Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:35].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:34](=[O:35])[CH2:33][N:3]2[C:4](=[O:31])[C:5]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=3[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[C:2]2=[O:1])=[CH:37][CH:38]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-fluorophenyl)ethanone (0.89 g) and N,N-dimethylformamide (50 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran to give the title compound as colorless crystals (1.08 g, 55%).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH:10]=[CH2:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[CH:10]=[CH2:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C=CCOC(=O)CN
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of glycine allyl ester, prepared as described by H. Waldmann and H. Kunz in Liebigs Ann. Chem., 1983, 1712-1725, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give glycine allyl ester isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[NH:18][C:17](=[O:19])[O:16][C:15]([CH2:25][CH3:26])([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28]C(C)([O-])C.[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:18]([CH3:28])[C:17](=[O:19])[O:16][C:15]([CH2:25][CH3:26])([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)[O-]
Reactant: CCC1(c2cccs2)OC(=O)Nc2ccc(Nc3ccc(F)c(Cl)c3)cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC1(c2cccs2)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a stirred solution of 6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.16 g, 0.39 mmol) in DMF (4 mL) was added potassium t-butoxide (0.05 g, 0.42 mmol) at room temperature. After 10 minutes, methyl iodide (0.05 mL, 0.80 mmol) was added. After 45 minutes, the reaction solution was quenched with ammonium chloride solution (sat) and extracted with ethyl acetate. The organic layer washed several times with brine and dried over magnesium sulfate. The solvent was removed to give 6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a red solid (0.12 g, 73%). 1H NMR (DMSO-d6): δ 8.31 (s, 1H), 7.53 (m, 1H), 7.27 (t, J=9.1 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 7.05 (m, 1H), 7.0 (m, 2H), 6.93 (m, 2H), 3.24 (s, 3H), 2.43 (m, 2H), 0.96 (t, J=5.9 Hz, 3H); MS (ESI) m/z 417/419 ([M+H]+); MS (ESI) m/z 415/417 ([M−H]−); Anal. calcd for C21H18ClFN2O2S: C, 60.50; H, 4.35; N, 6.72. Found: C, 60.22; H, 4.34; N, 6.63.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:21]2[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>CCOCC.C(Cl)Cl>[CH3:35][S:36]([OH:39])(=[O:38])=[O:37].[N:21]1([C:7]2[CH:8]=[CH:9][C:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)(=[O:13])=[O:12])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(=O)Nc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1S(=O)(=O)c1cccc(F)c1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1cc(N2CCCNCC2)ccc1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
To a mixture of tert-butyl 4-[3-(acetylamino)-4-[(3-fluorophenyl)sulfonyl]phenyl]-1,4-diazepane-1-carboxylate (0.508 g, 1.03 mmol) in 20 mL of a 1:1 Et2O:CH2Cl2 solvent is added anhydrous methanesulfonic acid (0.109 g, 1.14 mmol) and the mixture is stirred at rt for 2.5 h. Hot Et2O (10 mL) is added and the white solid is filtered, rinsed with Et2O and dried under vacuum to give 0.497 g (99%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[C:21]([O:32][CH3:33])=[C:22]([N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:23]=[C:24]([F:26])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:26][C:24]1[CH:25]=[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[C:21]([O:32][CH3:33])=[C:22]([N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:23]=1
Reactant: COc1c(C(=O)C=CN(C)C)cc(F)cc1N(C)C(C)=O
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1c(-c2ccnc3c(C(=O)c4cccs4)cnn23)cc(F)cc1N(C)C(C)=O
Yield: 40.5 %

Procedure:
A mixture of 0.180 g (0.93 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.275 g (0.93 mmol) of N-[3-(3-dimethylamino-acryloyl)-5-fluoro-2-methoxy-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 160 mg of N-{5-fluoro-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 40%).
Reaction SMILES: [O:1]=[C:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].Br[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=1[F:39].C(OCC)(=O)C.O>C(N(CC)CC)C.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>[O:1]=[C:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=2[F:39])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: C#CCN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
A mixture of 17.28 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)-piperidine-3-carboxylate in 173 cm3 of triethylamine is stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 g of 1-bromo-2,3,5-trifluorobenzene are added. The mixture is stirred for 2 hours at a temperature in the region of 80° C. After cooling to approximately 20° C., 150 cm3 of ethyl acetate and 150 cm3 of water are added to the reaction mixture, which is then separated after settling out. The aqueous phase is extracted with 3 times 150 cm3 of ethyl acetate. The organic phases are pooled, washed with 5 times 150 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20–45μ; diameter 7 cm; 600 g), eluting with pure ethyl acetate and collecting first a fraction of 2.5 1, and then fractions of 250 cm3. Fractions 2 to 29 are pooled and then concentrated as above. 18.4 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-piperidine-3-carboxylate, in the form of a yellow oil, are obtained.
Reaction SMILES: COC(=O)CC[S:6]([C:9]1[CH:14]=[C:13]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7].C[O-].[Na+].[Na].[NH2:40]OS(O)(=O)=O.C([O-])(=O)C.[Na+]>CS(C)=O.CO.O.CCOC(C)=O>[S:6]([C:9]1[CH:14]=[C:13]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])(=[O:7])[NH2:40]
Reactant: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccnc(S(=O)(=O)CCC(=O)OC)c1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1ccnc(S(N)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a solution of 3-[4-(1-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-butyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (60 mg, 0.12 mmol) in anhydrous DMSO (1.5 mL) is added sodium methoxide in methanol (2.7 M solution freshly prepared by dissolving 250 mg of sodium in 4.0 mL of methanol, 44 μL, 0.12 mmol). After stiffing at room temperature for 15 min, the reaction mixture is cooled to 0° C. and treated with a solution of hydroxylamine-O-sulfonic acid (260 mg, 2.3 mmol) and sodium acetate (150 mg, 1.9 mmol) in water (6 mL). The resultant mixture is warmed to room temperature and stirred overnight for 18 hours. EtOAc (100 mL) is added and the phases are separated. The organic layer is washed with water (4×15 mL, until pH of water layer is ˜5), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative reverse phase HPLC (eluted with 10 to 65% CH3CN/H2O and 0.1% TFA as additive) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(2-sulfamoyl-pyridin-4-yl)-butyl]-amide (39 mg, 75%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.C([Li])CCC.[CH:20](=[O:22])[CH3:21].O>O1CCCC1.CCCCCC>[C:4]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([CH:20]([OH:22])[CH3:21])=[CH:3]2
Reactant: BrC1=CC2(CCCC2)c2ccccc21
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: -70 °C
Reaction time: 2 h

Procedure:
3'-Bromospiro(cyclopentane-1,1'-indene) (23 g) is dissolved in tetrahydrofuran (200 ml) and cooled to -70° C. While stirring under nitrogen, n-butyllithium (75 ml of a 2 M solution in hexane) is added followed after 30 minutes by acetaldehyde (14 g) in one portion. Stirring and cooling is maintained for 30 minutes whereupon the mixture is allowed to come to about 20° C. and is kept there for 2 hours. Water (600 ml) is then added and the solution is extracted three times with diethyl ether. The ether extracts are washed, dried over sodium sulphate and the ether is distilled off. Distillation of the residual oil gives the title alcohol, b.p. 139° C./0.4 torr.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5].[BH4-].[Na+].O>CO>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)[OH:5]
Reactant: CC(C)CC(=O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CC(O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a 0° C. solution of 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (1.4 g, 4.7 mmol) in methanol (20 mL) was added sodium borohydride (367 mg, 9.4 mmol). The resulting mixture was stirred at 20° C. for 1 hour. Water was added and the mixture was extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-ol (1.4 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.82-7.79 (m, 2H), 4.82-4.77 (m, 1H), 1.83 (s, 1H), 1.75-1.64 (m, 2H), 1.47-1.43 (m, 1H), 0.88-0.92 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[O:13]C(=O)[NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[NH2:11][CH:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:24][CH:23]=1)[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[OH:13]
Reactant: CC(C)(C)c1ccc(CC2NC(=O)OC2c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (4RS,5SR)-4-(4-tert-butylbenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (9.50 g, 27.6 mmol) in ethanol (70 ml) was added 8N aqueous sodium hydroxide solution (17.3 ml, 138 mmol), and the mixture was stirred at 80° C. overnight. To the reaction solution was added water (20 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (8.82 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[S:31]1(=[O:37])(=[O:36])[CH2:35][CH2:34][CH2:33][NH:32]1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][CH2:35][S:31]4(=[O:37])=[O:36])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 44.2 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (85 mg) described in Preparation Example 241 and isothiazolidine 1,1-dioxide (36 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (45 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:19]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:27][CH2:26][CH2:25][CH2:24][C:20]1[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1ccnc(CCCN)c1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccnc(CCCNC(=O)/C=C/C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (64 mg, 0.46 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (40 μl, 0.46 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 3-(4-methyl-2-pyridyl)propan-1-amine hydrochloride (56 mg, 0.3 mmol) and EDIPA (240 μl, 1.4 mmol) in anhydrous dichloromethane (5 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 47 mg of a solid (0.17 mmol, 58% yield)
Reaction SMILES: [OH-].[Na+].CO.[N:5]1([C:10]2[CH:11]=[C:12]([CH:17]=[C:18]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:19]=2)[C:13]([O:15]C)=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O>[N:5]1([C:10]2[CH:11]=[C:12]([CH:17]=[C:18]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:19]=2)[C:13]([OH:15])=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(-c2nnn[nH]2)cc(N2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2nnn[nH]2)cc(N2CCCC2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Aqueous 2 N sodium hydroxide solution (1.26 mL) was added to an MeOH (5 mL) solution of methyl 3-pyrrolidin-1-yl-5-(tetrazol-5-yl)benzoate (35.6 mg), and stirred at 50° C. for 2 hours and 30 minutes. With cooling with ice, 2 N hydrochloric acid (2.52 mL) and water were added to it, and the formed precipitate was taken out through filtration, washed with water and dried to obtain the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:21][C@@H:22]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])[CH2:26][CH:27]1[CH2:29][CH2:28]1)(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and (S)-2-amino-3-cyclopropyl-propanamide hydrochloride as starting materials, MS (EI): m/e=384.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[C:10]2[CH:18]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[CH3:15])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1C=[N+]1CCOCC1
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3ccccc3C)N3CCOCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 4-(2-methyl-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1.[CH3:20][NH2:21]>O1CCCC1>[CH3:20][NH:21][C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CN
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 2-(2-pyridinyl)-3-H-imidazo[4,5-b]pyridine-3-acetic acid (2.44 g, 0.0096 mole), 1-1'-carbonyldiimidazole (1.56 g, 0.0096 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 5 hours. A solution of 1M monomethylamine in tetrahydrofuran (15 ml) was added and the reaction stoppered and stirred overnight. The tetrahydrofuran was evaporated in vacuo and the residue triturated in water (30 ml) and filtered. The filter cake was again triturated in water (30 ml) and filtered, giving 1.94 g (76%) of solid, mp 228°-230° C. Recrystallization from tetrahydrofuran-methanol gave 1.49 g of a white solid, mp 228.5°-230° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:28]3=[N:29][CH:30]=2)=[CH:7][N:6]=1)(=O)=O.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.CS(C)(=O)=O>O1CCOCC1>[CH3:23][CH:22]([CH3:24])[CH2:21][S:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([NH:11][C:9]2[C:8]([C:25]3[N:26]=[C:27]4[CH:33]=[CH:32][NH:31][C:28]4=[N:29][CH:30]=3)=[CH:7][N:6]=[C:5]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:10]=2)[CH2:13]1)(=[O:20])=[O:19]
Reactant: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(S(C)(=O)=O)ncc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Reactant: C1COCCN1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CCOCC3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of {2-methanesulfonyl-5-[5-(2-trimethysilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine from Example 3, step 1, morpholine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5 of Example 76 to give [(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-[2-morpholin-4-yl-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 501.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH3:20])[NH:8][C:9](=[O:19])[CH2:10][NH:11]C(OC(C)(C)C)=O.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH3:20])[NH:8][C:9](=[O:19])[CH2:10][NH2:11]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)CN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-Gly-Ala-Gly-OMe (6.4 g, 20.1 mmoles, described in Example 2) is dissolved in cold (ice bath) trifluoroacetic acid (120 ml) and the solution stirred at 0° C for 1 hr. The solvent is evaporated, the residue dissolved in methanol and the product precipitated with the addition of diethyl ether. The precipitiate is collected to give the title compound.