Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=CC=1Cl)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1Cl)c1cc(Br)ccc1OCc1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (468 mg, 11.16 mmol) in water (25 m) was added dropwise to a stirred solution of (2-chlorophenyl)methyl 5-bromo-2-{[(2-chlorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 27; 520 mg, 1.12 mmol) in THF (25 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 hours. The organic phase was evaporated and the aqueous phase (25 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and was extracted by ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a light yellow solid. 350 mg.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[CH:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(CO)n2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cccc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-methanol (729 mg, 3.74 mmol) in dry CH2Cl2 (10.0 mL) was treated at 0° C. with Et3N (0.67 mL, 4.83 mmol) followed by DMAP (46 mg, 0.37 mmol) and Ms-Cl (0.37 mL, 4.72 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 to 50:50 hept-EA) gave the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.79 min; [M+H]+=274.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[F:26][C:27]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[O:32][N:31]=1)([CH3:29])[CH3:28].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[F:26][C:27]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[O:32][N:31]=1)([CH3:28])[CH3:29]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Yield: 42.4 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (72 mg, 0.212 mmol) and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (56 mg, 0.212 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (46 mg, 43%). 1H NMR (300 MHz, DMSO-d6) δ 10.45 (brs, 1H), 9.12 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.39-7.45 (m, 2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 4.32-4.35 (m, 2H), 3.99 (s, 3H), 3.75-3.78 (m, 2H), 3.35 (s, 3H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 512 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([N+:23]([O-])=O)[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:6][CH2:5]1)[CH3:3].O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([NH2:23])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:6][CH2:5]1)[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN1CCN(C(C)C)CC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CCN1CCN(C(C)C)CC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 1-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.62 g, 1.65 mmol) in absolute ethanol (150 mL) and DMA (10 mL) was added tin (II) chloride dihydrate (2.23 g, 7.84 mmol) and 1M HCl(3.0 mL). After overnight stirring, reaction was quenched with excess saturated NaHCO3 solution, stirred for one hr, and filtered through a celite pad which was rinsed with methanol. After organic solvent removal, the aqueous layer was extracted with dichloromethane (2×200 mL), the organic layers were combined, adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 1-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=347.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)[CH2:4][O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reaction time: 16 h
Yield: 98.5 %

Procedure:
1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (14.5 g, 63.8 mmol) was diluted in 60 mL of ethanol and 10% palladium on carbon (1.4 g) was added. The mixture was hydrogenated on a Parr apparatus at 50 psi for 16 h. The mixture was filtered and the solvent was removed to afford the product 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (12.4 g, 98%) as a pale yellow oil. LR-ES-MS m/z calculated for C9H15N3O2 [M]+ 197, observed [M+H]+ 198. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 3H), 1.30 (s, 3H), 3.70 (dd, J=8.5, 6.0 Hz, 1H), 3.85-4.02 (m, 3H), 4.28 (quin, J=6.0 Hz, 1H), 4.56 (s, 2H), 5.36 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:18][CH3:19])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
To a stirred solution of 6-bromo-1H-indazole-3-carboxylic acid (5 g, 21 mmol) in ethanol (160 Ml), thionyl chloride (8 Ml, 104 mmol; SOCl2) was added. The mixture was refluxed for 3 h, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, DCM:MeOH=9:1) to give ethyl 6-bromo-1H-indazole-3-carboxylate (2.8 g).
Reaction SMILES: BrC[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>O1CCOCC1.O>[N+:13]([C:12]1[C:3]2[CH2:8][O:7][C:5](=[O:6])[C:4]=2[CH:9]=[CH:10][CH:11]=1)([O-:15])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Solvent: O
Solvent: C1COCCO1
Product: O=C1OCc2c1cccc2[N+](=O)[O-]
Yield: 59.7 %

Procedure:
A solution of 54.8 g of methyl 2-bromomethyl-3-nitrobenzoate in a mixture of 200 ml dioxane and 45 ml water was refluxed for 72 hours. The reaction solution was cooled and concentrated in vacuo. The resulting solid was slurried in water, collected, washed with water and dried. Recrystallization from 1-chlorobutane gave 21.4 g of 1,3-dihydro-4-nitrobenzo[c]furan-1-one, m.p. 133.5°-136°.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH2:3][OH:4].[N:14]#[C:15]Br>>[C:8]1([CH:6]([CH3:7])[CH2:5][C@H:2]2[CH2:3][O:4][C:15]([NH2:14])=[N:1]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Product: CC(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1b (S)-2-amino-4-phenyl-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-(2-phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine. Off-white waxy solid.
Reaction SMILES: C([O:3][C:4](=[O:53])[CH2:5][N:6]([CH2:47][C:48]([O:50]CC)=[O:49])[C:7](=[O:46])[C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:11]=[C:10]([NH:30][C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:9]=1)C.[OH-].[Na+]>CO>[C:4]([CH2:5][N:6]([C:7](=[O:46])[C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:11]=[C:10]([NH:30][C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:9]=1)[CH2:47][C:48]([OH:50])=[O:49])([OH:53])=[O:3]
Reactant: CCCCCCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCCCCCC)cc(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 79.9 %

Procedure:
A solution of 2.1 g (2.8 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[3,5-bis(1-oxotetradecylamino)benzoyl]glycine ethyl ester and 2.35 ml (14 mmol) of 6N NaOH in 75 ml of methanol was stirred at reflux for 5 hours under an argon atmosphere. The solvent was removed at reduced pressure and the residue was acidified. The product was extracted with ethyl acetate and the dried extract was concentrated to a solid which was recrystallized from acetonitrile to give 1.54 g (79% yield, mp 109°-111°) of N-(carboxymethyl)-N-[3,5-bis(1-oxotetradecylamino)benzoyl]glycine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3C3CCCC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][CH:27]1[CH2:29][CH:28]1[CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1CCCO1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:26][CH:27]1[CH2:29][CH:28]1[CH2:30][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[CH:16][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(O)cc3)CC2)cc1
Reactant: CC1CC1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(OCC4CC4C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 mg (0.15 mmol) (S)—N-{1-(4-[1-(4-Hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.48), 14 mg (0.16 mmol) 2-methylcyclopropanemethanol and 38.8 mg (0.15 mmol) triphenylphosphine are added to 2 mL 2-methyl-tetrahydrofurane at 0° C. 30.5 μl (0.15 mmol) di-iso-propyl azodicarboxylate are added and the mixture is allowed to warm to rt. Stirring is continued over night followed by addition of 0.5 equivalents of triphenylphosphine and 0.5 equivalents of di-iso-propyl azodicarboxylate. Stirring is continued for one day and again additional triphenylphosphine and di-iso-propyl azodicarboxylate are added and stirring is continued for 16 h at 50° C. Then the mixture is filtered and purified using reversed phase HPLC (water/MeOH, 0.1% FA) to yield the desired product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](OCC)=[O:31])[CH:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][OH:31])[CH:24]=2)[CH2:18][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a suspension of lithium aluminum hydride (150 mg, 4.0 mmol) in 10 mL of anhydrous THF was added dropwise a solution of 4-benzyl-1-(2-(3-(ethoxycarbonylmethyl)phenoxy)ethyl)piperidine (0.382 g, 1.00 mmol) in 2 mL of THF at -78° C. The resulting mixture was allowed to warm to room temperature and was stirred for 12 hr. Water (0.2 mL), 15% NaOH aqueous solution (0.2 mL) and water (1 mL) were added successively. The colorless solid was removed by filtration and washed with EtOAc (3×20 mL). The filtrate was dried over Na2SO4. Evaporation of solvents gave a residue, which was purified by flash chromatography giving the title product as colorless oil (223 mg, 66%) 1H NMR (CDCl3) 1.37 (m, 2 H), 1.60 (m, 1 H), 1.63 (m, 2 H), 2.05 (m, 2 H), 2.36 (d, J=6.6 Hz, 2 H), 2.76 (m, 2 H), 2.82 (m, 2 H), 2.95 (m, 3 H), 3.81 (t, J=6.9 Hz, 2 H), 4.08 (t, J=6.9 Hz, 2 H), 6.80 (m, 3 H), 7.17-7.29 (m, 6 H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.Cl>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([CH3:14])[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:1])[CH3:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)CC(=O)c1ccco1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)c1ccco1
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a stirred solution of 5.0 g (27.4 mmol) ethyl beta-oxo-2-furanpropionate in 15 ml dry THF under argon at −78° C. was added dropwise 27.4 ml (27.4 mmol, 1M solution in THF) lithium bis(trimethylsilyl)amide and stirring continued for 15 minutes at −78° C. 5.44 ml (87.4 mmol) methyl iodide was then added dropwise and stirring continued for 30 minutes at −78° C., 2.5 hours at 0° C. and 20 hours at room temperature. The reaction mixture was poured into 100 ml 1M hydrochloric acid at 0° C. and the phases separated. The aqueous phase was extracted twice with ether and the combined organic extracts washed with brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/3) afforded 4.42 g (82%) (RS)-3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester as a yellow oil. EI-MS m/e (%): 196 (M+, 10), 168 ([M—C2H4]+, 6), 151 ([M—OEt]+, 7), 95 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][N:12]=1>CN(C=O)C.[H-].[Na+]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:13][N:12]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nnc(CCCCc3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(CCCCc3ccccc3)c2c1
Yield: 25.9 %

Procedure:
Operating substantially as described in example 5 starting from 3,5-dichloro-4-methyl-pyridine (0.23 g, 1.4 mmoles) in dry DMF (10 ml), 55% NaH in oil (0.061 g, 1.4 mmoles) and 1-chloro-6-methoxy-4-(4-phenyl-butyl)phthalazine (0.23 g, 0.7 mmole), prepared as described in example 20, in DMF (5 ml), 0.082 g of the title compound were obtained in form of amorphous hygroscopic solid (yield: 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccncc1Br
Reactant: Oc1cc(F)ccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Fc1ccc(Cl)c(Oc2ccncc2Br)c1
Yield: 84 %

Procedure:
A mixture of 2-chloro-5-fluorophenol (1.50 g, 10.24 mmol), 3-bromo-4-chloropyridine (1.50 g, 7.79 mmol) and DBU (1.50 g, 9.85 mmol) were heated at 130° C. in NMP (10 mL) for 15 hours. The reaction mixture was cooled and partitioned between water (100 mL) and MTBE (100 mL). The organic layer was separated, washed with dilute aq NaOH and brine, dried (MgSO4) and concentrated in vacuo to provide 3-bromo-4-(2-chloro-5-fluorophenoxy)pyridine (1.98 g, 84% yield) as brownish oil suitable for use in the next reaction. MS (ESI) m/z: 303.9 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H:40]1[O:57][CH2:56][C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]1[O:42][C:43](=[O:45])[CH3:44])(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.CO>[F:11][C:10]1[C:2]([F:1])=[CH:3][C:4]2[N:8]([C@@H:56]3[O:57][CH2:40][C@@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:51]3[O:52][C:53](=[O:55])[CH3:54])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Fc1cc2nc[nH]c2cc1F
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(F)c(F)cc21
Temperature: 25 °C
Yield: 40 %

Procedure:
As per General Procedure III. 5,6-difluoro-1H-benzimidazole (1.0 g, 6.5 mmol), N,O-bis(trimethlsilyl)acetamide (1.6 ml, 6.5 mmol), in 50 ml 1,2-dichloroethane (Aldrich Sure Seal, Milwaukee) were heated at 85° C. for 2.5 h under a nitrogen atmosphere then allowed to cool to rt. Trimethylsilyl trifluoromethanesulfonate (1.4 ml, 7.2 mmol) and 2.0 g (6.3 mmol) solid 1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose 1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added and the mixture was heated in an oil bath at 85° C. for 24 h under a nitrogen atmosphere. The reaction was then poured into 7% aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with CH2Cl2 and an increasing gradient of methanol from 0.5 to 2% to provide the title compound as a white foam (1.1 g, 2.6 mmol, 40%); MS (API+): m/z (rel. intensity) 524 (0.10, M+1); 1H NMR (DMSO-d6) δ8.47 (s,1H), 8.20-8.16 (m, 1H), 7.76-7.71 (m, 1H), 6.02-6.00 (d, 1H, J=9.5 Hz), 5.75-5.69 (m, 2H), 5.53-5.40 (m, 1H), 4.05-3.94 (m, 1H), 2.22 (s, 3H), 2.00 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O.[NH2:16]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]#[N:16]
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Reactant: NO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccnc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (1.5 g, 6.6 mmol) in 5 mL of MeOH was added hydroxylamine (0.6 mL, 9.1 mmol, 50% aqueous soln) and the reaction stirred for 10 min at RT and then concentrated. The residue was dissolved in 10 mL of DCM and 5 mL of pyridine and cooled in an ice bath. To this mixture was added trifluoroacetic anhydride (4.2 g, 20 mmol) and the reaction stirred for 8 h at RT. The mixture was concentrated and then dissolved in EtOAc (50 mL) and washed with NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated to give 1.2 g (81%) of a brown oil of sufficient purity to use in the next step. 1H-NMR (CDCl3, 400 MHz): δ 7.28 (s, 2H), 5.48 (s, 2H), 3.56 (m, 2H), 0.96 (m, 2H), 0.00 (s, 9H). Mass spectrum (APCI, m/z): Calcd. for C10H17N3OSi, 224.1 (M+H), found 223.6.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].Br[C:13]1[N:14]=[CH:15][C:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[Cl:31])(=[O:23])=[O:22])=[N:17][C:18]=1[Cl:19]>>[Cl:31][C:25]1[C:26]([Cl:30])=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([NH:20][C:16]1[C:15]([O:11][CH2:10][C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)=[N:14][CH:13]=[C:18]([Cl:19])[N:17]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Nc1cnc(Br)c(Cl)n1)c1cccc(Cl)c1Cl
Reactant: CN(C)Cc1ccc(CO)o1
Product: CN(C)Cc1ccc(COc2ncc(Cl)nc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 31 using (5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.3 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.11 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([NH:15]C(OC(C)(C)C)=O)([CH3:14])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.Cl.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:23])[C:4]([NH2:15])([CH3:14])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)(CNc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C)(N)CNc1ccc(F)cc1
Temperature: 55 °C
Yield: 46.2 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-(4-fluoro-phenylamino)-2-methyl-propionic acid methyl ester (954 mg, 2.92 mmol) in methanol (10 mL) was added HCl (3 mL, 12 N). The mixture was heated to 55° C. until the MS indicated no starting material remained. After cooling to ambient temperature, the solution was treated with aqueous NaOH (40 mL, 1N) and extracted several times with DCM. The combined extracts were concentrated and purified by flash chromatography (SiO2, 5% MeOH/DCM) to yield the title compound as a yellow oil (305 mg, 46%).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([F:24])[CH2:22][CH:21]2[NH2:23])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([F:24])[CH2:22][CH:21]2[NH:23][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[CH:18][CH:19]=1
Reactant: NC1CC1(F)c1ccc(Cl)cc1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)NC2CC2(F)c2ccc(Cl)cc2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.105 g; 0.54 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of the amine from example P5 (compound Z1.004; 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine; 0.100 g; 0.54 mmol) and triethylamine (0.15 ml; 1.08 mmol) in dichloromethane (3 ml). The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 18 h. The reaction mixture was washed with 2M HCl (5 ml) and with saturated NaHCO3 (5 ml) and then dried over MgSO4. Evaporation of the solvent yielded 0.15 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (2-(4-chlorophenyl)-2-fluoro-cyclopropyl)-amide in the form of a yellow solid (81% of theory) as a 7:3 mixture of cis/trans isomers.