Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)cc3)CC1)O2
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)cc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-[2-(4-Chloro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (200 mg, 0.433 mmol) was suspended in DCM (10 ml). TEA (0.09 ml, 0.6 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-chloro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (130 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the requisite hydroxamic acid as a light yellow solid (89 mg, hydrochloride salt).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH3:21])=[C:8]([C:18]([NH2:20])=[O:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH3:21])=[C:8]([C:18]([NH2:20])=[O:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cc(F)cc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1C(N)=O
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide (61 mg, 0.19 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (61 mg, 99%). LCMS calculated for C16H13ClF2NO (M−NH2)+: m/z=308.1. found: 308.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])N(OC)C)[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]1)=[O:17].[CH2:42]([Mg]Br)[CH3:43].C1COCC1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:40])[CH3:41])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])[CH2:42][CH3:43])[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (22.7 g) in THF (20 ml) was added 1M-ethylmagnesium bromide-THF solution (119 ml) at room temperature, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:2) was concentrated under reduced pressure to give the object product (14.96 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C=C/C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
To a solution of ethyl (2E)-3-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylate (0.62 g, 1.3 mmol) in tetrahydrofuran (5 ml)-methanol (5 ml) was added 1N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 12 hrs. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether to give (2E)-3-[3{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylic acid (0.41 g, yield 70%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:31]([O:26][C@@H:20]([C:3]1[C:4]([CH3:19])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]=2[CH3:11])[C:2]=1[Cl:1])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H](O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 2.5 h
Yield: 56.6 %

Procedure:
A solution of (S)-ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (3.08 g, 7.81 mmol) in CH2Cl2 (130 ml) was treated with tert-butyl acetate (73.9 ml, 547 mmol) and perchloric acid (2.014 ml, 23.44 mmol), and the reaction was stoppered. The reaction was stirred for 2.5 hrs, then diluted with CH2Cl2 (130 ml) and carefully quenched with sat. NaHCO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give a light amber mobile oil. The crude product was purified by flash silica gel column chromatography, eluting with 10%-30% EtOAc in hexanes, to afford the product, (S)-ethyl 2-(tert-butoxy)-2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (2.05 g, 4.42 mmol, 56.5% yield) as a viscous oil, which began to crystallize upon standing. 1H NMR (500 MHz, CDCl3) δ: 7.87 (t, J=1.5 Hz, 1H), 7.74 (dt, J=7.3, 1.5 Hz, 1H), 7.46-7.36 (m, 2H), 5.63 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 2.68 (s, 3H), 2.51 (s, 3H), 1.26 (s, 9H), 1.21 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:15])[C:3]1=[O:16].[ClH:17]>CN(C)C=O>[ClH:17].[NH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:16])[C:4](=[O:15])[NH:5]2
Reactant: Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(=O)[nH]c2cc(N)ccc21
Yield: 98 %

Procedure:
A solution of 0.5 g (2.3 mmol) 1-methyl-6-nitroquinoxaline-2,3(1H,4H)-dione in 25 ml dimethylformamide was hydrogenated at atm. pressure by using 5% Pd-c (0.1 g) as a catalyst. The reaction mixture was added 1 ml 4N hydrochloric acid, filtered and evaporated in vacuo. The residue was stirred with ethyl acetate. The precipitate was filtered off to give 0.5 g (98%) of 6-amino-1-methyl-quinoxaline-2,3 (1H,4H)-dione hydrochloride. NMR (DMSO-d6 +D2O): 7.3 (1H, d), 7.13 (1H, s), 7.1 (1H, d), 3.5 (3H, s), 2.6 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:11][OH:12])=[CH:8][N:9]=1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]([Cl:19])=[N:11][OH:12])=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ncc(C(Cl)=NO)s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
To a solution of Example 30C (12 g, 42 mmol) in N,N-dimethyl formamide (80 mL) was added N-chlorosuccinimide (5.6 g, 42 mmol). The mixture was stirred at ambient temperature for 16 hours, water (1000 mL) was added and the resulting suspension was filtered. The solids were dried in a vacuum oven to provide 12.8 g of the title compound (95%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.04 (dd, J=8.82, 2.94 Hz, 1H) 7.26 (d, J=2.94 Hz, 1H) 7.54 (d, J=9.19 Hz, 1H) 7.66 (s, 1H) 12.48 (s, 1H); MS (ESI) m/z 319.9 (M+H)+.
Reaction SMILES: [CH:1]12[N:8](C(OC(C)(C)C)=O)[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:16]([O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:5]12[NH:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:16]([O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:4]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
A solution of 3-(9H-fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate in DCM (2 mL) from the step 1 was treated dropwise with TFA (2.2 g, 1.5 mL, 19.5 mmol) at room temperature and the reaction mixture was stirred for 1 h. The solvents were removed under reduced pressure and the crude material was dissolved in 1 N HCl (2 mL) and washed with ether. The solution was basified with saturated bicarbonate solution and the aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a solution of (9H-fluoren-9-yl)methyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate in DCM (2 mL), which was used directly for the next step. LC/MS m/z 335.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14](=[O:15])[CH2:13][Cl:12])=[C:3]([CH:9]([OH:11])[CH3:10])[CH:4]=1
Reactant: CC(O)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCl
Product: CC(O)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared by from 1-(2-amino-5-bromo-phenyl)-ethanol and chloroacetyl chloride generally according to the procedure described in Example 1. 1H-NMR (DMSO-d6) δ 10.11 (s, 1H), 7.64 (d, J=8.63 Hz, 1H), 7.57 (d, J=2.31 Hz, 1H), 7.44 (dd, J=2.34, 8.57 Hz, 1H), 5.77 (d, J=3.88 Hz, 1H), 4.93-4.89 (m, 1H), 4.35, (s, 2H), 1.31 (d, J=6.45 Hz, 3H); MS (ES) m/z 290/292/294 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].Br[CH:14]([F:26])[C:15]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25]>>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:14]([F:26])[C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: Fc1c(F)c(F)c(C(F)Br)c(F)c1F
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(F)c1c(F)c(F)c(F)c(F)c1F

Procedure:
α,2,3,4,5,6-Hexafluorobenzyl 3-(2,2-dichlorovinyl)2,2-dimethylcyclopropanecarboxylate was prepared from 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid and α-bromopentafluorobenzyl fluoride following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by p.m.r. spectroscopy. Chemical shift δppm (solvent CDCl3): 1.0-2.5 (8H, m, (CH3)2 and cyclopropyl protons); 5.67 and 6.24 (1H, both d of d, J=8 Hz and J=2 Hz, CH=); 7.53 (1H, d, J=52 Hz, CHF).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]1>>[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:2])=[N:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reactant: Cn1ccc(N)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)Nc2ccn(C)n2)n(C)n1
Yield: 48 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of N,N-dimethylhydrazine, to the title compound (58 mg, 48%) which was obtained as a yellow gum. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([CH3:10])[CH3:9])[C:3](=[CH2:7])[CH:4]([OH:6])[CH3:5].[C:11](O)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:5][CH:4]([O:6][C:11](=[O:15])[CH:12]=[CH:13][CH3:14])[C:3](=[CH2:7])[CH:2]([CH3:1])[CH:8]([CH3:10])[CH3:9]
Reactant: C/C=C/C(=O)O
Reactant: C=C(C(C)O)C(C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C(C)OC(=O)C=CC)C(C)C(C)C
Temperature: 125 °C
Yield: 70 %

Procedure:
The obtained 4,5-dimethyl-3-methylene-hexan-2-ol (280 g), crotonic acid (188 g,), PTSA (2.5 g), and toluene (250 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid 1,3,4-trimethyl-2-methylene-pentyl ester (290 g) with a boiling point of 114° C. at 11 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:33]1[CH:32]=[C:31]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:3]=2)[CH:35]=[N:34]1
Reactant: Clc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
4-(4-(5-Chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0400 g, 0.127 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0370 g, 0.191 mmol) and potassium carbonate (0.0527 g, 0.381 mmol) were suspended in a mixture of DME (2 mL) and water (1 mL) and de-gassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.00734 g, 0.00635 mmol) was added and the reaction sealed and heated at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5%-6% (9:1 MeOH:NH4OH)/DCM) to furnish 4-(4-(5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0160 g, 0.046 mmol, 36.4% yield). MS (apci) m/z=347.1 (M+H).
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)CO)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 24 h
Yield: 71.2 %

Procedure:
A mixture of 12.77 g of 3-(2-hexyl-5-tetradecylphenoxy)-1,2-propanediol, 13.5 g of trityl chloride and 40 ml of pyridine was stirred for 24 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, water and dried. This crude material was chromatographed on silica gel, eluting with 17% ethyl acetate in hexane, giving 14 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(OC)c1
Product: COc1cccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)c1

Procedure:
The title compound, yellow solid, MS: m/e=306.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-3-methoxybenzene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>O.CO>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(CNc2ccccc2)c1
Reaction time: 20 h

Procedure:
A mixture of 15.2 g 2-hydroxy-5-methoxy benzaldehyde, 93 g of aniline and 100 ml of methanol was stirred at 25° for 20 hours. The mixture was then cooled with an ice-bath and stirred, and 3.9 g of sodium borohydride was added slowly. The mixture was stirred for 1 hour at 25°, 150 ml of water was added and the pH was adjusted to 7.0 with 2.5N hydrochloric acid. The resultant solid was collected, washed with water and purified by chromatography on silica gel using 3:17 ethyl acetate:n-hexane as an eluant. A 17.7 g yield of N-(2-hydroxy-5-methoxybenzyl)aniline was obtained. M.p. 82°-84°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([C:16](=O)[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.NO.[N:25]1C=CC=CC=1>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH2:25])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: Cl
Agent: NO
Solvent: CCO
Product: NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A portion (16 g) of 4,5-dihydro-2-(2-phenylethyl)-6H-imidazo[4,5,1-ij]quinolin-6-one obtained in Example 1 was suspended in ethanol (160 mL) and hydroxylamine hydrochloride (8.06 g) and pyridine (14.1 mL) were added; following stirring for 17 hrs at room temperature, the precipitating crystals were collected by filtration and washed successively with ethanol and ether to yield the titled compound as colorless crystals (12.0 g).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:5]1)=[N+:2]=[N-:3].[OH-].[Li+]>O1CCCC1.O>[N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([OH:20])=[O:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@@H]1N=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
Benzyl (1R,3S,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (4.4 g) was dissolved in tetrahydrofuran (160 ml) and water (20 ml), and lithium hydroxide (366 mg) was added under ice cooling. After 10 minutes, the mixture was heated to room temperature to continue stirring. After 20 hours, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:10) to obtain the title compound (1.86 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[CH3:18][C:10]1[CH:11]=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][NH:24][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:4][CH:5]=1
Reactant: CC(C)CCN
Reactant: Cc1cc(C(N)=O)ccc1-c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(N)=O)ccc1-c1ccc(CNCCC(C)C)cc1
Reaction time: 12 h

Procedure:
4′-Formyl-2-methylbiphenyl-4-carboxamide (I-4a: 4.3 g, 18.0 mmol) and isoamylamine (36.2 mg, 0.425 mmol) were combined in methanol (100 ml). After 12 hours, the reaction mixture was treated with sodium borohydride (2.10 g, 53.9 mmol). After 1 hour, the reaction mixture was treated with concentrated (37%) aqueous hydrochloric acid solution and the volatiles were removed under reduced pressure. The residue was taken up in 2N sodium hydroxide and extracted with ethyl acetate (2 times). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (E4-01).