Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[NH2:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[NH:16][C:22]([NH:21][C:19]([O:18][CH3:17])=[O:20])=[S:23])(=[O:3])[CH3:2]
Reactant: C#CCS(=O)c1ccc(NC(C)=O)c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: C#CCS(=O)c1ccc(NC(C)=O)c(NC(=S)NC(=O)OC)c1

Procedure:
1 G. of 1-acetamido-2-amino-4-propargylsulfinylbenzene in 30 ml. acetone is treated overnight at room temperature with 2 g. methoxy carbonyl isothiocyanate. The solution is concentrated and the residue triturated with ether. Recrystallization yields 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-5-propargylsulfinylbenzene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:17]1([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2CCCC2)c1C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (2.5 g, 10.7 mmol) and cyclopentanone (4.5 g, 53.49 mmol) in methanol (25 mL) was added acetic acid (1.98 g, 21.44 mmol). After 3 h, sodium cyanoborohydride (1.68 g, 24.3 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 3-(cyclopentylamino)-2-methyl-5-(trifluoromethyl)benzoate (1.8 g, 55.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].[OH:24]O.[OH-].[Na+].O>CS(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]([NH2:6])=[O:24]
Reactant: OO
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound (158a) (0.100 g) was dissolved in DMSO (1.2 mL). A hydrogen peroxide solution (30 wt %) (0.053 mL) and a 4 mol % aqueous sodium hydroxide solution (0.233 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (158b) (0.090 g).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)([C:8]#[N:9])[C:6]#[N:7].C(N(S(F)(F)[F:27])CC)C>ClCCl>[F:27][CH2:2][CH2:3][CH2:4][C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)(CCCO)Cc1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#CC(C#N)(CCCF)Cc1ccc(C(F)(F)F)cc1
Yield: 5 %

Procedure:
Using 0.80 g of 2-(3-hydroxypropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile, 8 ml of dichloromethane and 0.3 ml of Diethylaminosulfur trifluoride, and according to the process described in the Production Example 11, there was obtained 0.05 g of 2-(3-fluoropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (14)).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]1([CH3:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]5([CH3:49])[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 10 mL of DMF were added EDCI (122 mg, 0.64 mmol), tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (103 mg, 0.48 mmol) and DMAP (78 mg, 0.64 mmol) in one portion at room temperature. Then the reaction mixture was stirred for 16 hours, then was poured into 50 mL of water and filtered. The filter cake was washed with water (10 mL) and passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2, v/v) to give tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpiperidine-1-carboxylate (100 mg, 61.6%) as a white solid which was used for the next step without further purification. MS: (M+H)+=508.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18]([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[C:28](OCC)(OCC)(OCC)[CH3:29]>>[CH3:28][C:29]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)C(CC)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Product: CCOC(=O)C(CC)Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1
Temperature: 25 °C

Procedure:
A solution of 7 g of 6B in 50 ml of triethyl orthoacetate was heated at 140° C. for 2 hours. The resulting mixture was cooled to room temperature, absorbed on silica gel and chromatographed, using the eluent described in Example 1, to give 6, as a viscous oil.
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:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]1>>[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:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and tert-butyl 4-aminopiperidine-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (qd, J=11.9, 3.8 Hz, 2 H) 1.54-1.66 (m, 5 H) 1.66-1.77 (m, 4 H) 1.98 (br. s, 2 H) 2.52 (d, J=1.8 Hz, 2 H) 2.98 (d, J=11.9 Hz, 2 H) 3.79-3.87 (m, 1 H) 3.93 (s, 3 H) 4.04 (t, J=14.2 Hz, 2 H) 4.76 (quin, J=8.1 Hz, 1 H) 7.48 (d, 1 H) 7.50 (s, 1 H) 7.96 (s, 1 H) 8.13 (d, J=8.1 Hz, 1 H) 8.26 (d, J=8.1 Hz, 1 H) 8.26 (s, 1 H). [M+H] calc'd for C26H33F2N7O3, 530; found 530.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O.O1CCOCC1>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:21]([O:23][CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a stirred solution of N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester (2.00 g, 10.6 mmol) and sodium carbonate (2.81 g, 26.6 mmol) in water (7 mL) at 0° C. was added a solution of 9-fluorenylmethyl chloroformate (2.75 g, 10.6 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 h and then poured into water (10 mL). This mixture was extracted with diethyl ether (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear oil. The oil was purified by silica gel flash chromatography (0-70% EtOAc in hexanes) to give the title compound (4.24 g, 77% yield) as a clear oil (product contained a minor impurity, but was used without further purification).
Reaction SMILES: C(O)C.F[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[N:6]=1.C(=O)(O)[O-].[Na+].[CH2:20]1[O:29][C:28]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=2[O:21]1>O>[F:14][C:7]1[N:6]=[C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:28]3[O:29][CH2:20][O:21][C:22]=3[CH:23]=2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(F)nc1Nc1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
In 75 ml. of ethanol was dissolved 3.2 g. (0.002 mole) of 2,6-difluoro-3-nitropyridine followed by 1.68 g. (0.02 mole) of sodium bicarbonate. To this stirred mixture, was added a solution of 2.74 g. (0.02 mole) of 3,4-(methylenedioxy) aniline in 50 ml. of ethanol dropwise over 45 minutes at room temperature. After one hour, 100 ml. of water was added and the deep-red crystalline solid product was collected. A small amount was crystallized from ethanol and melted at 161°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>O=S(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (1.0 g, 3.98 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) was added a few drops of DMF (0.05 mL). The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then 3-bromoaniline (0.69 g, 3.98 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired (3-bromo-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 1.2 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:9]1[C:10]2[C:15](=[N:14][C:13]([CH3:18])=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([F:1])[CH:3]=2)=[CH:8]1
Reactant: BrCc1cccc(Br)c1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ccc(C)nc3c2=O)cc1F
Yield: 38.9 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 112 mg (0.358 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 107.5 mg (0.430 mmol) of 3-bromobenzyl bromide, 17.2 mg (0.430 mmol, 60% dispersion in oil), and 2 mL of N,N-dimethylformamide. The crude product was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 67 mg of 1-(3-Bromo-benzyl)-3-(3-fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C24H18BrFN2O3 [M+H]: 481.05. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.7 min
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][OH:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(CCO)CC1
Yield: 56.3 %

Procedure:
A mixture of 1-acetylpiperazine (2.5 g, 19.5 mmol), 2-bromoethanol (1.38 ml, 19.5 mmol) and potassium carbonate (6.7 g, 48.8 mmol) in acetonitrile (30 ml) was heated at reflux for 3 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 2-(4-acetylpiperazin-1-yl)ethanol (1.89 g, 56%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C=CC=CC1=O>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(Oc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-aminobenzonitrile (101 mg, 0.86 mmol) in 1-methyl-2-pyridone (1 mL) was added NaH (34 mg, 0.86 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.17 mmol) in 1-methyl-2-pyridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 64 mg (82%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=2)[CH2:17]1)=O)(C)(C)C>O1CCOCC1>[NH2:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=2)[CH2:17]1
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC(N)C2)nc1C
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 79.6 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (0.96 mL, 3.82 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (218a) (261 mg, 0.76 mmol) in 1,4-dioxane (8 mL) at 0° C., and the mixture was stirred at room temperature for 7.5 hours. Then, a 4 N hydrochloric acid/ethyl acetate solution (0.96 mL, 3.82 mmol) was added, and the mixture was further stirred for 45 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to the resulting residue. Thereafter, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure to obtain 146 mg of the title compound as a pale yellow oily substance (79%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]([O:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH3:23])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:22][C:21]1[CH:20]=[C:17]([CH2:18][OH:19])[CH:16]=[C:15]([CH3:23])[C:14]=1[O:13][C:11](=[O:12])[CH2:10][NH:9][CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7]
Reactant: Cc1cc(C=O)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(CO)cc(C)c1OC(=O)CNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 2.88 g of 4-(tert-butoxycarbonylmethylamino)acetoxy-3,5-dimethylbenzaldehyde and 0.34 g of sodium borohydride in 25 ml of tetrahydrofuran was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and was washed with 0.25N HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester (2.9 g) as a colourless syrup. To a solution of 2.8 g of (tert-butoxycarbonylmethylamino)acetic acid 2,6-dimethyl-4-hydroxymethylphenyl ester and 2.73 g of triphenylphosphine in 30 ml of dichloromethane, 3.44 g of carbon tetrabromide was added and the mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2)to obtain (tert-butoxycarbonylmethylamino)acetic acid 4-bromomethyl-2,6-dimethylphenyl ester (2.97 g, 89% ) as a colourless oil.
Reaction SMILES: [C:1]1([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:29]([BH3-])#N.[Na+]>CO>[CH3:29][N:19]1[C:17]2[C:18]3[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [BH3-]C#N
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1c2cccc3c(=O)[nH]nc(c23)C(c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (1.04 mmol) in methanol (20 mL) is treated with formaldehyde (37 wt % in water, 270 μL, 3.61 mmol) at room temperature for overnight. Sodium cyanoborohydride (228 mg, 3.61 mmol) is added and the solution is stirred at room temperature for 3 h. After concentration under reduced pressure, the residue is dissolved in a mixture of trifluoroacetic acid and water and is purified by HPLC giving the 7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one in good yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[Si:11]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxyproprionitrile (7.11 g, 100 mmol) and imidazole (68.08 g, 100 mmol) in dry THF (100 ml) was stirred at room temperature for 45 mins and tert-butyldiphenylsilylchloride (28.86 g, 105 mmol) was added slowly by syringe over 10 mins. The clear solution was stirred at room temperature overnight during which time a white precipitate formed. The reaction was filtered and the filtrate evaporated in vacuo to leave an oil which was chromatographed on silica (eluting with 10% petrol in ether) to give the product as a clear slightly yellow oil (31.41 g, quant.) δH (CDCl3) 7.76-7.65 (4H, m, PhH4), 7.48-7.35 (6H, m, PhH6), 3.86 (2H, t, J 6.5, OCH2CH2CN), 2.54 (2H, t, J 6.5, OCH2 CH2CN), 1.09 (9H, s, tert-Bu).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:26]2[CH:31]=[CH:30][C:29](C3OCC(C)(C)N=3)=[CH:28][CH:27]=2)([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)(C)(C)C.C[C:41]([OH:43])=[O:42]>CO.C(Cl)(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:41]([OH:43])=[O:42])=[CH:28][CH:27]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc2)=N1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1
Temperature: 75 °C
Yield: 96 %

Procedure:
In a 50 mL round bottomed flask placed with [3-(3-{[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-hydroxy-phenyl-methyl}-phenoxy)-propyl]-carbamic acid tert-butyl ester (3, 220 mg) was added 3 mL of 80% aqueous AcOH and the reaction mixture was heated 75° C. for overnight. Then the reaction mixture was concentrated and dried and added 3 mL of 20% NaOH/EtOH (1:1, v/v) and refluxed for 3 h. Residue obtained on evaporation of the solvent was dissolved in CH3OH/CHCl3 mixture and adsorbed with silica gel and dried. The dried silica gel with compound was purified by silica gel column already flashed with 1% NH4OH in Et2O solution. Elution of the column at 50% CH3OH/CH2Cl2 gave 4-{[3-(3-Amino-propoxy)-phenyl]-hydroxy-phenyl-methyl}-benzoic acid, 4 as a colorless gelly solid. Yield: 96%. Mass: 378 (MH+), 376 (M-H), 360 (M-OH).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[CH3:31][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
A solution of the product of Example 44, step C (85 mg, 0.189 mmol), trimethylboraxine (0.026 mL, 0.189 mmol), potassium carbonate (78 mg, 0.567 mmol) and tetrakis-(triphenylphosphine)palladium (21.8 mg, 0.0189 mmol) in water/1,4-dioxane (1:10, 0.55 mL) was heated to 110° C. for 5 h and then stirred at ambient temperature for 15 h. The reaction mixture was then filtered through a celite bed and concentrated in vacuo to afford the crude product which was then purified by column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to provide tert-butyl 6-methyl-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (43 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 7.98-7.94 (m, 3H), 7.63 (s, 1H), 7.54-7.46 (m, 3H), 4.56 (s, 2H), 3.83 (br s, 2H), 2.86 (br s, 2H), 2.51 (s, 3H), 1.51 (s, 9H).