Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:35][C:34]([F:37])([F:36])[CH2:33]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:33][C:34]([F:37])([F:36])[CH2:35]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(Cl)ccc1CN1CC(F)(F)C1)[C@@H]1CCCN1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
TFA (1 mL) was added to a stirred solution of N-{5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (64.2 mg, 0.14 mmol) in CH2Cl2 (2 ml) at 0° C. After 3 h, another 0.3 mL TFA was added. After 30 additional min the reaction mixture was concentrated and the residue was partitioned between CH2Cl2 and 10% NaHCO3. The CH2Cl2 layer was washed with water and brine, dried (Na2SO4) and evaporated to give N-{5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzyl}-L-prolinamide (45.0 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 1.70 (m, 2H), 1.90 (m, 2H), 2.16 (m, 1H), 2.85-3.04 (m, 2H), 3.58 (t, J=12.1 Hz, 4H), 3.73 (m, 3H), 4.37-4.52 (m, 2H), 7.19 (m, 2H), 7.32 (d, J=2.19 Hz, 1H), 8.45 (br s, 1H).
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[C:9](OC)=[O:10])=[N+:2]=[N-:3].[BH4-].[Na+]>>[N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][OH:10])=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CO

Procedure:
Methyl cis-3-azido-4-oxoazetidine-2-carboxylate was reduced with sodium borohydride as described in Preparation 3 and the product was chromatographed on silica gel with ethyl acetate as eluant to give cis-3-azido-2-hydroxymethyl-4-oxoazetidine.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:16])[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[N:6]=1.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:20](Cl)[N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:20]([N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=3[N:6]=[C:5]2[CH:4]([F:3])[F:16])[N:19]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.6 %

Procedure:
NaH (148 mg, 6.17 mmol) was added to a solution of 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (638 mg, 3.22 mmol) in DMF (10 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 45 min. 2,6-Dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (800 mg, 2.93 mmol) was then added and the resulting mixture was stirred at room temperature for 5 days, quenched with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (3×), dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with hexanes/EtOAc (100:0 to 60:40), gave 2-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-tetrahydro-2H-pyran-2-yl-9H-purine (645 mg, 51%): 1H NMR (CDCl3) δ 8.38 (s, 1H), 7.52 (t, JHF=54.2 Hz, 1H), 7.37-7.31 (m, 2H), 6.84 (m, 1H), 5.86 (dd, J=10.7, 2.5 Hz, 1H), 4.23 (ddd, J=10.0, 3.8, 1.8 Hz, 1H), 4.07 (s, 3H), 3.83 (dt, J=11.7, 2.8 Hz, 1H), 2.26 (m, 1H), 2.14 (m, 1H), 2.03 (m, 1H), 1.91-1.69 (m, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C@@H:21]([CH2:24][OH:25])[O:20][C:19]=3[CH:26]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C@@H:21]([CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[O:20][C:19]=3[CH:26]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@H](CO)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1COc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.550 g; 0.0048 mol) at 0° C. was added drop-wise to a solution of (7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-yl)-methanol (0.73 g; 0.00238 mol) and triethyl amine (0.48 g; 0.0048 mol) in dichloromethane (10 mL). The mixture was stirred at 0° C. for 45 minutes, and then diluted with dichloromethane (20 mL), washed with water, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 1:1) to give methansulfonic acid 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(S)-yl-methyl ester as a foam (0.67 g; 73%): MS (M+H)+ 385.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([O:13]C(=O)C(C)=C)[CH2:9][CH:10](C)C)[C:3]([O:5][CH2:6]C)=[O:4].CO.[C:22](=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[F:19][C:2]([F:1])([CH:8]([OH:13])[CH:9]([CH3:10])[CH3:22])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OCC
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(F)(F)C(O)C(C)C
Yield: 85 %

Procedure:
To a mixture of 50 g of Intermediate 2 (Example 2), 200 g of methanol and 250 g of benzene was added 0.3 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with hexane. The hexane solution was washed, dried, and concentrated, obtaining 45.78 g (yield 85%) of methyl 2,2-difluoro-3-hydroxy-4-methylpentanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]([CH:22]=[O:23])=[C:20]([Cl:24])[N:19]=[C:18]2[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=1)([OH:3])=[O:2].[C-]#N.[Na+].[C:32](O)(=[O:34])C>CO.[O-2].[O-2].[Mn+4]>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:21]([C:22]([O:34][CH3:32])=[O:23])=[C:20]([Cl:24])[N:19]=[C:18]2[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][CH:15]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of 1.45 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.91 g of sodium cyanide in 20 mL of methanol at 25° C. was added 0.32 mL of acetic acid followed by 7.25 g of manganese dioxide. The resulting mixture was stirred at 25° C. for 40 hours. The reaction mixture was filtered through Celite®, and the filtrate diluted with water. The aqueous solution was adjusted to pH 3 using hydrochloric acid and extracted with methylene chloride. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized from diethyl ether to afford 0.90 g of methyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxylate (m.p. 154°-155° C.). NMR (200 MHz, DMSO-d6); δ 12.75 (br s, 1H), 7.73 (d, 1H) 7.58 (t, 1H), 7.46 (t, 1H), 7.34 (m, 3H), 7.07 (d, 2H), 5.63 (s, 3H), 3.78 (s, 3H), 2.67 (t, 2H), 1.56 (quint., 2H), 1.29 (sext., 2H), 0.83 (t, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:13](Cl)(=[O:15])[CH3:14]>[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[C:13]([NH:12][C@@H:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:9]([OH:11])=[O:10])(=[O:15])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.5 %

Procedure:
To a solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na2CO3 (resulting solution at pH 10) was added acetyl chloride (0.5 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1N HCl. The organic phase was dried over Na2SO4, filtered and evaporated to an oil, which solidifies to yields 70 mg (60%) of the desired material. This crude intermediate was used as such in the next step.
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[C:3]#[C:4][C@@H:5]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CO.[Ni]>[CH3:1][CH:2]([CH3:34])[CH2:3][CH2:4][C@@H:5]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: C=C(C)C#C[C@H](CC1CCOCC1)N1CC[C@@H](CC(=O)OC)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C[C@@H]1CCN([C@H](CCC(C)C)CC2CCOCC2)[C@H](c2ccc(C(F)(F)F)cc2)C1

Procedure:
A solution of methyl {(2S,4R)-1-[(1S)-4-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (ester intermediate from the preparation of Example 20, 221 mg, 0.46 mmol) in MeOH (10 ml) was hydrogenated over Raney Nickel (500 mg) for 4 hrs at 45 psi. The catalyst was removed by filtration washing with CH2Cl2. The filtrate was evaporated and the residue was purified by chromatography (silica, 25% Et2O/isohexane) to give the alkane (154 mg) as an oil. 1H NMR (360 MHz, CDCl3): δ 0.62-0.70 (1H, m), 0.81-1.03 (10H, m), 1.08-1.95 (12H, m), 2.17-2.31 (4H, m), 2.95 (1H, brd, J 12.0), 3.33 (1H, t, J 11.6), 3.41 (1H, t, J 11.5), 3.58 (1H, d, J 9.0), 3.64 (3H, s), 3.86 (1H, brd, J 10.6), 3.92 (1H, brd, J 11.0), 7.38-7.40 (2H, d, m), 7.53 (2H, d, J 8.1); M/Z (ES+) 484 (MH+).
Reaction SMILES: [CH3:1][S:2](Br)(=[O:4])=[O:3].[CH2:6]([O:9][CH3:10])[CH:7]=[CH2:8].OO.C(N(CC)CC)C>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([CH:8]=[CH:7][CH2:6][O:9][CH3:10])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Br
Reactant: C=CCOC
Agent: OO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC=CS(C)(=O)=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
159 g (1 mole) of methanesulfonyl bromide are slowly added dropwise, at 45° C., to a mixture of 78 g (1.07 moles) of methyl allyl ether, 7.5 g of zinc chloride and 3.3 ml of 50% strength hydrogen peroxide. After the exothermic reaction has subsided, the mixture is stirred for a further 30 minutes and is diluted with 450 ml of benzene, and 135 g (1.33 moles) of triethylamine are added at room temperature, whilst cooling. After 2 hours, the precipitate is filtered off and the solvent is distilled off. Distillation of the residue gives 125 g of 1-methylsulfonyl-3-methoxy-prop-1-ene, boiling point 114°-115° C./0.3 mm Hg. According to the NMR spectrum, the product is a mixture of cis and trans isomers in the ratio of 15:85.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]1[O:14][C@H:13]1[CH2:15]Cl.ClCCl.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([C:10]#[N:11])[CH2:15][CH:13]2[CH2:12][OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClC[C@H]1CO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#C[C@@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Temperature: -25 °C
Yield: 64.2 %

Procedure:
3,4-Dichlorophenyl acetonitrile (40 g, 215 mmole) was dissolved in dry tetrahydrofuran (THF, 350mL) under nitrogen atmosphere, The solution was cooled to −25° C. and soda amide (8.3 g, 215 mmol) was added portion wise maintaining the temperature of the reaction mass −25° C. The reaction mixture was allowed to warm to room temperature and maintained for 2 hours. It was then cooled to −25° C. A solution of R-(−) epichlorohydrin (19.89 g, 215 mmol) in tetrahydrofuran (50 mL) was added drop wise at −25° C. followed by the portion wise addition of soda amide (8.3 g, 250 mmol). The temperature of the reaction mass was then gradually raised to room temperature over a period of 8 hours. The reaction was monitored by TLC (dichloromethane/hexane (1:1)). The reaction mass was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (3×500 mL).The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 58 g of crude oil. The crude oil was purified by column chromatography (silica gel, dichloromethane/hexane (9:1) to yield 33.4 g (64%) of product. 1H NMR δ(300 MHz,CDCl3): 1.59-1.67 (3H,m), 1.88-1.97 (1H,m), 3.72-3.79 (1H,m), 4.06-4.12 (1H,m), 7.13-7.17 (1H,m) 7.39-7.52 (2H,m).
Reaction SMILES: [CH:1]1([CH3:12])[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH:3]([OH:11])[CH2:2]1.N1C=CC=CC=1.[C:19](Cl)(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[C:19]([OH:37])(=[O:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[CH:1]1([CH3:12])[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH:3]([OH:11])[CH2:2]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Agent: CC1CCC(C(C)(C)O)C(O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250 mL one necked bottomed flask, was charged with 7.0 g (0.040 moles) of 3,8-p-menthanediol, 100 mL of anhydrous methylene chloride and 6.9 g (0.87 moles) of anhydrous pyridine. 25.5 g (0.085 moles) of Linoleoyl chloride was pre-dissolved in 25-30 mL of anhydrous methylene chloride and charged into the additional funnel. The acid chloride solution was then added dropwise to the solution at room temperature under a nitrogen blanket over a period of 30 minutes. Upon completion of the addition, the reaction was stirred for two hours before the addition funnel was replaced with a reflux condenser. The reaction was then heated to reflux for two additional hours before cooling to ambient temperature and stirring overnight.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(N[C@H](C(=O)O)C1CCCCC1)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H](NC(=O)OCc2ccccc2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-benzyloxycarbonylamino-cyclohexyl-acetic acid (5.4 g, 18.66 mmol) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 18.66 mmol) in dimethylformamide were added HATU (7.09 g, 18.66 mmol) and collidine (2.46 ml, 18.66 mmol) at 0° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. The mixture was evaporated and separated between ethyl acetate and sodium bicarbonate solution. The organic layer was washed with aqueous solution (pH 4), dried and evaporated. The resulting residue was taken up in ethyl acetate and washed with potassium hydrogen sulfate solution, dried and evaporated to give the desired product. Yield: 8.29 g (91%), MS m/z: 488.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2=[CH:11][CH:12]=[C:13]3[C:22]([N:21]=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[C:19]4[C:23](=[O:30])[NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[N:14]3)=[C:9]2[CH:8]=[CH:7][CH:6]=1)=O.[BH4-].[Li+]>O1CCCC1.CC(O)C>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][NH:24][C:23]([C:19]1[C:20]2[C:15](=[N:14][C:13]3[C:22]([N:21]=2)=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[C:10]2=[CH:11][CH:12]=3)[CH:16]=[CH:17][CH:18]=1)=[O:30]
Reactant: COC(=O)c1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(CO)cccc4c3nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a solution of 11-(2-dimethylamino-ethylcarbamoyl)-benzo[a]phenazine-4-carboxylic acid methyl ester (317 mg) in tetrahydrofuran (18 mL) and 2-propanol (10 mL) at 0° C. was added lithium borohydride (2.0M solution in tetrahydrofuran, 1.97 mL) The reaction mixture was stirred at room temperature overnight, and then quenched with ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated in vacuo. The residue was purified using flash chromatography (10% MeOH in dichloromethane) to yield the title compound as a yellow solid (98 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:33][C:34]([O:36][CH2:37]C)=[O:35]>C1COCC1>[C:34]([O:36][CH3:37])(=[O:35])[CH3:33].[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)OC(=O)N1CCC(CCC2CCNC2=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)=O
Temperature: -20 °C

Procedure:
To a stirred solution of 36a (340 mg, 1.1 mmol) in THF (10 mL) at -78° C. was added NaN(TMS)2 (1.0M in THF, 1.1 mL). After 15 minutes ethyl bromoacetate (250 uL, 2.2 mmol) was added and the reaction mixture to warm to -20° C. After 2 hours the reaction was quenched with HOAc (0.1 mL) and then concentrated. Flash chromatography (silica gel, 50% ethyl acetate/hexanes) gave 37a (380 mg, 90%) as an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[CH2:21][OH:22])[CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:22][CH2:21][C:11]1[CH:12]=[C:13]([O:16][C:17]([F:19])([F:20])[F:18])[CH:14]=[CH:15][C:10]=1[O:9][CH:6]1[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(OC(F)(F)F)ccc1OC1CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.31 mL, 0.46 g, 4.0 mmol) was added dropwise to a stirred, cooled (−10° C.) solution of 2-(cyclopropyloxy)-5-(trifluoromethoxy)benzenemethanol (WO9900368, 0.5 g, 2.0 mmol) and triethylamine (0.56 mL, 0.40 g, 4.0 mmol) in dichloromethane (10 mL) and the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 20 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.28-7.22 (3H, m), 5.20 (2H, s), 3.80-3.77 (1H, m), 3.01 (3H, s), and 0.85-0.79 (4H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[N:17]1.COCCOC.C(N(CC)CC)C>CO.C(Cl)Cl>[CH3:15][N:16]1[C:20]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:19][CH:18]=[N:17]1
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1cnc2cc(-c3ccnn3C)ccn12
Temperature: 85 °C

Procedure:
A dried flask equipped with a reflux condenser and a nitrogen line was charged with methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (200 mg, 0.784 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.869 mmol) and PdCl2(dppf)dichloromethane adduct (64 mg, 0.078 mmol). To the flask was added 3 mL 1,2-dimethoxyethane containing 1% absolute ethanol, followed by addition of triethylamine (0.22 mL, 1.57 mmol). The flask was degassed under nitrogen and heated at 85° C. for 10 hours. The reaction mixture was allowed to cool to ambient temperature and then diluted with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 4% MeOH/DCM as eluent to afford 47.4 mg of pure, desired product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=O>>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cnn2c(-c3ccncc3)ccnc12

Procedure:
Following the general procedure of Example 8 and reacting (3-amino-1H-pyrazol-4-yl)phenyl-methanone with 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one gave the desired product, mp 185°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[O:42]([NH2:44])[CH3:43].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:44][O:42][CH3:43])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A vessel was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]benzoic acid (1.0 g, 3.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (677 mg, 3.53 mmol) and hydroxybenzotriazole (HOBT) (541 mg, 3.53 mmol) in N,N-dimethylformamide (DMF, 7.0 mL) and was stirred at room temperature for 30 min. To this solution methoxylamine hydrochloride (0.3 g, 3.53 mmol) was added and reaction mixture was stirred for another 10 min. The reaction mixture was cooled to 0° C. by using an ice bath. To this reaction mixture diisopropylethylamine (1.2 mL, 7.06 mmol) was added and the mixture was stirred at room temperature overnight. After concentrating under vacuum, the residue was worked up by using a saturated aqueous solution of NaHCO3 and CH2Cl2. The organic phase was washed with brine then dried over MgSO4 and filtered. The CH2Cl2 was removed by rotary evaporation. The crude material was loaded on silica gel column and eluted by MeOH in CH2Cl2 with NH4OH 0.1%, which gave the desired product 2-[(2, 5-dichloro-4-pyridinyl) amino]-N-(methyloxy)benzamide (850 mg, 2.72 mmol, 77% yield) MS: M(C13H11C12N3O2)=312.15, (M+H)+=312, 314; 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 9.57 (br. s., 1 H) 8.72 (s, 1 H) 8.22 (s, 1 H) 7.51 - 7.67 (m, 3H) 7.25 (s, 1 H) 7.07 - 7.21 (m, 1 H) 3.92 (s, 3 H).