Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-4-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-4-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[O:26])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[H-].[Na+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][N:20]([CH2:29][CH:31]5[CH2:32][O:33]5)[CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[O:26])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: ClCC1CO1
Reactant: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)c1c-2c(N2CCN(CC3CO3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of compound 5x (0.35 g, 1 mmol, obtained from the above Synthesis Example 12) in dry DMF (20 mL) was added NaH (60% in oil, 2.64 g, 66.0 mmol) at 0° C. for 1 hr. After stirring at room temperature for 8 hrs, epichlorohydrin (0.92 g, 10 mmol) was added and stirred for a further 1 hr. The reaction mixture was partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The resultant residue was purified by column chromatography (MeOH/CH2Cl2=1:10) to give the title compound 5kkk (0.33 g, 84% yield).
Reaction SMILES: C(N)(C)C.[BH4-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([OH:28])[CH2:15][CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].CS(O[CH2:36][CH2:37][CH2:38][O:39][CH3:40])(=O)=O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([O:28][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:15][CH2:16][N:17]([CH:25]([CH3:26])[CH3:27])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)N(CCC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: COCCCOS(C)(=O)=O
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)N
Solvent: C1CCOC1
Product: COCCCOC(CCN(C(=O)OC(C)(C)C)C(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(isopropyl)carbamate was obtained using procedures analogous to Preparation A, Steps 1-6, using isopropylamine in Step 1 and NaBH4 in Step 6. To a 0° C. solution of tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(isopropyl)carbamate (158 mg, 0.48 mmol) in THF (5 mL) was added NaH (60 mg, 1.45 mmol) and the reaction was allowed to stir for 5 minutes. 3-methoxypropyl methanesulfonate (810 mg, 4.8 mmol) was then added and the reaction was heated to reflux for 2.5 hrs. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution at 0° C. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, evaporated and purified via ISCO to afford tert-butyl 3-(3-chlorophenyl)-3-(3-methoxypropoxy)propyl(isopropyl)carbamate. MS ESI+ve m/z 422 (M+Na).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]#[N:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(C#N)c2)nc2cc(F)ccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.17 mmol), 3-cyanophenylboronic acid (319 mg, 2.17 mmol), Pd(PPh3)4 (251 mg, 0.22 mmol) in toluene:water (10 mL:4 mL) and heating at reflux overnight. After purification, 3-(4-chloro-7-fluoro-3-methylquinolin-2-yl)benzonitrile was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:24])[C:16]=2[NH:17][N:18]=1)=[O:13])[CH3:2].[CH3:25]N(C=O)C.CI>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:24])[C:16]=2[N:17]([CH3:25])[N:18]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCCC2=O
Reactant: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (1.04 g, 3.211 mmol) in DMF (12 mL) Cs2CO3 (1.255 g, 3.85 mmol) and methyl iodide (0.22 mL, 3.532 mmol) were added. The reaction was stirred at room temperature for 1 h, then AcOEt (60 mL) was added and the organic phase washed with water (3×50 mL). The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 1/9) provided 0.99 g (91% yield) of the title compound as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)([CH3:3])[CH3:2].BrC1C=CC=[C:15]([O:19]C(C)C)C=1>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:15]=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(Br)c1
Reactant: CC(C)Oc1ccccc1Br
Product: CC(C)Oc1ccccc1C=O
Yield: 70 %

Procedure:
The title compound was prepared as in Example 257A but employing 2-iso-propyloxybromobenzene in lieu of 1-bromo-3-isopropoxybenzene. Purification on silica, gel with 10% ether/hexane afforded the title compound (2.3 g, 70%).
Reaction SMILES: [F:1][CH:2]([F:35])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:13])[F:12])=[CH:7][C:6]=1[C:14]1[C:15]2[N:16]([N:20]=[C:21]([NH:23][C:24]3[CH:34]=[CH:33][C:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][C:26]=4[CH:25]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1.Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>>[F:35][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:13])[F:12])=[CH:7][C:6]=1[C:14]1[C:15]2[N:16]([N:20]=[C:21]([NH:23][C:24]3[CH:34]=[CH:33][C:27]4[CH2:28][CH2:29][N:30]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:31][CH2:32][C:26]=4[CH:25]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C(=O)CCl
Reactant: FC(F)COc1ccc(C(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(C(F)F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-difluoromethyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.065 g, 0.130 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.045 mL, 0.200 mmol) in a manner analogous to Example 313 to give product (0.045 g, 59%). MP=200-201° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.49 (s, 1H), 8.78 (d, 1H), 7.90 (s, 1H), 7.65 (m, 2H), 7.42 (m, 3H), 7.05 (m, 2H), 7.02 (br m, 1H), 6.30 (br m, 1H), 4.42 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.80 (m, 7H), 2.60 (m, 4H). MS=571 (MH)+.
Reaction SMILES: CS[C:3]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.C1(C)C(C)=[CH:23][CH:24]=[CH:25][CH:26]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH2:26]([N:4]1[CH2:32][CH2:31][N:8]([C:3]2[C:9]3=[CH:10][C:11]4[C:16]([N:8]3[CH2:7][C:6]3[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=3[N:4]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][CH2:3]1)[CH2:25][CH2:24][CH3:23]
Reactant: Cc1ccccc1C
Reactant: CSC1=Nc2ccccc2Cn2c1cc1ccccc12
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(C2=Nc3ccccc3Cn3c2cc2ccccc23)CC1

Procedure:
A mixture of 7.1 g of 12-methylthio-6H-indolo[2,1-c][1,4]benzodiazepine, the product of Example 1c, 6.64 g of 4-n-butyl-1-piperazine and 20 ml of xylene in a pressure bottle was heated to 240° C. for 3 hours. The reaction mixture was dissolved in EtOAc, washed with water, and dried anhydrous over Na2SO4. The crude product (after removal of solvent) was dissolved in MeOH and treated with one equivalent of fumaric acid to give a solid. Recrystallization of the fumarate salt from DMF yielded the title compound, a colorless solid, mp 197° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 87 %

Procedure:
To 3 ml of a DMF solution containing 100 mg (0.2591 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 281.1 μl (2.591 mmol) of butyl bromide, there were added 42.9 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 23 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 10 g of WAKO-gel C-200 eluent: hexane and toluene/ethyl acetate of 100/1 and 50/1) to obtain 99.6 mg (0.2253 mmol, 87%) of 2-butoxy-2'-hydroxy-5,5'-bis (2ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[C:12]2[O:17][CH2:16][O:15][NH:14][C:13]=2[CH:18]=[CH:19][C:20]=1[F:21]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:18]=[C:19]3[O:15][CH2:16][O:17][C:12]=2[C:11]([F:10])=[C:20]3[F:21])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Fc1ccc2c(c1F)OCON2
Product: Fc1cnc(Cl)nc1Nc1cc2c(F)c(F)c1OCO2

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoromethylenedioxyaniline gave 2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.09 (d, 1H, J=3 Hz), 7.70 (d, 1H, J=2.4 Hz), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.97 (bs, 1H); 19F NMR (CDCl3): −14175 and −44562; LCMS: purity: 95%; MS (m/e): 304 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[H-].[Na+]>CN(C)C=O.Cl.O>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)(=[O:20])=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 4,6-dichloropyrimidine (1.33 g) and 4-tert-butylbenzenesulfonamide (1.96 g) in dimethylformamide (20 ml) is added sodium hydride (60% dispersion-type, 714 mg). The mixture is stirred at room temperature for two hours, and the reaction solution is diluted with 10% hydrochloric acid and water. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate to give 4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (2.02 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[C:7]([N+:23]([O-])=O)=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:10][CH2:9]2)[CH3:2]>CO.[Ni]>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[C:7]([NH2:23])=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:10][CH2:9]2)[CH3:2]
Reactant: CCOC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCC2Nc1ccc(F)cc1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)Nc1ccc2c(c1N)CCC2Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A solution of [4-nitro-1-(4-fluoro-phenylamino)-indan-5-yl]-carbamic acid ethyl ester (200 mg) in 20 ml of methanol was added a catalytic amount of Raney Ni. The resulting mixture was hydrogenated under regular pressure at room temperature for 4 hours. The reaction mixture was filtered through celite and washed with methanol. The filtrate was evaporated to dryness in vacuo and the residue was purified by column (hexane/EtOAc, 3:1) to give a white solid product. 1H-NMR (DMSO-d6): δ 8.51 (brs, 1H, NH, exchangeable with D2O), 6.94 (dd, 2H, J=9.0, 18.6 Hz), 6.88 (d, 1H, J=8.1 Hz), 6.66 (dd, 2H, J=4.2, 9.0 Hz), 6.49 (d, 1H, J=8.1 Hz), 5.70 (brs, 1H, NH, exchangeable with D2O), 4.80 (m, 3H, NH2 and CH)), 4.05 (q, 2H, J=7.2 Hz), 2.74 (ddd, 1H, J=3.6, 8.7, 15.6 Hz), 2.60-2.36 (m, 2H), 1.71 (m, 1H), 1.20 (t, 3H, J=7.2 Hz). MS: 330 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.O>O1CCCC1>[C:18]([O:17][C:15]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mL tetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC2O. The mixture was stirred for about 16 h at 22° C. and 100 mL of water was added. The mixture was extracted with ethyl acetate (2×100 mL) and the organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 20% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was further converted to 2d in a manner analogous to Method B.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:5][CH2:4][CH:3]([OH:6])[CH2:2][F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC(O)CF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CF)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-fluoropropane-1,2-diol (from Sigma, 0.750 g, 7.97 mmol) and triethylamine (1.39 mL, 9.96 mmol) in DCM (20 mL) was added p-toluenesulfonyl chloride (1.60 g, 8.37 mmol). The reaction was stirred at RT for 2 h. The mixture was concentrated to dryness and used in next step.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[N:25]=[C:26]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[N:27]=[CH:28][C:29]=3[N:30]=2)=[CH:18][CH:17]=1)=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[O:31][C:26]1[N:27]=[CH:28][C:29]2[N:30]=[C:22]([C:19]3[CH:20]=[CH:21][C:16](/[CH:15]=[CH:14]/[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6]([OH:7])=[O:5])=[O:39])=[CH:17][CH:18]=3)[O:23][C:24]=2[N:25]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Yield: 75.2 %

Procedure:
A solution of 55 mg (S)-1-((E)-3-{4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenyl}-acryloyl)-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml of dichloromethane and 1 ml trifluoroacetic acid was stirred at room temperature for 1 h. Then the mixture was concentrated in vacuo and freeze-dried. 37 mg of the title compound were obtained.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:10]2[CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8][CH2:9]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1
Reactant: c1cn(C2CCNCC2)nn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(n3ccnn3)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 44.4 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (126 mg, 0.66 mmol) and DBU (130 mg, 0.85 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.34 mmol) in acetonitrile (10 ml). The reaction mixture was refluxed for 24 hrs and then concentrated to dryness. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 65 mg of the desired product. m.p. 274°-276° C.; 1H NMR (TFA) δ: 9.38 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 5.25 (m, 1H), 4.60 (m, 1H), 4.15 (m, 2H), 3.80 (m, 2H), 2.65 (m, 4H), 1.34-1.70 (m, 4H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])/[C:5](OC)=[O:6].[CH3:24][NH2:25]>>[CH3:24][NH:25][C:5](=[O:6])/[C:4](=[N:3]/[O:2][CH3:1])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1ccccc1C
Reactant: CN
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccccc1C
Temperature: 40 °C

Procedure:
250 g of methyl E-2-methoxyimino-2-[(2-methylphenyloxymethyl)-phenyl]acetate were suspended in 1 l of 40% strength aqueous methylamine solution, and the suspension was heated for 4 hours at 40° C. After the mixture had been cooled to room temperature (20° C.), the solid was filtered off with suction, washed repeatedly with water and dried at 50° C. This gave 229.8 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH2:14]Br)[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-:19].[Na+].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=[O:19])[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC)c2oc(CBr)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a well stirred solution of Methyl-2-bromomethyl-7-methoxybenzo[b]furan-4-carboxylate (step 6) (3.1 g, 10.36 mmol) in dimethyl sulfoxide (30.0 mL) was added powdered sodium carbonate (1.64 g, 15.55 mmol) at 90-95° C. and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (2.9 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 2.2 g of pure product.
Reaction SMILES: C([O-])C.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C:17]#[N:18].[CH:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])=O>>[C:17](/[C:16](/[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH3:5])[CH:8]=2)[NH:12][CH:11]=1)=[CH:19]\[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])#[N:18]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: CC[O-]
Agent: [Na+]
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3cccc(C#N)c3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of sodium ethanolate [prepared from sodium (30 mg, 1.3 mmol, 1.2 eq.) and anhydrous ethanol (8 mL)] were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (200 mg, 1.1 mmol, 1.0 eq.) and, after 10 minutes stirring, 3-formyl-benzonitrile (200 mg, 1.5 mmol, 1.4 eq.). The reaction apparatus was protected from light and the mixture stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the crude purified by silica gel flash-column chromatography (eluent: heptane/CH2Cl2, 50:50 à 20:80). The residue was triturated with ethanol and diethyl ether to the compound (30) as a yellow powder (110 mg, 34%). mp: 149° C.; IR νmax (cm−1): 2227 (νCN), 3338 (νN—H); 1H NMR (DMSO, 500 MHz) δ (ppm): 3.84 (3H, s, 5′-methoxy), 6.90 (1H, m, H6′), 7.41 (1H, m, H7′), 7.49 (1H, s, H4′), 7.73 (1H, m, H5″), 7.76 (1H, s, H3), 7.79 (1H, s, H2′), 7.88 (1H, m, H6″), 8.24 (1H, m, H″), 8.28 (1H, m, H″), 11.70 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.8 (5′-methoxy), 102.2 (C4′), 108.6 and 110.3 (C2 and C3′), 112.0 (C3″), 112.6 (C6′), 113.3 (C7′), 118.0 and 118.6 (C1 and nitrile C), 124.1 (C3a′), 128.1 (C2′), 130.1 (C5″), 132.3 (C6″), 132.4 and 132.5 (C2″, C5″ and C7a′), 133.1 (C3), 136.2 (C1″), 154.8 (C5′); ESI-MS: m/z 322.1 ([M-Na]+); HRESI-MS: m/z 322.0946 (calcd for C19H13N3ONa, 322.0956).