Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dimethylamine (2.26 g, 0.050 mole) in tetrahydrofuran (20 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was evaporated to an oil and partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed once with water (50 ml), twice with 5% potassium hydroxide solution (50 ml portions), and once more with water (50 ml). Drying over magnesium sulfate, treatment with charcoal, filtration and evaporation of the solvents gave a residue which upon recrystallization from hot isopropyl ether and drying under high vacuum gave 3.20 g (59%) of title compound, mp 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH3:18].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Yield: 89.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-methyl-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine (9.4 g, 34.06 mmol) and dimethylformamide dimethyl acetal (9.0, 68.12 mmol) in dimethylformamide (70 mL) was heated to 140° C. for 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure (50° C. bath temperature). The residue was slurried in methanol and concentrated at reduced pressure. This methanol slurry/concentration procedure was repeated twice. The residue was triturated with methanol and the light yellow crystalline solid which formed was collected and dried to give 10.1 g (85%) of 3-(2-chloro-phenyl)-2-(dimethylamino-vinyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine which had: 1H NMR δ 7.83 (d, J=12.5 Hz, 1 H), 7.68 (d, J=5 Hz, 1 H), 7.57 (m, 1 H), 7.41 (m, 2 H), 7.31 (m, 1 H), 7.14 (d, J=5 Hz, 1 H), 4.06 (d, J=12.5 Hz, 1 H), 2.77 (br s, 6 H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([N:32]([CH3:36])[C:33](=[O:35])[CH3:34])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[C:31]([N:32]([CH3:36])[C:33](=[O:35])[CH3:34])[C:26]([O:25][CH3:24])=[N:27][CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)C(C)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)C(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide (Stage 62.1.1) to give the title compound as a white solid. (HPLC: tR 2.52 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.40-8.31 (m, 1H), 8.18-8.06 (m, 2H), 8.03-7.90 (m, 1H), 7.86-7.71 (m, 1H), 7.55-7.43 (m, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.57 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H), 1.74 (s, 3H))
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([C:8]1[N:9](C(=O)C)[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[C:12]([Cl:18])[CH:11]=2)=[O:7])[CH3:4]>O>[NH2:17][C:16]1[C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:6]([O:5][CH2:3][CH3:4])=[O:7]
Reactant: CCOC(=O)c1c(N)c2ccc(Cl)cc2n1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1N
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
Add 1N ethanolic potassium hydroxide solution (100 mL) to 3-amino-1-(ethanoyl)-6-chloro-1H-indole-2-carboxylic acid ethyl ester (3.5 g, 12.5 mmol) and permit the reaction to stand for 20 min. Pour the resulting slurry into water at 5° C. with rapid stirring. Age at 0° C. for 10 min., collect the solid, wash it with water dry it at 40° C. under vacuum and obtain 2.42 g (81%) of the title compound: MS 239(M+H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][NH:14][N:13]=1)=[O:11])(=[O:3])[NH2:2].CC(O)=O.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:7]1[S:6][C:5]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)=[O:11])=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: NC(=O)c1ccsc1NC(=O)c1cc[nH]n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cc(Br)sc1NC(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-Pyrazole-3-carboxylic acid (3-carbamoyl-thiophen-2-yl)-amide (355 mg, 1.5 mmol) is mixed with AcOH (5 mL). NBS (280 mg, 1.58 mmol) is then added and the mixture is stirred at room temperature overnight. Evaporation gives a residue that is subsequently dissolved in DCM, the resulting organic phase is washed with aqueous NaHCO3, dried over MgSO4, filtered and evaporated to give a residue that is used as such.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[CH2:2]([N:9]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
N-Benzylglycine hydrochloride was taken up in 2-N sodium hydroxide and the mixture was stirred at -5° C. while 4-N sodium hydroxide and benzyl chloroformate were simultaneously added dropwise. The mixture was stirred in the cold for 2 hours and then stirred at room temperature for 0.5 hour. Excess benzyl chloroformate was removed by extraction with ether. The aqueous layer was cooled to -5° C. and acidified with concentrated hydrochloric acid. The mixture was stirred in the cold for 1 hour, then brought to room temperature and extracted 4 times with diethyl ether. The diethyl ether extracts were back-washed with water, filtered and then dried over anhydrous sulphate and again filtered. Evaporation gave N-benzyl-N-benzyloxycarbonyl-glycine in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][OH:10]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:9]=[O:10]
Reactant: CO
Reactant: Oc1ccccc1Br
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Over 0.25 hours 2-bromophenol (22.38 g, 129 mmol) was added to a solution of Mg(OMe)2 in methanol (111.9 ml, 8% w/w) and toluene (35 ml). The reaction was heated to reflux and maintained at reflux for 1 hour, then toluene (118 ml) was added. The solvent was distilled off until the temperature reached 92-94° C. A solution of paraformaldehyde in toluene was added portionwise over 1 hour at 80-90° C. and the reaction mixture heated to reflux and maintained at reflux for 3 hours. The reaction mixture was then allowed to cool to ambient temperature and left to stand overnight. Toluene (140 ml) was added to the reaction mixture, which was then washed with 2M H2SO4 (140 ml). The organic phase was dried and evaporated and the crude material used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:19]CC(C1C=CC(OCC(N2CCOCC2)=O)=CC=1)=O>>[Br:19][CH2:2][C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1
Reactant: O=C(CBr)c1ccc(OCC(=O)N2CCOCC2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CBr)cc1

Procedure:
Ethyl 2-[4-acetylphenoxy]-2-methylpropionate was brominated using an analogous procedure to that described for 4-[4-(bromoacetyl)phenoxyacetyl]morpholine, used as a starting material for Example 6, to give ethyl 2-[4-(bromoacetyl)phenoxy]-2-methylpropionate as an oil, which was pure by thin layer chromatographic (TLC) analysis (on silica plates; eluant : 50% ether/50% petrol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cn1nccc1N
Product: Cc1ccc(Nc2ccnn2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 5-Amino-1-methyl-pyrazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=312.3 (M+H+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][CH2:21][CH:22]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C@@H:6]1[NH:41][C:42]([O:44]CC(Cl)(Cl)Cl)=O)(=[O:3])[CH3:2].[C:50](OC(=O)C)(=O)C>[Zn]>[C:42]([NH:41][C@@H:6]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7]1[O:20][CH2:21][CH:22]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:44])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCC(CO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)OCC(Cl)(Cl)Cl)NC(=O)OC(C)(C)C
Agent: [Zn]
Product: CCCCCCCCCCC(CO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 49 %

Procedure:
tert-Butyl 1-{[3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloro-ethoxycarbonyl-amino)-β-D-glucopyranosyloxy]methyl}-(R/S)-undecyl-carbamate 50(27.0 mg, 0.0353 mmol) was dissolved in acetic anhydride (1 ml) into which activated zinc powder (4.6 mg, 0.0706 mmol) had been added. The reaction was stirred for 6 hours, after which it was filtered and evaporated (and co-evaporated with benzene and toluene). The residue was purified by column chromatography to give 51 (11 mg, 49%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].C=O.C([C:14](=[O:20])CCCCC)C.S(=O)(=O)(O)O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:6]([C:3]([CH2:1][CH3:2])([CH2:14][OH:20])[CH2:4][OH:5])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)CC
Reactant: CCCCC(C=O)CC
Agent: C=O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCCCC(CC)(CO)CO

Procedure:
The molar ratio of the 2-ethyl hexanal to the formaldehyde, used as the initial materials of the reaction, should be within the range 1:2 to 1:4, preferably within the range 1:2.5 to 1:3.5. To the mixture is added a neutral or cationic phase transfer catalyst, such as neutral polyethylene glycol (e.g. PEG 400) or a cationic tetrabutylammoniumhydrogen sulfate (TBAHSO4) or tricaprylmethylammonium chloride (Aliquat 336). These are added in an amount of 1-50% by weight, preferably 5-30% by weight, of the mass of the formalin solution or, if solid paraformaldehyde is used, in an amount of 1-20% by weight, preferably 3-10% by weight, of the mass of the aqueous solution and solid paraformaidehyde, or in an amount of 1-50% by weight, preferably 5-15% by weight, of the amount of 2-ethyl hexanal. The mixture of the initial materials is heated to 30°-100° C., preferably to 50°-80° C., and most preferably to 60°-80° C., and an aqueous solution of the alkali metal hydroxide or earth alkali metal hydroxide is added to the mixture, drop by drop, in the course of up to 5 h, preferably 1-3 h, and the reaction is continued at the said temperature for up to 3 h, preferably 15 min-2 h, most preferably 15 min-1 h 15 min. The alkali metal hydroxide or earth alkali metal hydroxide is used in a molar amount 1:1 to 2:1, preferably in a molar amount of 1.25:1 to 1.75:1 to that of 2:1-ethyl hexanal. After this reaction step the mixture is neutralized with an organic acid or a mineral acid, preferably for example sulfuric acid, and the phases are separated from each other, preferably while they are hot. The organic phase is washed with water once or several times, preferably 1-2 times, by using for the wash an amount of water at minimum 50% of the mass of the organic phase. The phases are separated and the organic phases are combined and vacuum distilled. The boiling point of the final product is 130°-132° C./9 mmHg. The yield obtained for 2-n-butyl-2-ethyl-1,3-propane diol was up to more than 92%, depending on the reaction conditions and the molar proportions.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:18])[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.[H-].[Na+].[CH2:21](Br)[C:22]#[CH:23].[OH-].[Na+]>CN(C)C=O>[CH2:23]([N:9]1[C:8](=[O:18])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2][CH2:1][N:12]([C:13]=23)[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2)[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: O=C1Nc2ccccc2N2CCc3cccc1c32
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2cccc3c2N(CC3)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
A mixture prepared from 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepin-6-one (8.3 gm, 35 mmole) and sodium hydride (1.65 gm, 50% in oil, 1.0 eq) in dimethylformamide (DMF, 80 ml) was stirred at room temperature for 1.5 hours under N2. It was cooled to ~0° C. To this solution was charged propargyl bromide (16.5 gm, 80% in toluene, 3 eq) and the mixture was stirred for another 1.5 hours at 0° C. At the end of the reaction, the solution was poured into 10% NaOH (250 ml), and extracted with dichloromethane (DCM 1 l). The DCM solution was washed with NaOH (250 ml), water (2×300 ml) and brine (2×300 ml), then dried over MgSO4 and concentrated to an oil. Purification was accomplished by flash chromatography (SiO2 column, 200 gm, eluted with 1:1 hexane:DCM, 4 l). The material thus purified weighed 7.1 gm, (74%) as an oil. It turned to solid upon trituration with ether. A 3 gram portion of this material was recrystallized from ether (150 ml) to afford 1.9 gm of yellow crystals, m.p. 104°-105° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](C=O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([OH:31])=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Solvent: ClCCl
Product: Oc1cccc(-c2ccccc2)c1OCc1ccccc1
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (14.4 g, 50 mmol) in dichloromethane (250 mL) was stirred on an ice bath and m-chloroperbenzoic acid (70%, 13 g) was added in portions over 20 min. Stirring was continued overnight at room temperature. The reaction mixture was diluted with dichloromethane (to 600 mL) and washed with saturated sodium bicarbonate (2×300 mL) and water (300 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator. The residue was taken in methanol (250 mL), potassium hydroxide (5 g) was added and this mixture was stirred at room temperature for 2 hr. The solvent was removed in a rotary evaporator. The residue was taken in water (200 mL) and made acidic with 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (450 mL). The organic extract was washed with water (100 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by chromatography on silica (360 g) with 10% ethyl acetate in heptane (4 L) to afford 30 (12 g, 87%).
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[NH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:29]4[CH:34]=[C:33]([NH2:35])[C:32]([F:36])=[CH:31][C:30]=4[CH3:37])[C:22](=[O:28])[N:23]3[CH2:26][CH3:27])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:29]3[CH:34]=[C:33]([NH2:35])[C:32]([F:36])=[CH:31][C:30]=3[CH3:37])[C:22](=[O:28])[N:23]2[CH2:26][CH3:27])=[CH:18][N:17]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NCc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(N)cc21
Temperature: 50 °C
Yield: 46 %

Procedure:
TFA (2 mL, 26.9 mmol) was added to a solution of 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one in DCM (10 mL) and the reaction mixture was refluxed at 50° C. for 2 h. After cooling to RT, the reaction mixture was washed with water and the combined aqueous layers were neutralized with satd. NaHCO3. The aqueous layer was extracted with EtOAc (3×) and the extracts were dried (Na2SO4) and concentrated to give 7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (0.9 g, 46% yield, over 2 steps). 1H NMR (300 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.56 (s, 1H), 6.83 (d, J=12.3 Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.40 (s, 2H), 6.32 (s, 1H), 4.85 (s, 2H), 4.07 (q, J=6.9 Hz, 2H), 1.94 (s, 3H), 1.19 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 313.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27]([O:29][CH3:30])=[O:28])[O:22][C:21]4=[O:31])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])(C)(C)C.Cl>C(OCC)C>[CH3:1][O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH:26][C:27]([O:29][CH3:30])=[O:28])[O:22][C:21]4=[O:31])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7]
Reactant: COC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)OC(C)(C)C)C4)cc2)C(=O)O1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)OC)C4)cc2)C(=O)O1

Procedure:
To a solution of compound (310 mg, 0.72 mmol) obtained in Step 2, in diethylether (10 mL) was passed HCl gas for about 30 min. at r.t. The solid precipitates were washed with diethylether (10 mL) and ethyl acetate (10 mL) and dried under reduced pressure to give the title compound.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[S:4][N:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][C:5]2[S:4][N:3]=[C:2]([NH:22][CH:19]([CH3:21])[CH3:20])[N:6]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(CNc1nc(Cl)ns1)c1ccc(F)cc1
Reactant: CC(C)N
Product: CC(C)Nc1nsc(NCC(C)(C)c2ccc(F)cc2)n1
Temperature: 110 °C

Procedure:
3-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5-amine (50 mg, 0.18 mmol, 1.0 equiv) and i-PrNH2 (0.5 mL, 5.8 mmol) were loaded into a microwave vial, and the resulting mixture was heated to 110° C. for 30 minutes. The reaction mixture was then concentrated in vacuo. Purification by silica gel (20-30% EtOAc/Hexanes) provided the title compound as an off white solid (55 mg, 99%). m/z=309.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cc(F)cc21
Reaction time: 1 h
Yield: 130.3 %

Procedure:
Aq. 4 M NaOH (5 mL) was added to a stirring mixture of 4-bromo-6-fluoro-1H-indole (500 mg, 2.34 mmol; Intermediate 35), benzenesulfonyl chloride (329 μL g, 2.57 mmol) and tetrabutylammonium hydrogen sulfate (78 mg, 0.23 mmol) in DCM (30 mL). The reaction mixture was stirred 1 h, combined with an earlier batch of this intermediate (followed this experimental and starting with 4-bromo-6-fluoro-1H-indole, 152 mg, 0.71 mmol; Intermediate 35), washed twice with water, dried and concentrated. The product (1.08 g, 100%) was obtained as a beige solid. MS (ESI+) for C14H9BrFNO2S m/z 354 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>C(#N)C.[Cl-].[Na+].O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCCCC3)C2)cc1
Yield: 0.2 %

Procedure:
A mixture of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (see Preparation 54) (1.5 g, 1 mol. equiv.), piperidine (0.6 g, 1.5 mol. equiv.) and potassium carbonate (1.31 g, 2 mol. equiv.) in acetonitrile (20 ml) was heated under reflux under nitrogen for four hours. Saturated aqueous sodium bicarbonate solution and brine were added and the mixture extracted with ethyl acetate (2×40 ml). The organic extracts were combined and dried using magnesium sulphate. The organic solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica gel eluting with methanol:dichloromethane (1:9, by volume) to give the title compound (0.65 g). TLC Rf=0.5 (silica, methanol:dichloromethane, 1:9, by volume). LRMS m/z=307(m+1)+. Found: C, 81.50; H, 8.51; N, 9,02. C21H26N2.0.06 CH2Cl2 requires C, 81.14; H, 8.45; N, 8.99%.