Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:20])[CH:18]=[O:19].CC(C)=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:20])[C:18]([OH:23])=[O:19]
Reactant: CC(C)=O
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 2 h
Yield: 40 %

Procedure:
0.4 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)-propionaldehyde is dissolved in 15 ml. of acetone and the solution is cooled to 0° C. under nitrogen. 0.4 ml. of 8N Jones reagent is added and the mixture is stirred for 2 hours, then diluted with water and extracted with ethyl acetate. The extract is washed with water then extracted with aqueous sodium carbonate. The aqueous solution is acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is dried and evaporated to yield 40% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetonehexane) 113°-115° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][O:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(C(C)=O)C>[N:1]1([CH2:8][CH2:9][O:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCN1CCCCC1

Procedure:
21.3 g (0.25 mol) of piperidine are added to a solution of 54 g (0.2 mol) of N-(2-bromoethoxy)phthalimide in 800 ml of methyl ethyl ketone, in the presence of 31.5 g (0.3 mol) of sodium carbonate and 1 g of sodium iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Yield: 98.1 %

Procedure:
4-methyl-3-(trifluoromethyl)benzonitrile (10 g, 54 mmol) was dissolved in 200 mL of carbon tetrachloride and treated with N-bromosuccinimide (10.5 g, 59 mmol) and benzoyl peroxide (1.3 g, 0.54 mmol). The reaction mixture was heated to reflux temperature and stirred for one week. Then, 80 mL of water was added and the layers were separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water (2×50 mL), dried over magnesium sulfate, and concentrated to provide 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile (14 g, 53 mmol) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(F)c2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The compound prepared in Step 1 was dissolved in ethanol (10 ml) and water (1.0 ml), added with iron (powder, 2.0 g) and ammonium chloride (1.0 g), and stirred at 80° C. for 2 hours. Then, the resultant was filtered with celite, distilled under reduced pressure to remove the solvent. The thus obtained target compound as a white solid was used in the subsequent reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1>CCO.C(O)(=O)C.[Fe]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]2[C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([Br:1])[C:3]=3[CH3:23])[O:8][C:7](=[O:13])[CH:6]=2)=[CH:19][CH:18]=1
Reactant: Cc1cc2oc(=O)cc(-c3ccc([N+](=O)[O-])cc3)c2c(C)c1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2oc(=O)cc(-c3ccc(N)cc3)c2c(C)c1Br
Temperature: 110 °C
Yield: 0.8 %

Procedure:
To a stirred solution of the crude material (22 mg) containing 6-bromo-5,7-dimethyl-4-(4-nitrophenyl)-2H-chromen-2-one (7-2) in EtOH (0.75 mL) and acetic acid (0.15 mL) was added iron (16 mg, 0.29 mmol) at room temperature. The mixture was heated at 110° C. for 2.5 h. The reaction mixture was then cooled at room temperature and filtrated. To the filtrate was added EtOAc and saturated NaHCO3 solution, and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The residues was purified by silica gel column chromatography (hexane:EtOAc=5:1˜2:1) to give the title compound 7-3 (4.0 mg, 0.8% yield, 2 steps) as an orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:25]([C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:26]
Reactant: COCCCN
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COCCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 3-methoxy-propylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) in DCM (16 mL) was added acetic anhydride (177 μL, 1.88 mmol) and triethylamine (656 μL, 4.71 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (16 mL), washed with water (3×10 mL) and brine (1×10 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the 9-acetyl-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (466 mg, 100%). This intermediate was dissolved in DCM (4 mL), treated with HCl (4 M in dioxane, 4 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a white powder (365 mg, 100%). MS (ESI): mass calcd. for C11H20N2O, 196.16; m/z found, 197.1 [M+H]+. 1H NMR (400 MHz, MeOD): 3.63-3.51 (m, 4H), 3.23-3.17 (m, 4H), 2.13 (s, 3H), 1.82-1.73 (m, 4H), 1.67-1.53 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:28](O)(=O)[CH3:29]>>[CH2:28]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][CH:21]1[CH2:23][CH2:24][CH3:25])[CH3:29]
Reactant: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCC1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 118 was prepared according to General Method 6 (EXAMPLE 3) from (±)-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (11 mg, 0.03 mmol) and NaBH4 pellets (>10 equiv) in 1 mL acetic acid (0.03 M) stirred at rt for 12 h to afford 9 mg of (±)-4-ethyl-3,4-dihydro-8-isopropoxy-3-propyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (9 mg, 0.02 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (5.9 mM) and heated at 90° C. for 6 h to afford 6 mg (75%) of Compound 118 after flash chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.91 (bs, 1H), 7.12 (s, 1H), 7.07 (d, J=8.8, 1H), 6.96 (d, J=8.8, 1H), 4.27 (dd, J=10.3, 2.0, 1H), 3.90 (dd, J=10.3, 2.7, 1H), 3.44 (m, 1H), 3.27 (m, 1H), 3.26 (m, 1H), 1.52 (m, 2H), 1.41 (m, 2H), 1.18 (t, J=7.1, 3H) 0.94 (t, J=7.3, 3H).
Reaction SMILES: [C:1]([C:9]1[C:18]([OH:19])=[CH:17][C:12]2[C:13]([CH2:15][OH:16])=[CH:14][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:22])C>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:9]1[C:18]([OH:19])=[CH:17][C:12]2[C:13]([C:15]([OH:22])=[O:16])=[CH:14][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(CO)=C2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Reaction time: 16 h

Procedure:
1.0 g of 4-benzoyl-5-hydroxybenzocyclobutene-1-methanol is dissolved in 50 ml of acetic acid and then 4.0 g of chromium trioxide are added in portions. The whole is stirred for 16 hours at 40°, concentrated to dryness by evaporation under reduced pressure, taken up in 20 ml of water and extracted by shaking with 80 ml of dichloromethane. The organic phase is dried over magnesium sulphate and concentrated by evaporation. After recrystallisation of the residue from ether/hexane, 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 167°-169°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[CH2:8]([NH2:10])[CH3:9]>>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:10][CH2:8][CH3:9])=[O:5]
Reactant: CCN
Reactant: CN(C)CC(=O)O
Product: CCNC(=O)CN(C)C
Reaction time: 72 h
Yield: 94.9 %

Procedure:
N,N-dimethylglycine (0.8 g, 6.8 mmol) was dissolved in an aqueous solution of 70% ethylamine (5.7 g, 68 mmol), and the solution was placed in a closed vessel and stored at 5° C. for 3 days. The solution was concentrated under reduced pressure, and the resultant oily product was subjected to column chromatography, followed by extraction with a chloroform/methanol mixed solvent, to thereby obtain Exemplified Compound (6) (0.84 g, 94.4%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:15][C:16]1[C:17]([F:31])=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1>C1COCC1>[Cl:30][C:26]1[CH:25]=[C:24]([C:18]2[C:19]([O:22][CH3:23])=[CH:20][CH:21]=[C:16]([CH2:15][N:1]3[CH:5]=[C:4]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[N:3]=[CH:2]3)[C:17]=2[F:31])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Reactant: c1cncc(-c2c[nH]cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(-c3cccnc3)c2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A flask was charged with 3-(1H-Imidazol-4-yl)-pyridine (165 mg, 0.75 mmol) and THF (5 mL). Then NaH (60% dispersion in mineral oil, 60 mg, 1.5 mmol) was added slowly (gas evolution). After 2 min. of stirring at room temperature 3-Bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (165 mg, 0.5 mmol) was added. The reaction mixture was stirred at rt. After overnight stirring the reaction mixture was quenched with water (20 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane/MeOH (200:5) to produce 77.1 mg (39% yield) of the product (P-479) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d) δ 3.75 (s, 3H), 5.26 (s, 2H), 7.02 (d, J=, 8.59 Hz, 1H), 7.28-7.50 (m, 6H), 7.78-7.88 (m, 2H), 8.04-8.11 (m, 1H), 8.38 (dd, J=4.7, 1.2 Hz, 1H), 8.96 (d, J=1.5 Hz, 1H) ppm.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]I)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCOCC4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Cyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methanesulfonylmethyl-1H-indol-7-yl}-amine (116 mg, 0.22 mmol) prepared in Step A was dissolved in N,N-dimethylformamide (4 mL). Morpholine (57 mg, 0.66 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (68 mg, Yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([O:20]C(C)(C)C)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@@H:16]([OH:20])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O[C@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
8-chloro-11-[(6S,8S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenzo[b,f]-1,4-oxazepine (0.211 g, 0.495 mmol), prepared as described above, was dissolved in trifluoroacetic acid (10 mL) and stirred for 15 minutes. The solvent was removed and the resulting residue was redissolved in methylene chloride (20 mL). Triethylamine (0.100 g, 0.991 mmol) was then added via syringe and the resulting solution was stirred for 1 hour. Washing with water (50 mL), drying over MgSO4 and concentrating resulted in a white solid (0.180 g, 99%); mp 94°-96° C.; Rf(35% acetone/hexanes): 0:15; HRMS (FAB) MH+ of C20H20N3 O2Cl, calculated 370.1322, found 370.1318.
Reaction SMILES: C([O:8][P:9](=[O:53])([O:45]CC1C=CC=CC=1)[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:17]=[CH:16][C:15]=1[C:41]([CH3:44])([CH3:43])[CH3:42])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:41]([C:15]1[CH:16]=[CH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][O:10][P:9](=[O:8])([OH:53])[OH:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCOP(=O)(O)O

Procedure:
Hydrogenate a mixture of phosphoric acid 2-{2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-phenoxy}-ethyl ester dibenzyl ester (65 mg) and 10% Pd/C (60 mg) in methanol under 1 atmosphere of hydrogen for 12 hours. Filter the mixture through Celite and evaporate to dryness to give the title compound. MS 563 (M+1).
Reaction SMILES: [S:1](N)([NH2:4])(=[O:3])=[O:2].[CH:6]1([CH2:9][NH:10][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:8][CH2:7]1.C(Cl)Cl>O1CCOCC1>[CH:6]1([CH2:9][N:10]([CH2:11][CH:12]([O:13][CH3:14])[O:15][CH3:16])[S:1]([NH2:4])(=[O:3])=[O:2])[CH2:7][CH2:8]1
Reactant: COC(CNCC1CC1)OC
Reactant: NS(N)(=O)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(CN(CC1CC1)S(N)(=O)=O)OC
Yield: 68 %

Procedure:
Sulfamide (5 eq) was added to a solution of N-(cyclopropylmethyl)-(2,2-dimethoxyethanamine) in dioxane (0.12 M). The reaction was stirred at reflux overnight. The solvent was removed in vacuo, the residue taken up in EtOAc and washed with H2O, brine, before being dried (Na2SO4), filtered and concentrated in vacuo to give the crude material. DCM was added and the resultant precipitate removed by filtration, while the filtrate was concentrated in vacuo to afford the product (68%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 0.15-0.19 (m, 2H), 0.44-0.47 (m, 2H), 1.03-1.05 (m, 1H), 2.95-2.98 (m, 2H), 3.17-3.19 (m, 2H), 3.28 (s, 6H), 4.51 (t, J 5.0, 1H), 6.63 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH:16]([NH2:21])[CH2:15]2)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:30]1[C:31]2[C:38]([CH3:39])=[CH:37][S:36][C:32]=2[N:33]=[CH:34][N:35]=1>C(O)C>[CH2:2]([NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH:16]([NH:21][C:30]1[C:31]3[C:38]([CH3:39])=[CH:37][S:36][C:32]=3[N:33]=[CH:34][N:35]=1)[CH2:15]2)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccc(C(=O)NCc5ccccc5)cc4C3)c12
Yield: 63.6 %

Procedure:
Using N-benzyl-2-amino-5-indan carboxamide hydrochloride (660 mg, 2.2 mmol), ethanol (19 ml), triethylamine (0.94 ml, 6.7 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (410 mg, 2.2 mmol), a similar procedure to b) in Production Example 208 was carried out. A solid obtained by purifying the product by silica gel chromatography (methylene chloride:ethanol=95:5) was washed with ether to obtain the title compound (580 mg, 1.4 mmol) having the following physical properties:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](N3CCN(CC4CC4)CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
8.5 g (20 mmol) of cis-dibenzyl-[4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-amine are dissolved in 170 mL MeOH and hydrogenated on 1.7 g Pd/C (10%) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and concentrated HCl. Yield: 4.4 g (91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:30])[C@@H:18]([NH:25][C:26](=[O:29])[O:27][CH3:28])[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:11][C:7]=1[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]3[C:49](=[CH:50][CH:51]=2)[CH:48]=[C:47]([C:52]2[NH:56][C:55]([C@@H:57]4[CH2:61][CH2:60][CH2:59][N:58]4[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=2)[CH:46]=[CH:45]3)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:28][O:27][C:26]([NH:25][C@@H:18]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:10]1[NH:9][C:8]2[C:31]3[C:4]([CH2:5][CH2:6][C:7]=2[N:11]=1)=[CH:3][C:2]([C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([C:52]1[NH:56][C:55]([C@@H:57]4[CH2:61][CH2:60][CH2:59][N:58]4[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=1)[CH:46]=[CH:45]2)=[CH:33][CH:32]=3)=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(Br)cc1CC2)C1CCOCC1
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
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Temperature: 85 °C
Reaction time: 17 h
Yield: 39.8 %

Procedure:
Methyl (S)-2-((S)-2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (211 mg, 0.408 mmol), (S)-tert-butyl 2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.449 mmol), Pd(PPh3)4 (47 mg, 0.0408 mmol) and K2CO3 (2M in H2O, 0.45 mL, 0.9 mmol) were suspended in DME (4 mL). The reaction mixture was degassed for 10 min with N2 then heated to 85° C. After 17 h, it was cooled to RT, diluted with MeOH, filtered over a thiol SPE column and concentrated. The crude residue was purified by silica column chromatography (0% to 40% MeOH/EtOAc) to afford the title compound (130 mg, 40%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]1[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[C:32]=2[Cl:38])[N:24]=1>O1CCCC1>[Cl:37][C:33]1[C:32]([Cl:38])=[C:31]([C:25]2[N:24]=[C:23]([N:11]3[CH2:12][CH2:13][O:14][C@@H:9]([C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=4)[CH2:10]3)[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Cn1c(Cl)nc(-c2ccnc(Cl)c2Cl)cc1=O
Reactant: Fc1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(F)cc3)C2)nc(-c2ccnc(Cl)c2Cl)cc1=O
Reaction time: 12 h
Yield: 68.8 %

Procedure:
To a solution of (2S)-2-(4-fluorophenyl)morpholine hydrochloride (0.8 g, 3.68 mmol) and triethylamine (2.1 g, 20.8 mmol) in tetrahydrofuran (20 ml) was added 2-chloro-6-(2,3-dichloropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (2.0 g, 6.88 mmol) portionwise and the mixture was stirred for 12 hours. The resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(2,3-dichloropyridin-4-yl)-2-((2S)-2-(4-fluorophenyl)morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (1.1 g, 2.53 mmol, 69%) as white crystals.