Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:15]=2)[CH2:10]1.[N:50]([C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1)=[C:51]=[O:52]>C1COCC1>[C:44]1([CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:36][NH:35][C:16]2[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:51]([NH:50][C:53]4[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=4)=[O:52])[CH2:10]3)[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]2[OH:34])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C=Nc1cccnc1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide trifluoroacetate (0.2 g, 0.28 mmol) in dry THF (10 ml) is treated with TEA (113 mg, 1.12 mmol) followed by 3-isocyanato-pyridine (38 mg, 0.31 mmol). The reaction mixture is heated at 50° C. overnight. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute™ C18, 10-50% acetonitrile in water—0.1% TFA) affords the product. The product is further purified by dissolving in MeOH and treating with saturated sodium bicarbonate solution. The mixture is passed through a pre-washed (400 ml MeOH followed by 400 ml water) eluting with 0.5% ammonia 880: water (100 ml) followed by water (400 ml) and finally MeOH to afford the title compound. (MH+ 693.4)
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:42])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=2[O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])=[CH:17][C:16]1=[O:43])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2]>CC#N.O.CC(O)=O>[P:1]([OH:8])([OH:3])([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:42])[C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:24]=2[O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])=[CH:17][C:16]1=[O:43])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 30.2 %

Procedure:
A solution of di-tert-butyl [4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (24) (23 mg, 0.03659 mmol) in CH3CN (460.0 μL), water (460.0 μL) and AcOH (460.0 μL) was heated at 90° C. for 15 min then evaporated and co-evaporated with CH3CN (3×). The material was triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (10) (6 mg, 0.01104 mmol, 30.2%) as a white solid. ESI-MS m/z calc. 516.0709, found 517.4 (M+1)+; Retention time: 1.45 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.22 (dd, J=8.8, 2.2 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.67 (dd, J=9.5, 3.1 Hz, 1H), 7.65-7.50 (m, 2H), 7.35 (d, J=2.3 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 6.88 (dd, J=7.6, 2.4 Hz, 1H), 5.95 (d, J=9.8 Hz, 2H), 2.57 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.17 (t, J=9.7 Hz) ppm.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]([C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
290.0 mg (0.75 mmol) tert. Butyl (2S,4R)-2-azidomethyl-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylate are dissolved in a mixture of 4 ml THF and 0.4 ml of water and combined with 0.3 g (1.1 mmol) triphenylphosphine. The reaction mixture is stirred at RT for 16 hours. Then the mixture is concentrated i. vac., combined with water and dil. Sodium hydroxide solution and extracted three times with DCM. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 9:1→1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(OCC)(=O)C>[CH2:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)CCn1cc([N+](=O)[O-])cn1
Temperature: 55 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
A mixture of 4-Nitro-1H-pyrazole (234 mg, 2.06 mmol, 1.0 eq), 1-Bromo-3-methylbutane (0.30 ml, 2.48 mmol, 1.2 eq), and Cesium carbonate (1.01 g, 3.10 mmol, 1.5 eq) in 5.0 mL 1,2-Dimethoxyethane was stirred at 55° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with 25 mL ethyl acetate and filtered. The filtrate was then concentrated and the residue was dissolved in 5 mL dichloromethane and purified by flash column chromatography (silica, 0-80% ethyl acetate in heptane in 30 minutes) to yield 357.6 mg (94.32%) of Isopentyl-4-nitro-1H-pyrazole as a white solid. LCMS (ESI) m+H=184.1 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 8.06 (s, 1H), 4.20-4.14 (m, 2H), 1.80 (dd, J=14.8, 7.1, 2H), 1.60 (dp, J=13.4, 6.7, 1H), 0.97 (d, J=6.6, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:18]=[CH:17][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 49 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 1.21 g, 5.44 mmol), 2-naphthaleneboronic acid (Lancaster; 1.00 g, 5.8 mmol), copper(II) acetate (990 mg, 5.45 mmol) and triethylamine (1.9 mL, 13.6 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 50° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-30% ethyl acetate/hexanes, to give N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (929 mg, 49%) as a yellow oil that solidified on standing.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([N:41]([CH3:49])[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[CH:35][CH:34]=1>>[CH:1]1([CH:7]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:41]([CH3:49])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[CH:37][CH:38]=2)[C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1CCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 40.7 %

Procedure:
Using cyclohexyl{3-(2-phenylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized in Example 11(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.35 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.30 g, 41%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:5]=1[O:6][CH:7]([CH3:15])[C:8](OCCCC)=[O:9])([O-])=O>C(O)(=O)C.[Fe]>[CH3:15][CH:7]1[C:8](=[O:9])[NH:1][C:4]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:5]=2[O:6]1
Reactant: CCCCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1Oc2ccc(C(F)(F)F)cc2NC1=O
Yield: 54.3 %

Procedure:
A mixture of butyl 2-(2-nitro-4-trifluoromethylphenoxy)propionate (12.0 g) and iron powder (5 g) in acetic acid (100 ml) was heated to reflux for 1.5 hours. After cooling the reaction mixture was quenched with water and the 2-methyl-6-trifluoromethyl-benzo[1,4]oxazin-3-one (4.49 g, 54% yield) as a grey solid was filtered off and dried mp 142°-4° C.; 1 H NMR (270 Mz): 1.61(3H,d), 4.76(1H,q), 6.7-7.4(2H,m), 8.89(1H,brs) ppm.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][C:15]=1[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CON(C)[C:26]([C:28]1[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=1)=[O:27].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:6]([O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:26]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)=[O:27])=[CH:16][C:15]=1[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 2.8 mL (4.5 mmol) of a 1.6 M n-butyllithium solution were added to a mixture of 1.2 g (4.0 mmol) 2-benzyloxy-5-bromo-1,3-dimethyl-benzene in mL THF cooled to −75° C. and the mixture was stirred for 1 h at −75° C. Then 0.96 g (4.3 mmol) 6-chloro-pyrimidine-4-carboxylic acidmethoxy-methyl-amide, dissolved in 10 mL THF, were added dropwise. After another 30 min stirring at −75° C. the reaction mixture was slowly heated to 0° C. The mixture was combined with saturated sodium hydrogen carbonate solution and extracted with diethyl ether. The organic phase was dried and evaporated down. The residue was purified by flash chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4](S(C2C=CC=CC=2)(=O)=O)[C:3]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].[OH-].[Na+]>CO>[Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Nc1ccccc1)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccccc1)c1[nH]ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
To a solution of 3-bromo-N-phenyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxamide (2.70 g of crude material) in 50 mL of methanol was added 15 mL of an aqueous 1N solution of sodium hydroxide and the mixture was stirred at room temperature during 1.5 h. At the end of this period, no starting material was detected and the reaction was elaborated in the following way: methanol was evaporated and a precipitate was formed which was filtered off and washed several times with water. The solid was dried in the vacuum oven to afford 1.14 g of the title compound that was used in the following step without any further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:33])[CH2:6][NH:7][C:8]([C:10]1[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]#[N:20])=[CH:14][CH:13]=2)=[O:9])C.[BH4-].[Li+]>O1CCCC1.O>[OH:3][CH2:4][CH:5]([CH3:33])[CH2:6][NH:7][C:8]([C:10]1[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]#[N:20])=[CH:14][CH:13]=2)=[O:9]
Reactant: CCOC(=O)C(C)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
3-{[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methylpropionic acid ethyl ester (170 mg, 0.36 mmol) was dissolved in dry tetrahydrofuran (10 ml) and lithium borohydride (28 mg, 1.28 mmol) was added and heated to reflux for 90 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×30 ml), the organic layers were combined and washed with water (20 ml) and saturated sodium chloride solution (20 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (3-hydroxy-2-methylpropyl)amide as a pale yellow solid which was purified by preparative HPLC (75 mg, 48%).
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:7]([CH3:15])[CH2:8][O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1.CC[O:27]C(C)=O.CCCCCCC.O>>[C:19]([O:18][C:17]([N:16]([CH3:24])[C@@H:6]([C@H:7]([CH3:15])[CH2:8][O:9][C@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1)[C:2]([OH:1])=[O:27])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](CO[C@H]1CCOC1)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: O
Solvent: CCCCCCC
Product: C[C@H](CO[C@H]1CCOC1)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A flask was charged with 2.16b (50 mg, 0.15 mmol), NalO4 (189 mg, 0.88 mmol, 6 equiv.) and EtOAc/heptane/water (1.5 mL/0.5 mL/2 mL). With vigorous stirring, RuCl3 (6 mg, 0.03 mmol, 0.2 equiv) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by addition of saturated aqueous NaHSO3 solution and the mixture was extracted with EtOAc. The combined organic layers was washed with saturated aqueous NaHSO3 solution, brine, dried over Na2SO4 and concentrated to give product 2.16c (34 mg, 73% yield). MS (m/z): 318 [M+1].
Reaction SMILES: C(OC[Li])C.C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[CH2:26]([O:28][CH2:29]Cl)[CH3:27].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:40]([CH:49]=[O:50])=[CH:41][C:42]3[NH:46][CH:45]=[N:44][C:43]=3[C:47]=2[F:48])=[C:34]([Cl:51])[CH:33]=1>C1COCC1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:40]([CH:49]([OH:50])[CH2:29][O:28][CH2:26][CH3:27])=[CH:41][C:42]3[NH:46][CH:45]=[N:44][C:43]=3[C:47]=2[F:48])=[C:34]([Cl:51])[CH:33]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CCOCCl
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]COCC
Solvent: C1CCOC1
Product: CCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of lithiomethyl ethyl ether in THF (6 mL) (prepared from 4,4′-di-tert-butylbiphenyl (585 mg, 2.20 mmol), Li (18 mg, 2.59 mmol), and EtOCH2Cl (0.20 mL, 2.05 mmol) by the procedure reported in Tetrahedron 1996, 52, 1643) is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (29 mg, 0.080 mmol) in THF (1 mL) at −78° C. The resulting solution is stirred for 1 hour and then quenched with saturated aqueous NH4Cl at −78° C., warmed to room temperature, and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (100% CH2Cl2 to 3% to 5% MeOH in CH2Cl2) to give the desired product (15 mg, 44%): MS APCI (+) m/z 428, 430 (M+, Br pattern) detected.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:28]C)=[CH:10][C:11]([O:26]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][C:13]3=[O:25])[CH2:6][CH2:5][N:4]1[CH3:30].Cl.N1C=CC=CC=1>>[NH2:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([OH:28])=[CH:10][C:11]([OH:26])=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][C:13]3=[O:25])[CH2:6][CH2:5][N:4]1[CH3:30]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CN
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CN

Procedure:
Compound of example 108 (0.45 g, 1.0 mmol) was demethylated using pyridine hydrochloride (5.0 g, 43.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][C:19]1[N:20]=[CH:21][O:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CN(C=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:23]3[O:22][CH:21]=[N:20][C:19]=3[CH3:18])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cocn1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3ocnc3C)c(C)nc12
Temperature: 130 °C
Yield: 39.2 %

Procedure:
686 mg of 8-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.0 mmol), 830 mg of 4-methyl-oxazole. (10 mmol), 105 mg of triphenylphosphine (0.4 mmol) and 1.30 g of cesium carbonate (4.0 mmol) are placed into tube with 10 ml of dry DMF. N2 gas is bubbled in for 20 min and 92 mg of Pd2 dba3 (0.1 mmol) is added. The tube is sealed and heated at 130° C. overnight. After being cooled to room temperature, water and CHCl2 are added to the mixture. The CHCl2 layer is separated, washed with sat. NaCl, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to give 234 mg of the title product. Yield 39%. mass spectrum (m/e): 299 (M+1). 1H-NMR (CDCl3): 8.06 (s, 1H), 6.75 (s, 1H), 3.34 (m, 1H), 2.56 (s, 3H), 2.50 (s, 3H), 2.29 (s, 3H), 1.86 (m, 4H), 0.90 (t, J=7.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]([CH2:14][C:15]#[CH:16])[C:12](=[O:17])[C:11]([CH2:22][CH3:23])(C(OC)=O)[CH:10]([CH2:24][CH3:25])[N:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[I-].[Li+]>N1C=CC=CC=1>[Cl:26][C:4]1[CH:5]=[C:6]([C:8]2[N:13]([CH2:14][C:15]#[CH:16])[C:12](=[O:17])[CH:11]([CH2:22][CH3:23])[CH:10]([CH2:24][CH3:25])[N:9]=2)[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: C#CCN1C(=O)C(CC)(C(=O)OC)C(CC)N=C1c1cc(Cl)nc(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: C#CCN1C(=O)C(CC)C(CC)N=C1c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To 5.0 g (12.6 mmol) of 2-(2,6-dichloro-4-pyridyl)-5,6-diethyl-5-methoxycarbonyl-3-propargyl-5,6-dihydropyrimidin-4-one in 50 mL of pyridine was added 11.5 g (76 mmol) of lithium iodide and refluxed overnight. The reaction was cooled to room temperature, quenched onto 250 mL of water andextracted with EtOAc (2×300 mL). The organics were combined, washed with water (1×200 mL), dilute HCl (2×200 mL), water (1×200 mL), dilute sodium bisulfite (1×200 mL) and saturated sodium chloride (1×200 mL). The EtOAc was diluted with 600 mL of hexanes and vacuum filtered through a pad of silica gel. The filtrate was dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was triturated with diethyl ether and solid impurities removed by filtration. The filtrate was once again evaporated to dryness in vacuo to give 2.2 g (5.75 mmol, 46%) of desired product as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:10]([OH:17])=[C:9]([CH3:18])[C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:5])[CH3:4].Br[CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>CN(C)C=O>[C:3]([O:6][C:7]1[C:12]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:11][C:10]([O:17][CH2:26][CH:25]=[CH2:24])=[C:9]([CH3:18])[C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:5])[CH3:4]
Reactant: BrCCCBr
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C)c1C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1C
Reaction time: 0.5 h

Procedure:
Sodium hydride (110 mg) was suspended in N,N-dimethylformamide (5 ml) and a solution of 4-acetoxy-3,5-di-tert-butyl-2-methylphenol (0.6 g) in N,N-dimethylformamide (5 ml) was added dropwise to the suspension at 0° C. After stirring for 30 min, 1,3-dibromopropane (0.36 ml) was added in one portion and the mixture was stirred for an additional 2 h. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and subjected to extraction with diethyl ether. The extract was washed with water and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in N,N-dimethylformamide (5 ml) and added to a solution prepared in the same manner as described above (4-acetoxy-3,5-di-tert-butyl-2-methylphenol, 0.4 g; sodium hydride, 86 mg; N,N-dimethylformamide, 5 ml). The mixture was allowed to warm from 0° C. to room temperature and stirred for 2 h. Subsequently, it was poured into a saturated aqueous solution of ammonium chloride and treated as described above. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane). The first fraction gave 1-acetoxy-4-allyloxy-2,6-di-tert-butyl-3-methylbenzene (370 mg). The next fraction gave 1,3-bis(4-acetoxy-3,5-di-tert-butyl-2-methylphenoxy)propane (200 mg).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:24][C:25]([F:33])([F:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:27]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Product: COC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Yield: 88.1 %

Procedure:
In a manner similar to Example 16, 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate was treated with 4.05 g of m-trifluoromethylphenol to give 8.07 g of product as a pale yellow glass.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].[CH2:16]([O:18][C:19](=O)[O:20]CC)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:20])[CH:13]([C:14]#[N:15])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:6]=1[Cl:5])[CH3:17]
Reactant: N#CCc1cccc(Cl)c1Cl
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cccc(Cl)c1Cl

Procedure:
Sodium (1.2 g) was added portionwise to ethanol (50 ml) with stirring. After the sodium had dissolved a solution of 2,3-dichlorophenylacetonitrile (9.4 g) in diethylcarbonate (25 ml) was added dropwise. The reaction mixture was heated until EtOH distilled over. The rate of addition was controlled such that it equalled the rate of distillation. After the completion of the addition, the reaction mixture was heated and distilled for a further 4 hours. The cooled reaction mixture was partitioned between water and EtOAc (300 ml each). The organic layer was dried and evaporated in vacuo and the residue was purified by flash column chromatography to give the title product. (5 g, 39%).