromosuccinimide in carbon tetrachloride is irradiated with a 500 W tungsten lamp for 4 hours. The mixture is filtered and the filtrated is shaken with a solution of aqueous potassium carbonate. The organic layer is evaporated in vacuo to give 3,4-dinitrobenzaldehyde.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11]C1(C([O-])=O)C(C=C(Cl)Cl)C1(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)=CC1C(C(O)=[O:34])C1(C)C>>[O:1]([C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C(C=C(Cl)Cl)C1(Cc1cccc(Oc2ccccc2)c1)C(=O)[O-]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Product: OCc1cccc(Oc2ccccc2)c1

Procedure:
A process according to claim 1 for the preparation of 3-phenoxybenzyl-[3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylate], which comprises reacting 3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylic acid with dimethylchloromethylydene-ammonium chloride and further reacting dimethyl-[3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarbonyloxy]-methylydene-ammonium chloride obtained with 3-phenoxybenzyl alcohol in the presence of said organic base.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:61])([CH3:60])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:49][CH2:48]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]4[CH2:39][CH2:38][C:30]5([CH2:35][O:34]C(C)(C)[O:32][CH2:31]5)[CH2:29][CH2:28]4)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:48][CH2:49][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:60])([CH3:61])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:51][CH2:52]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]4[CH2:39][CH2:38][C:30]([CH2:31][OH:32])([CH2:35][OH:34])[CH2:29][CH2:28]4)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(OCC5CCC6(CC5)COC(C)(C)OC6)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(OCC5CCC(CO)(CO)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 391G (680 mg) in dichloromethane (3514 μl) was added para-toluenesulfonic acid monohydrate (535 mg) and the reaction was allowed to stir for 3 hours. Triethylamine (490 μl) was added and the reaction was concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix 0.5-5% dichloromethane/methanol). 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.69 (s, 1H) 8.35 (s, 1H) 8.03 (d, 2H) 7.46-7.58 (m, 3H) 7.29-7.42 (m, 3H) 7.04 (d, 2H) 6.68 (dd, 1H) 6.39 (d, 1H) 6.20 (s, 1H) 4.19-4.35 (m, 2H) 4.05 (d, 2H) 3.37 (d, 2H) 3.17 (d, 2H) 3.09 (bs, 4H) 2.10-2.31 (m, 6H) 1.96 (bs, 2H) 1.62-1.75 (m, 1H) 1.46-1.62 (m, 4H) 1.39 (t, 2H) 1.05-1.32 (m, 4H) 0.93 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccccc1F
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1F)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@H:28]2[N:29]([C:34]([O:36][CH2:37][CH:38]3[C:50]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:44]4[C:39]3=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])[CH2:30][C@H:31]([S:32][CH3:33])[C@H:27]2[O:26][CH2:25]1>ClCCl>[CH3:33][S:32][C@H:31]1[CH2:30][N:29]([C:34]([O:36][CH2:37][CH:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=3[C:45]3[C:50]2=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:35])[C@@H:28]2[C:24](=[O:23])[CH2:25][O:26][C@H:27]12
Reactant: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@@H]2C(=O)CO[C@H]12
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Dess-Martin periodinane (130 mg, 0.65 mmol) was added to a stirred solution of alcohol (55) (278 mg, 0.33 mmol) in dichloromethane (10 mL) under an atmosphere of argon. The mixture was stirred for 1 hour then diluted with dichloromethane (25 mL). The organic phase was washed with a mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodium thiosulphate solution (1:1, 20 mL), then dried (Na2SO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 60:40 to 65:35 gave ketone (56) (113 mg, 87%) as a white solid. TLC (Rf=0.24, Et2O:pentane 2:1); analytical HPLC two main peaks, Rt=15.71 and 15.91 min.; HPLC-MS 396.1 [M+H]+, 414.1 [M+H2O+Na]+, 813.2 [2M+H]+; [α]D18−137.3° (c=2.33, CHCl3). δH(500 MHz, CDCl3) mixture of rotamers approx. 1:1; 2.15 (1.5H, s, SCH3), 2.19 (1.5H, s, SCH3), 3.30-3.38 (1H, m, CHSMe), 3.68-3.80 (1.5H, m, FmocNCH2), 3.93-4.05 (1.5H, m, 0.5×FmocNCH2 and OCH2C═O), 4.10-4.35 (2.5H, m, OCH2C═O, Fmoc-CH, and 0.5×Fmoc-CH2), 4.40-4.54 (2.5H, m 1.5×Fmoc-CH2 and FmocNCH), 4.74-4.84 (1H, m, OCHCHSCH3), 7.28-7.77 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3); 14.662 (SCH3), 47.133 (Fmoc-CH), 48.449/48.954 (CHSCH3), 50.539/53.419 (FmocNCH2), 61.005/61.420 (FmocNCH), 67.710/68.437 (Fmoc-CH2), 70.733 (OCH2C═O), 85.174/86.042 (OCHCHSCH3), 119.916, 119.987, 124.917, 124.964, 125.240, 125.448, 127.069, 127.712 and 127.969 (Fmoc aromatic CH), 141.255/141.317, 143.627, 143.778 and 144.264 (Fmoc quaternary), 154.942/155.049 (Fmoc C═O), 207.818/207.973 (ketone C═O).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[Cl:22][CH2:23][C:24]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([O:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[N:1]=1
Reactant: COc1cc(N)c(C(=O)Nc2ccccc2Cl)cc1OC
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 45.8 %

Procedure:
Prepared according to Procedure B with 1a (2.95 g, 9.63 mmol) and chloroacetyl chloride (2.3 mL, 28.9 mmol) in acetic acid (30 mL). Purified by extraction from aq. K2CO3 and recrystallization from isopropanol to afford 1.61 g of a brown crystalline solid (46%). 1H NMR (CDCl3) δ: 7.59-7.66 (m, 2H) 7.45-7.56 (m, 3H); 7.20 (s, 1H); 4.37 (d, J=12 Hz, 1H), 4.08 (d, J=12 Hz, 1H); 4.04 (s, 3H); 4.00 (s, 3H). MS (ES): m/z 365.0 (M+).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F-].C([N+:47]([CH2:56][CH2:57][CH2:58][CH3:59])([CH2:52][CH2:53][CH2:54][CH3:55])CCCC)CCC>O1CCOCC1.O>[CH3:33][C@H:28]1[O:29][C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:59]4[CH:55]=[CH:54][CH:53]=[C:52]5[C:58]=4[CH:57]=[CH:56][NH:47]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:27]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.103 mmol) in 1,4-dioxane (1.5 ml) and water (0.15 ml) was added {1-[1,1-dimethylethyl)(dimethyl)silyl]1-Hindol-4-yl}boronic acid (37 mg, 0.133 mmol), chloro[Z-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5.75 mg, 10.27 μmol) and potassium phosphate tribasic (65 mg, 0.308 mmol). The reaction mixture was heated under microwave irradiation at 100° C. for 40 min. The solvent was removed and the residue dissolved in 10% methanol in dichloromethane (2 ml) and purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The appropriate fractions were concentrated to give a brown gum which was treated directly with tetra-n-butylammonium fluoride (0.2 ml, 0.2 mmol, 1M in tetrahydrofuran) and allowed to stand at 20° C. for 18 h. The solvent was removed and the residue dissolved in 1,4-dioxane (1 ml) and treated with 2M sodium hydroxide (1 ml) and allowed to stand at 20° C. for 48 h. The solvent was removed and the residue triturated with 10% methanol in dichloromethane then purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give a pale brown solid which was further purified by SCX SPE (1 g), eluting with 0.5M ammonia in 1,4-dioxane. The solvent was removed and the residue further purified by MDAP to give the title compound as a white solid (14 mg).