Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)C=O.[OH:12]O>[OH-].[Na+]>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([OH:12])[C:3]=1[OH:11]
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred suspension of 3-bromo-5-chloro-2-hydroxybenzaldehyde (49.5 g, 0.21 mol) in 0.5N aqueous NaOH (500 ml, 250 mmol) at 40° C. was added dropwise hydrogen peroxide (21.4 g of a 35% aqueous solution, 220 mmol) over 15 minutes and the resultant mixture stirred for 16 hours. The mixture was cooled to room temperature, diluted with 1N aqueous NaOH (200 ml) and washed with diethyl ether (3×300 ml). The aqueous layer was acidified with concentrated HCl to pH 2 and extracted with diethyl ether (3×200 ml). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a red/brown solid (46.0 g, 99% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.C([O:30][C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[O:33])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[OH:30][C:31]([CH3:36])([CH3:35])[C:32]([NH:34][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:33]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: CC(=O)OC(C)(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)C(C)(C)O)C2=O)cnc1OCC(F)(F)F
Temperature: 170 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 0.052 mmol, Intermediate-2, single enantiomer), 1-amino-2-methyl-1-oxopropan-2-yl acetate (15 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.2 micro mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.0 mg, 0.016 mmol) and tripotassium phosphate (16 mg, 0.075 mmol) in dioxane (2 mL) is heated at 170° C. for 40 min by microwave irradiation. The reaction mixture is filtered through a short column of NH-gel eluting with EtOAc and volatiles are removed. The residue is dissolved in THF (1.0 mL) and 2 M aqueous sodium hydroxide solution (0.50 mL) is added, and the mixture is stirred overnight at rt. The mixture is neutralized by the addition of 2 M hydrochloric acid (0.50 mL), diluted with THF (4.0 mL) and extracted with EtOAc. The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The mixture is purified by a strong cation exchange cartridge (BondElute™ SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 7.2 mg (31% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1I)[CH3:2].[CH3:15][O:16][CH2:17][C:18]#[CH:19].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:19]#[C:18][CH2:17][O:16][CH3:15])[CH3:2]
Reactant: C#CCOC
Reactant: CCOC(=O)COc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccccc1C#CCOC
Reaction time: 4 h

Procedure:
A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the above prepared (2-iodo-phenoxy)-acetic acid ethyl ester, 128 ml of acetonitrile, 5.793 g (2 eq.) of 3-methoxy-1-propyne, 17.28 ml (3 eq.) of NEt3, 1.45 g (0.05 eq.) of (PPh3)2PdCl2, and 0.394 g (0.05 eq.) of CuI. After stirring for 4 h the bulk of the solvent was removed i. V. and the residue distributed between HCl and EtOAc. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/EtOAc=8/2), yielded 9.54 g of the title compound as light brown oil, MS: 248.2 (M)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[Cl:12].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH:23]=[O:24].O>CCCCCC.C(OCC)C>[Cl:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[OH:24]
Reactant: Clc1sccc1Br
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccc2ccccc2c1)c1ccsc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Under nitrogen atmosphere, to a solution of 3.2 mL of 1.57 M n-butyllithium in hexane in 7 mL of diethyl ether was added a solution of 1.00 g of 3-bromo-2-chlorothiophene in 8 mL diethyl ether at −78° C., and stirred at this temperature for 1 hour. At the same temperature, 0.87 g of 2-naphthaldehyde was added, stirred for 3 hours while raising the temperature to room temperature, then added with water, extracted with ethylacetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20-1:5), to afford 1.18 g of the title compound as colorless crystals.
Reaction SMILES: [BH4-].[Li+].C([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:11]([O:22][CH3:23])[CH:10]=1)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH3:23][O:22][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][OH:6])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCOCOc1ccc(CCOC(C)=O)cc1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(CCO)cc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
1.2 g (57.1 mmol) of lithium borohydride is added in portions to a solution of 5.4 g (19.0 mmol) of [3-methoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl acetate diluted in 60 ml of tetrahydrofuran. After stirring at 60° C. for 2 hours and then at room temperature for 15 hours, the reaction mixture is poured into 100 ml of a saturated aqueous solution of ammonium chloride cooled to 0° C. and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product obtained is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 50/50 to give 3.55 g (74%) of 2-[3-methoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl-].[NH4+]>[Fe].CCO.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Yield: 71.2 %

Procedure:
A solution of 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.118 g, 0.378 mmol), ammonium chloride (0.0101 g, 0.189 mmol) in 4:1 EtOH/water (2 mL) was treated with iron (0.211 g, 3.78 mmol) and refluxed for 2 hours. The solvent was removed and the residue taken in EtOAc-water and filtered through glass fiber filter paper. The organic phase was separated, dried (phase separator silicone treated filter paper), and concentrated to provide 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (0.076 g, 71% yield) as a yellow gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.C(N(CC)C(C)C)(C)C.Br[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:27].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[Cl:35][C:30]1[CH:29]=[C:28]([CH:26]([N:1]2[CH2:6][CH2:5][O:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)[CH3:27])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: CC(Br)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 89.4 %

Procedure:
tert-Butyl (2R)-morpholin-2-ylmethylcarbamate (2.00 g) in N,N-dimethylformamide (16 ml) was treated with N,N-diisopropylethylamine (1.6 ml) followed by 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g). After stirring for five days at room temperature, further portions of 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g) and N,N-diisopropylethylamine (1.6 ml) were added and stirring continued for 24 h at room temperature. The solution was treated with dichloromethane (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) and the mixture shaken vigorously. The organic phase was separated and applied equally onto sulphonic acid ion exchange cartridges (5×10 g Isolute SCX, pre-treated with methanol). The cartridges were each eluted with methanol (one column volume) followed by 10% 0.880 ammonia in methanol (one column volume); evaporation in vacuo of the combined basic fractions gave the title compound as a clear colourless gum (3.22 g)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 56.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.053 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.043 g, 0.103 mmol, 56.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (m, 1H), 7.78 (s, 1H), 7.50 (m, 1H), 7.44 (s, 1H), 7.36 (t, J=8.03 Hz, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 4.54 (d, J=5.36 Hz, 2H), 2.33 (s, 3H). LC-MS (ES−) m/z 417.04, 419.01 [M−1]. LC-MS (ES+) m/z 418.79, 420.06 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1>O>[CH:22]1[CH:21]=[CH:20][C:19]2[S:15][N:16]=[C:17]([N:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:28][CH2:29]3)[C:18]=2[CH:23]=1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 99 °C
Reaction time: 1.17 h

Procedure:
To de-ionized water (2.0 Lit), was added 5-(2-chloroethyl)-6-chloro-oxindole (100 g) and 1-(1,2-benzisothiazol-3-yl)piperazine (210 g) at 30-35° C. The mixture was slowly heated under stirring to 98-100° C. over 60-80 minutes. The resultant mass was stirred for 10-15 hours at 98-100° C. After completion of reaction as monitored by HPLC, the suspended solid material was filtered at 98-100° C. The wet cake so obtained was suspended in de-ionized water (2.0 Lit) and heated to 90-95° C. and maintained at this temperature for 30 minutes. The solid suspension was filtered at 90-95° C. The wet cake was further added to isopropyl alcohol (1.5 Lit) and stirred for 2 hours at 30-35° C. The solids were filtered and washed with isopropyl alcohol (500 ml) and dried under vacuum at 50-55° C. for 7-8 hours till moisture content was not more than 1.0% w/w.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](NC(=O)CC4C=CC(F)=CC=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:44]=[CH:43][CH:42]=[C:41](C(O)=O)[C:40]2=[O:48])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[C:8]2[CH:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:41]4[C:40](=[O:48])[N:39]([C:36]5[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=5)[CH:44]=[CH:43][CH:42]=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1nccc2c1ccn2-c1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2c1ccn2-c1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 8 h
Yield: 14.7 %

Procedure:
Bis-tert-butyl 1-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl-dicarbamate (Compound B of Example 3, 0.18 g, 0.043 mmol, 1.0 eq) was added to a solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.011 g, 0.047 mmol, 1.1 eq) and TBTU (0.018, 0.047 mmol, 1.1 eq) in DMF (0.50 mL) at room temperature. Diisopropylethylamine (0.008 mL, 0.047 mmol, 1.1 eq) was added to the reaction mixture and stirring was continued for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (YMC C-18 column, 30 min. gradient 25-90% aq. MeOH with 0.1% TFA). The appropriate fractions were concentrated in vacuo and the residue treated with anhydrous HCl (4 N in dioxane) at 0° C. The solution was concentrated in vacuo and the later procedure repeated three times. The residue was triturated with Et2O, discarding the filtrate and the solid was dried in vacuo to afford the title compound (0.003 g, 17%) as a white solid. 1H NMR (CD3OD) δ 7.85-7.87 (m, 2H), 7.56-7.63 (m, 3H), 7.24-7.46 (m, 6H), 7.03-7.09 (m, 3H), 6.94 (br m, 1H); MS(ESI+) m/z 440 (M+H)+, calc: 440.1523, found: 440.1517.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-methoxyphenyl]acetic acid (1.8 g, 6.61 mmol) was dissolved in DMF (5 ml) and azetidine (0.566 g, 9.92 mmol), DIEA (3.46 ml, 19.8 mmol), and HATU (4.02 g, 10.6 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.O>[C:3]([C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:5][CH2:6][C:7]([F:8])([F:9])[F:10])[CH3:11])#[N:4]
Reactant: CC(N)(C#N)CCC(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C#N)(CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
8.7 g (52.36 mmol) of rac-2-amino-5,5,5-trifluoro-2-methylpentanonitrile from Example 60A were initially charged in 128 ml of tetrahydrofuran/water=9/1, and 22.43 g (162.3 mmol) of potassium carbonate were added. At 0° C., 8.93 g (52.36 mmol) of benzyl chloroformate were added dropwise. Then the mixture was allowed to warm up gradually to room temperature and stirred at room temperature overnight. The supernatant solvent was decanted off, the residue was twice stirred with 100 ml each time of tetrahydrofuran, and then the supernatant solvent was decanted off each time. The combined organic phases were concentrated and the crude product was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient 9/1 to 4/1). 11.14 g of the title compound were obtained (68% of theory).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10].C(=O)(O)[O-].[Na+]>CO.ClCCl>[C:9]([O:12][C:13]1[CH:14]=[C:15]([Br:1])[C:16]2[N:23]([CH3:24])[CH:22]3[CH2:25][CH:18]([CH2:19][CH2:20][N:21]3[CH3:26])[C:17]=2[CH:27]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)C1CCN(C)C(C1)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1cc(Br)c2c(c1)C1CCN(C)C(C1)N2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.5 %

Procedure:
N-Bromosuccinimide (2.40 g) was added in three portions to a solution of 3.50 g of crude 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate in 135 ml of deoxygenated methanol. The resulting solution was stirred at room temperature for five minutes and then diluted with dichloromethane and a saturated sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. Column chromatography of the oil (silica gel elution with triethylamine-methanol-ethyl acetate) afforded 1.80 g (33%) of 10-bromo-1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocine-8-ol acetate as a solid.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCNCC2)nc(N2CCOCC2)n1

Procedure:
Reaction of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidine-carboxylate (0.23 g, 0.37 mmol) with TFA (0.45 mL) in CH2Cl2 (8 mL) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole, which was treated subsequently with methanesulfonyl chloride and Et3N in CH2Cl2. The reaction mixture was purified by chromatography on silica eluting first with hexanes/EtOAc (1:1) and then hexanes/EtOAc (3:5) to give 0.13 g (67% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 256-258° C.; 1H NMR (CDCl3) δ 7.99 (dd, J=8.4, 0.7 Hz, 1H), 7.55 (t, JHF=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.06 (s, 3H), 4.02-3.89 (m, 6H), 3.87-3.76 (m, 4H), 2.92-2.75 (m, 6H), 2.24-2.16 (m, 2H), 2.10-1.97 (m, 2H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.6; H, 5.3; N, 18.6%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(Cl)Cl.CC#N>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:27]2[CH2:28][CH:29]3[O:31][CH:25]([CH2:24][N:23]([CH2:22][CH:11]([OH:10])[CH2:12][O:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:30]3)[CH2:26]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(OCC(O)CN2CC3CNCC(C2)O3)cc1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(OCC(O)CN2CC3CN(Cc4ccc(F)cc4)CC(C2)O3)cc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 4-fluorobenzyl bromide (14.17 mg, 0.075 mmol) in DCM (0.5 mL) of was added, together with TEA (20 mg, 0.2 mmol) to a solution of 4-{[2-hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-propyl]oxy}benzonitrile (Preparation K; 15.2 mg, 0.05 mmol) in MeCN (0.5 mL). The mixture was stirred at 50° C. for 4 days before being concentrated in vacuo. The resulting residue was dissolved in CHCl3 and added to a solid-phase extraction plug (CBA, 0.4 g). The plug was washed with CHCl3 (4×0.3 mL), and the product was finally eluted with CHCl3:MeOH:TEA (5×0.3 mL of 8:1:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9](O)[C:8]1=[O:15])=[O:5])[CH3:2].P(Br)(Br)([Br:18])=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[Br:18][C:9]1[C:8](=[O:15])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]([CH3:13])=[CH:11][N:10]=1
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Reactant: O=P(Br)(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Temperature: 25 °C

Procedure:
A stirred slurry of 505 mg (2.38 mmol) of 1-(ethoxycarbonyl-methyl)-3-hydroxy-6-methylpyrazinone and 756 mg (2.64 mmol) of phosphorous oxybromide in 1.7 ml of CHCl3 was stirred at 50° C. under a slow stream of Ar for 1.5 h, then allowed to cool to rt overnight. The reaction mixture was diluted with CHCl3 and ice water, basified with NH4OH, and extracted with CHCl3. The combined organic layers were dried over Na2SO4, treated with activated carbon, filtered and concentrated to give 2-5 as an orange colored solid: 1H NMR (CDCl3) δ7.06 (s, 1H), 4.77 (s, 2H), 4.27 (q, 2H, 7.2 Hz), 2.24 (s, 3H), 1.31 (t, 3H, 7.2 Hz).