Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 107 mg (0.31 mmol) of the carbodiimide from Example 15A and 56 mg (0.31 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative HPLC result in 50 mg (28% of theory) of product.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([F:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(F)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2c(F)cccc2c1Cl

Procedure:
3-Butyryl-8-fluoro-4(1H)-quinolone (2.7 g, 12 mmol) and phosphoryl chloride (40 ml) were heated at reflux for 3 hours. Excess phosphoryl chloride was evaporated in vacuo. the residue poured onto ice and neutralised with aqueous ammonia. Filtration and washing with water gave 3-butyryl-4-chloro-8-fluoroquinoline ((1.75 g), m.p. 57°-60°.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:7]([CH3:25])[C:8]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)=[C:9]([CH3:16])[C:10]=1[C:11]([O:13]CC)=[O:12])C.Cl>[OH-].[Na+]>[CH3:25][N:7]1[C:8]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)=[C:9]([CH3:16])[C:10]([C:11]([OH:13])=[O:12])=[C:6]1[CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2cccnc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1cccnc1

Procedure:
Two grams of ethyl-1,4-dimethyl-3-ethoxycarbonyl-5-nicotinoylpyrrole-2-acetate (6 mmole) is heated to reflux with 10 ml of 20% aqueous sodium hydroxide solution for two hours. The reaction mixture is cooled to room temp. and acidified to pH 1 with 6 N HCl. The resulting white precipitate is filtered, washed with cold water and dried at room temperature to give crude 1,4-dimethyl-3-hydroxycarbonyl-5-nicotinoylpyrrole-2-acetic acid which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:6][CH2:5]1.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8]>C(O)C>[OH:6][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][NH:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:13]
Reactant: COCC1CO1
Reactant: CCOC(=O)CN
Solvent: CCO
Product: CCOC(=O)CNCC(O)COC
Yield: 100 %

Procedure:
A solution of glycidyl methyl ether (1.00 g) and glycine ethyl ester (5.91 g) in ethanol was stirred overnight, and concentrated under reduced pressure to obtain the title compound (2.17 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH:11]1([CH2:21][NH2:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][O:12]1.C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:22][CH2:21][CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][O:12]2)[CH:7]=1
Reactant: NCC1OCCc2ccccc21
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCC2OCCc3ccccc32)n1
Yield: 109.9 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.45 g, 2.5 mmol), C-isochroman-1-yl-methylamine (0.53 g, 3.2 mmol), and NaHCO3 (0.63 g, 7.5 mmol) in EtOH (5 mL) is heated to reflux for 4 h. The mixture is diluted with water, concentrated in vacuo. The residue is partitioned between EtOAc and water, and extracted with EtOAc. The extracts are dried (Na2SO4), and concentrated to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-isochroman-1-ylmethyl-amine (0.84 g). LCMS: RT=2.94 minutes; MS: 306 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH2:20])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH:20][C:28](=[O:31])[CH2:29][CH3:30])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)Cl
Reactant: Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Temperature: 25 °C

Procedure:
0.3 g (1.1 mmol) of the compound obtained in Example 71 are suspended in 15 ml dichloromethane, combined with 0.4 ml (2.5 mmol) triethylamine and gently refluxed. 0.2 ml (2.3 mmol) propionic acid chloride are added and the mixture is refluxed for 5 hours with stirring. After cooling to ambient temperature the reaction solution is washed with sodium hydrogen carbonate and water, dried and evaporated to dryness. The residue is stirred with diethyl ether and suction filtered. Yield: 0.2 g (m.p.: 274-275° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C@H:10]([OH:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C@H:10]([O:28][CH2:34][CH2:33][O:32][CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-trans-N-tert-butoxycarbonyl-3-hydroxy-4-(4-phenoxyphenoxy)-piperidine (1.47 g, 3.8 mmol) in dry DMF (30 ml) was added sodium hydride (300 mg 60% suspension in mineral oil, 4.2 mmol). After 1 h, 2-bromoethyl methyl ether (1.7 g, 7.6 mmol) was added. After 6 days water was added and the product was extracted with ethyl acetate (2×30 ml). After drying and evaporation the crude product was obtained as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[CH:18][C:19]=2[F:20])=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[C:10]([OH:25])[CH:9]=1.[C:26](=[O:34])([O:31][CH2:32][CH3:33])[O:27][CH:28](Cl)[CH3:29]>CO>[F:20][C:19]1[CH:18]=[C:17]([F:21])[CH:16]=[CH:15][C:14]=1[C:13]1[CH:12]=[C:11]([C:22]([O:24][CH:28]([O:27][C:26]([O:31][CH2:32][CH3:33])=[O:34])[CH3:29])=[O:23])[C:10]([OH:25])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CCOC(=O)OC(C)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of 1.76 g of the triethylamine salt of diflunisal and 1.0 g of 1-chloroethyl ethyl carbonate are heated in an oil bath at 100°-110° with magnetic stirring for 3 hours. The reaction mixture is then cooled to room temperature and 5 ml of methanol are added. After cooling to 0°-5°, the resulting precipitate is collected by filtration, washed with 3 ml of cold methanol then with 5 ml of 10% ethyl ether in hexane. After air drying there is obtained 1.38 g (75%) of 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate, m.p. 76°-78°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:19]([S-])=[S:20])C.[K+].C(O)C>O>[S:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1

Procedure:
A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.), potassium ethylxanthate (6.33 g.), ethanol (38 ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate, and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2SO4) organic solution was evaporated to yield ethyl 2-(2-chloro-5-benzoxazolyl)propionate as a brown oil which was shown to be a single compound by thin layer chromatography.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[N:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4]2[C:9](=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: OCc1cccc2cn[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCc1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
In a round-bottomed flask, (1H-indazol-7-yl)-methanol (572 mg, 3.09 mmol) was dissolved in DMF (8 ml) and potassium hydroxide (671 mg, 12.0 mmol) and iodine (1.57 g, 6.18 mmol) were added. The dark brown suspension was stirred at room temperature overnight then quenched with aqueous 10% Na2S2O3 and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 433 mg (51%) of (3-iodo-1H-indazol-7-yl)-methanol as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C>CO.Cl.O1CCOCC1>[CH3:19][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H]1CCC[C@H](C(=O)c2ccc(Br)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
To a solution of trans-3-(4-bromobenzoyl)cyclohexane-1-carboxylic acid (500 mg, 1.61 mmol, obtained from Rieke Metals Inc., Lincoln, Nebr., USA) and 2,2-dimethoxypropane (669 mg, 6.43 mmol) in methanol (20 mL), 5 drops of 4 M HCl in dioxane was added, and this reaction mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation to give the product 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester as a brown oil (500 mg, yield 95.7%). 1H NMR (300 MHz, DMSO) δ 7.80 (d, 2H), 7.60 (d, 2H), 3.70 (s, 3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90 (m, 4H), 1.70-1.50 (m, 4H); LC-MS ret. time 3.30 min, m/z 324.9 (MH+).
Reaction SMILES: COC([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=O.[CH3:16][O:17][C:18](C1NC2C(C=1)=CC=C(Br)C=2)=[O:19]>>[CH3:16][O:17][C:18]([C:6]1[N:7]([CH3:15])[C:8]2[C:13]([CH:5]=1)=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[O:19]
Reactant: COC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Product: COC(=O)c1cc2ccc(Br)cc2n1C

Procedure:
The title compound is prepared essentially as described in the preparation of 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester utilizing 6-bromo-1H-indole-2-carboxylic acid methyl ester, ES/MS m/e 270.0 (M+2).
Reaction SMILES: [H-].[Na+].[I-].[CH4:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1)([O-:7])=[O:6].O>CN(C)C=O>[CH3:4][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=2)=[C:15]1[C:23]([NH2:25])=[O:24]
Reactant: C
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(N)=O)c(-c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.047 g of sodium hydride and then 73 μl of methane iodide are added to a solution of 0.3 g of 3-(4-nitro-phenyl)-1H-indole-2-carboxamide in 8 ml of anhydrous dimethylformamide under argon. The reaction mixture is stirred at ambient temperature for 2 hours and 45 ml of water are added. The solid formed is filtered off, washed with 3 times 15 ml of water, and filter-dried. After drying under vacuum, 0.22 g of 1-methyl-3-(4-nitrophenyl)-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:5](=O)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:25]([C:24]1[CH:28]=[C:20]([N:19]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=3[CH:6]=[C:5]2[C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[OH:29])([OH:27])=[O:26]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(Cl)c(Cl)c3)cc3c2CCCC3)ccc1O

Procedure:
A solution of 15 g. (0.05 mole) of 2-(3,4-dichlorophenacyl)cyclohexanone, 7.7 g. (0.05 mole) of 5-aminosalicylic acid, and 63 ml. of glacial acetic acid was heated under reflux under nitrogen for 11/2 hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetonitrile to provide 19.4 g. (97%) of yellow crystals, m.p. 210°-211°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)C>O>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(Cl)nc3Cl)oc2c1
Reactant: C1COCCN1
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N4CCOCC4)nc3Cl)oc2c1

Procedure:
1.1 g (2.9 mmol) 6-[2-(2,6-dichloro-pyridin-3-yl)-benzoxazol-6-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 1 ml morpholine and 50 ml of ethanol are refluxed together for 3 h, then the solv. is eliminated by rotary evaporation i.V., the residue is stirred with water and filtered off. The crude product is recrystallised from aqueous isopropanol.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[CH3:3].Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.ClCCl>[CH3:1][N:2]([CH3:3])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)C(=O)CCl
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-N,N-dimethylamino phenol (69) (3.43 g, 25 mmol) and 2-chloro N,N-dimethylacetamide (3.66 g, 30 mmol) in DMSO (30 mL) was added K2CO3 (6.7 g, 50 mmol) and the resulting suspension was stirred at room temperature for 16 h. The reaction was then diluted with dichloromethane (125 mL), and washed with water (2×100 mL), and brine (100 mL), and dried, and filtered, and the solvent was removed under vacuum. The crude product, Compound 70, was obtained as purple, thick oil that was used in the next step without additional purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a stirred solution of 2-dimethylamino-ethylamine (1.61 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/MeOH) to yield the title compound (1.23 g, 99%) as a light yellow oil. MS (ISP) 269.0 [(M+H)+].
Reaction SMILES: [CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([OH:33])=[O:32]>>[CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([C:28]5[CH:36]=[C:35]([F:37])[CH:34]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=5)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2ccc(OCc3cccc(B(O)O)c3)cc2sn1C1CCCC1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Product: O=C(O)c1cc(F)cc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)c1

Procedure:
A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), 3-bromo-5-fluorobenzoic acid (0.044 g, 0.20 mmol) were coupled according to the general procedure to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as pale yellow solid (0.010 g, over two steps 15%). 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.91-7.66 (m, 4H), 7.50-7.24 (m, 4H), 7.03 (s, 1H), 5.24 (s, 2H), 4.64-4.60 (m, 1H), 2.18-2.15 (m, 2H), 1.88-1.66 (m, 6H). LC-MS (ESI) Calcd for C26H22FNO4S [M+H]+: 463.12. Found: 464.00.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=2[C:29]([F:32])([F:30])[F:31])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 99.2 %

Procedure:
4-(4-Nitro-2-trifluoromethyl-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.5 g, 1.0 mmol) was suspended in a 5:1 mixture of ethanol and water (20 ml). To this solution was added iron powder (0.16 g, 2.6 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.44 g, 94% yield) as a yellow solid. Tr=2.03 min, m/z (ES+) (M+H)+ 444.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])[CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH3:57])[CH2:54][CH2:55]6)=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)c2cc(Cl)ccn2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)c2cc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)ccn2)CC1
Yield: 69.1 %

Procedure:
Using 4-chloropicolinic acid chloride and N-ethylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (232 mg, 0.430 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone (120 mg, 0.473 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-ethyl-piperazin-1-yl)-methanone as a yellow solid (225 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-201) as a yellow powder (85 mg, 57%).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:15]([NH2:16])=[C:14]([Cl:23])[CH:13]=1.O>C(#N)C>[Br:11][C:12]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:15]([NH:16][C:8](=[O:9])[CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([Cl:23])[CH:13]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyclopentyl propionyl chloride (1.28 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (22 μl, 3 eq) followed by addition of DIEA (94 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/brine. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (162) (13.9 mg, yield: 63.9%, purity>95%) as white solid.