Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]2=[O:23])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)oc3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1oc2ccccc2n1C1CCNCC1

Procedure:
3-(1-t-Butyloxycarbonyl-4-piperidinyl)benzoxazolidin-2-one from Step 1 was N-deprotected with HCl in EtOAc using the procedure given in Step 4 of Example 1. The hydrochloride salt of 3-(4-piperidinyl)benzoxazolidin-2-one was obtained as a solid (96% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[OH:15])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[O:15][CH2:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc3ccc(NC(C)=O)cc3c(=O)c2O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2oc3ccc(NC(C)=O)cc3c(=O)c2OCc2ccccc2)cc1
Yield: 95 %

Procedure:
Prepared analogously to Example 5d) starting from 2-(4-methoxyphenyl)-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 95%; TLC (9/1 Chloroform/Methanol) Rf: 0.51; 1H-NMR (d6-DMSO): 10.31 (s broad, 1H), 8.40 (d, 1H), 8.02 (m, 3H), 7.70 (d, 1H), 7.32 (m, 5H), 7.11 (d, 2H), 5.08 (s, 2H), 3.86 (s, H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[CH:21]=[C:22]([S:27]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1
Yield: 47.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150 mg, 0.611 mmol) prepared in Example 14a, 3-chloro-4-fluorobenzenesulfonyl chloride (280 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (127 mg, 47%) as a colorless amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[OH-].[Na+].[SH:13][CH2:14][CH2:15][OH:16]>COC1C=CC(O)=CC=1.O1CCCC1>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][S:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:5]=1)=[CH2:8]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: OCCS
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(CSCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
A polymerization inhibitor, p-methoxyphenol (1.24 g; 0.01 mole), was added to a mixture of 152 g (1.0 mole) of p-(chloromethyl)styrene, 60 g (1.5 moles) of sodium hydroxide and 0.5 liter of tetrahydrofuran. The resulting mixture was boiled, and 78 g (1.0 mole) of 2-mercaptoethanol was added dropwise over 0.5 hour. The boiling was continued for 3 hours. After cooling to room temperature, the reaction mixture was filtered by the same operation as in Example 1, and distilled under reduced pressure (140-145 ° C./1-2 mmHg) to give 93 g of 2-(4-vinylbenzylthio)ethanol as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[BH3-][C:30]#N.[Na+].C(O)(=O)C>CC#N.O.C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([N:18]([CH3:30])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CNC(=O)c1ccc(NC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(N(C)C2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}amino)-N-methylpyridine-2-carboxamide (34 mg, 92 μmol) was dissolved in 1:1 MeCN/water (3 ml) and formaldehyde (50 μl of a 37% wt. soln, 1.8 mmol) followed by NaBH3CN (34 mg, 0.56 mmol) were added. After 10 minutes, acetic acid (40 μl, 0.72 mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction mixture was concentrated at reduced pressure and purified by FCC (DCM/MeOH/NH3 gradient, 98:2:1 to 90:10:1) giving the title compound as colourless oil (7 mg, 19%).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[N:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:37]([CH3:44])([CH3:43])[C:38]([O:40]CC)=[O:39].[OH-].[Na+]>C(O)C>[Cl:4][C:5]1[N:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:22][CH2:23]3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:37]([CH3:44])([CH3:43])[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1nc2ccc(NCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Yield: 91.3 %

Procedure:
633 mg of ethyl 2-[3-chloro-6-[3-[4-(diphenylmethyl)-1-piperazinyl]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate trihydrochloride was dissolved in 6 ml of ethanol; 2.31 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 5 by the addition of 1 N hydrochloric acid. Methanol was added; the crystal precipitated was collected by filtration, washed with water-ethyl acetate and dried to yield 462 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[C:6](Cl)[N:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:18]=2)[N:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([C:4]2[N:5]=[CH:6][C:7]([N:8]3[CH2:9][CH:10]4[O:15][CH:13]([CH2:12][CH2:11]4)[CH2:14]3)=[CH:2][N:3]=2)=[N:18]1
Reactant: Fc1ccccc1Cn1nc(-c2nc(Cl)c(N3CC4CCC(C3)O4)c(Cl)n2)c2cccnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccccc1Cn1nc(-c2ncc(N3CC4CCC(C3)O4)cn2)c2cccnc21

Procedure:
400 mg (0.68 mmol) of 3-[4,6-dichloro-5-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-pyrimidinyl]-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (example XII, step 7) are dissolved in 200 ml of methanol, and 86 mg of ammonium formate are added. Under argon, 26 mg of palladium on activated carbon (10%) are added, and the mixture is heated under reflux for 3 days. The reaction mixture is filtered and the residues are washed with methanol. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 99 mg (35% of theory) of the product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[CH:7]=[C:6]2[C:16]([F:19])([F:18])[F:17].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O.ClCCl.CC(C)=O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[C:7]([N+:20]([O-:22])=[O:21])=[C:6]2[C:16]([F:19])([F:18])[F:17]
Reactant: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc2[nH]c(=O)c([N+](=O)[O-])c(C(F)(F)F)c2cc1OC
Temperature: 25 °C
Yield: 70 %

Procedure:
3.5 g of 6,7-dimethoxy-4-trifluoromethyl-2-(1H)-quinolone are nitrated with 50 ml of a semi-concentrated mixture of nitric acid and sulphuric acid under ice cooling. The mixture is heated to room temperature and poured on water. The precipitation formed is cleaned with Flash Chromatography (silica gel, dichloromethane:acetone 9:1). Yield 70%, melting point 270° C., UV λ max 391 nm (DMSO), IR (KBR) CO: 1670cm-1.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][S:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[S:11][CH:12]=1)C.C1(NC2CCCCC2)CCCCC1.C(OC(=O)CSCC1N=C(N)SC=1)C>>[CH:23]1([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:10]2[S:11][CH:12]=[C:8]([CH2:7][S:6][CH2:5][C:4]([OH:29])=[O:3])[N:9]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)CSCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)CSCc1csc(N)n1
Product: O=C(O)CSCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1

Procedure:
[2-(3,3-Dicyclohexyl-ureido)-thiazol-4-ylmethylsulfanyl]-acetic acid ethyl ester prepared as described in general procedure (A) using dicyclohexylamine and (2-amino-thiazol-4-ylmethylsulfanyl)-acetic acid ethyl ester (prepared by reaction of 4-chloromethyl-thiazol-2-ylamine, ethyl-2-mercaptoacetate and potassium carbonate in DMF for 1 h at room temperature). Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: C([Li])CCC.[I:6][C:7]1[N:8]=[C:9]([CH3:25])[N:10]([C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH3:23])[CH:22]=2)[NH:19][C:18](=[O:24])[CH:17]=[CH:16]3)[C:11]=1I.[Cl-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.O1CCCC1>[I:6][C:7]1[N:8]=[C:9]([CH3:25])[N:10]([C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH3:23])[CH:22]=2)[NH:19][C:18](=[O:24])[CH:17]=[CH:16]3)[CH:11]=1
Reactant: Cc1cc(-n2c(C)nc(I)c2I)cc2ccc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Yield: 23.4 %

Procedure:
n-Butyllithium (16.42 cm3 of a 1.55M solution in n-hexane) was added dropwise to a stirred solution of 6-(4,5-di-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (5.0 g) in tetrahydrofuran (100 cm3) at -30° under nitrogen. After 30 minutes saturated aqueous ammonium chloride solution (20 cm3) was added, and the mixture was warmed to room temperature. The mixture was then basified with saturated sodium carbonate solution to pH 10 (approximately) and extracted with methanol:ethyl acetate (1:19 by volume, 100 cm3) and then methanol:dichloromethane (1:19 by volume, 2×200 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with methanol:dichloromethane, 1:19 by volume, followed by combination and evaporation of the appropriate fractions gave a solid which was recrystallised from methanol/ethyl acetate to afford the title compound, (0.87 g), which was shown spectroscopically to be identical to the product of Preparation 4. Also eluted were fractions which when combined and evaporated afforded a solid, (2.28 g), which was shown to be a mixture of the title compound, 6-(5-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, and 6-(2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:19].[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([F:31])[CH:24]=1>CN(C=O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[C:5]3[CH:10]=[CH:9][C:8]([C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]#[N:14])=[CH:7][C:6]=3[N:2]([CH3:1])[C:3]2=[O:19])=[C:25]([F:31])[CH:24]=1
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)cc21
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(Cc2ccc(Br)cc2F)c2ccc(-c3ccccc3C#N)cc21
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzonitrile (6-4, 20 mg, 0.08 mmol) in anhydrous DMF (1 ml) was charged with Sodium Hydride (6.42 mg, 0.16 mmol, 2.0 eq) and 4-Bromo-2-fluorobenzyl bromide (42.5 mg, 0.16 mmol, 2.0 eq). The resulting dark mixture was irradiated in a microwave at 200 deg C. for 15 min, then quenched with water, filtered and purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 2-[1-(4-bromo-2-fluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]benzonitrile (6-5), as an orange-tan solid-oil. LRMS m/z: Calc'd for C22H15BrFN3O (M+H) 436.0, found 435.9.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CO>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na]
Solvent: CO
Product: CC(=O)c1ccc(Oc2ncccc2C(=O)O)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 1.03 g of metallic sodium in 27 ml of methanol are added 10 g of p-hydroxyacetophenone and 3.36 g of 2-chloronicotinic acid. The methanol is removed by raising the temperature. The mixture is allowed to stand at 160°-170°C for 2.5 hours. Water is added to the reaction mixture, and the precipitate (excess p-hydroxyacetophenone) is removed by filtration. The filtrate is acidified with hydrochloric acid to yield crystals. The crystals are filtered off, washed with water and chloroform to give 2-(p-acetylphenoxy)nicotinic acid melting at 184°-186°C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([CH:39]=O)[CH:35]=[CH:34]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCO.C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:39]([C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[C:29]([O:28][CH3:27])[CH:30]=[CH:31][CH:32]=4)[N:37]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.279 g, 0.67 mmol) and 8-methoxyquinoline-2-carbaldehyde (0.125 g, 0.67 mmol) in EtOH (10 mL) was stirred at ambient temperature for 18 hours. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and iodobenzene diacetate (0.259 g, 0.80 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (20:1 ethyl acetate/MeOH) to give tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.140 g, 38.6%) as a solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:7]=[N:8][C:9]([Cl:15])=[CH:10][C:11]=1[C:12](O)=[O:13].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:20][C:21]1[C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>ClCCCl>[Cl:5][C:6]1[N:7]=[N:8][C:9]([Cl:15])=[CH:10][C:11]=1[C:12]([C:23]1[CH:22]=[C:21]([CH3:20])[C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=1)=[O:13]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)[nH]c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.00 mL (27.4 mmol) thionyl chloride were added to 1.92 g (9.95 mmol) 3,6-dichloro-pyridazine-4-carboxylic acid in 10 mL 1,2-dichloroethane and the mixture was refluxed for 2 h. The reaction mixture was evaporated to dryness and coevaporated with 1,2-dichloroethane. Then 5.30 g (39.8 mmol) aluminium trichloride and 1.56 g (10.5 mmol) 4-methyl-3H-benzoxazol-2-one were added and the mixture was stirred for 1 h at 100° C. under a nitrogen atmosphere. Then it was stirred for a further 2 h at 120° C., 3 h at 130° C. and then cooled for 48 h at RT. The mixture was decomposed with ice water and extracted with DCM. The organic phases were combined, washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]5[CH2:32][N:31]([CH:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:41][CH3:42])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[CH:47]1([CH:50]=O)[CH2:49][CH2:48]1>CO>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]5[CH2:30][N:31]([CH:33]6[CH2:38][CH2:37][N:36]([CH2:50][CH:47]7[CH2:49][CH2:48]7)[CH2:35][CH2:34]6)[CH2:32]5)=[O:27])=[CH:24][C:23]=4[O:41][CH3:42])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: COc1cc(C(=O)NC2CN(C3CCNCC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)NC2CN(C3CCN(CC4CC4)CC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(piperidin-4-yl)azetidin-3-yl)benzamide (13 mg, 0.023 mmol) in MeOH (2.5 mL) was added AcOH (0.03 mL), cyclopropane aldehyde (3 μL, 0.034 mmol), borane-pyridine complex (10 μL, 0.08 mmol), and left to stir overnight. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (6.4 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm −0.03-0.14 (m, 3 H) 0.34-0.51 (m, 2 H) 0.80 (s, 1 H) 1.17 (d, J=2.53 Hz, 2 H) 1.60 (br. s., 6 H) 1.71 (br. s., 2 H) 1.94 (br. s., 5 H) 2.13 (d, J=6.32 Hz, 2 H) 2.82 (br. s., 2 H) 2.96 (t, J=7.20 Hz, 2 H) 3.52 (t, J=7.20 Hz, 2 H) 3.92 (s, 1 H) 4.05 (t, J=14.02 Hz, 2 H) 4.38-4.50 (m, 1 H) 4.70-4.82 (m, 1 H) 7.41-7.58 (m, 2 H) 7.98 (s, 1 H) 8.22-8.33 (m, 2 H) 8.61 (d, J=6.57 Hz, 1 H). [M+H] calc'd for C33H44F2N8O3, 638; found 638.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)(=O)=O.[CH3:38][N:39]([CH3:49])[C:40]([C:42]1[CH:43]=[C:44]([OH:48])[CH:45]=[CH:46][CH:47]=1)=[O:41]>>[CH3:38][N:39]([CH3:49])[C:40]([C:42]1[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=1)[O:48][C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:41]
Reactant: CCOC(=O)CNc1nc(S(C)(=O)=O)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CN(C)C(=O)c1cccc(O)c1
Product: CCOC(=O)CNc1nc(Oc2cccc(C(=O)N(C)C)c2)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (M), prepared as described below in Preparation 4, is treated with 3-(dimethylaminocarbonyl)phenol, a compound of formula (B) to afford 2-(3-dimethylaminocarbonylphenoxy) -4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (N).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[CH2:12]1[O:20][C@@H:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:12][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:20]
Reactant: c1c[nH]cn1
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: O[C@H](Cc1ncc[nH]1)c1ccccc1
Yield: 32 %

Procedure:
In a manner similar to that of Example 49, step 1, imidazole (2.83 g, 41.6 mmol) is dissolved in absolute ethanol (45 mL). Pyridine (0.11 mL) is added followed by addition of (R)-(+) styrene oxide (5.0 g, 41.6 mol, Aldrich Chemical Co.), followed by heating at reflux for 18 hours. The mixture is evaporated in vacuo to a syrup and suspended between ethyl ether (250 mL) and water (100 mL) to give a solid precipitate. The suspension is filtered and washed with ethyl ether. The solid is recrystallized from hot ethyl acetate and dried in vacuo (2.52 g, 32% yield). MS: APCI: M+1, 189.1 (M: 188.2). NMR spectrum is consistent with structure.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[C:12](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:33])=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[N:36]=[N:37][N:38]([CH3:40])[CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[C:12]([C:35]4[N:36]=[N:37][N:38]([CH3:40])[CH:39]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:33])=[O:5])[CH2:3][CH2:2]1
Reactant: Cn1cc(Br)nn1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2Oc2ccccc2F)N1C(=O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CCc2c(ccc(-c3cn(C)nn3)c2Oc2ccccc2F)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.140 g, 0.31 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (0.050 g, 0.31 mmol), sodium carbonate (0.090 g, 0.85 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.010 g, 0.01 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was stirred overnight at 80° C. The reaction mixture was cooled to room temperature, filtered through a short pad of Celite, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 2:1, petroleum ether-ethyl acetate). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge C18, 19×150 mm, 5 um; Mobile Phase water (0.05% ammonium bicarbonate) and acetonitrile (35% to 65% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV254&220 nm. This afforded (S)-cyclopropyl(5-(2-fluorophenoxy)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.033 g, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.74-0.81 (m, 1H), 0.89-1.03 (m, 2H), 1.11-1.21 (m, 4H), 1.35-1.47 (m, 1H), 1.95-2.05 (m, 1H), 2.17-2.40 (m, 2H), 2.65-2.78 (m, 1H), 4.07 (s, 3H), 4.75-4.81 (m, 1H), 6.40-6.49 (m, 1H), 6.89-6.97 (m, 2H), 7.21-7.27 (m, 1H), 7.51 (d, J=8.40 Hz, 1H), 8.03 (s, 1H), 8.08 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 407 [M+H]+.