Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[C:9]([O:23][CH3:24])[CH:8]=1)[CH3:2].ClCCl.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.CN(C)C1C=CN=CC=1.O.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([S:37]([CH3:36])(=[O:39])=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[C:9]([O:23][CH3:24])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(OC)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc(Oc2ccc([N+](=O)[O-])cn2)c(OC)c1)S(C)(=O)=O
Temperature: 30 °C
Reaction time: 14 h

Procedure:
A solution of ethyl[3-methoxy-4-(5-nitropyridin-2-yloxy)phenylamino]acetate (2.43 g, 7.00 mmol) was dissolved in THF (15 mL), dichloromethane (20 mL) and DMF (10 mL), and to the resulting solution were added triethylamine (1.95 mL, 13.99 mmol), 4-dimethylaminopyridine (0.86 g, 7.00 mmol) and methanesulfonyl chloride (1.08 mL, 13.99 mmol) under ice cooling. The resulting solution was stirred for 14 hours at 30° C. Water was added to the reaction mixture, and extracted with dichloromethane. The dichloromethane layer was washed with water and brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to thereby yield 1.10 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:15]2[N:14]=[C:13]([CH3:21])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[I:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[N:7]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:20])[C:19]([I:28])=[C:15]2[N:14]=[C:13]([CH3:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)cc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(I)c2n1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a 0° C. stirred solution of cyclopentyl-[2-(2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino)-ethyl]-carbamic acid tert-butyl ester (89 mg, 0.24 mmol) in chloroform (5 mL) was added N-iodosuccinimide (54 mg, 0.24 mmol). After stirring 30 minutes the reaction was extracted from saturated aqueous sodium thiosulfate with chloroform. The combined extracts were dried (Na2SO4), concentrated under reduced pressure to give the product as a slightly yellowed glass (102 mg, 85%): +APcI MS (M+1)+ 500; 1H NMR (CDCl3) δ: 5.82 (s, 1H), 4.25-4.10 (br s, 1H), 3.46 (s, 4H), 2.51 (s, 3H), 2.41 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [F-:1].[K+].[F-].[Cs+].Cl[C:6]1[C:11]([F:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1>S1(CCCC1)(=O)=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:6]1[C:11]([F:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(C(F)(F)F)cnc1F
Temperature: 140 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
47.7 g (0.82 mol) of potassium fluoride and 10.0 g (0.065 mol) of caesium fluoride are suspended in 300 ml of sulfolane and the suspension is heated to 140° C. 60 ml of sulfolane are distilled off by decreasing the pressure and subsequently 65.6 g (0.329 mol) of 2-chloro-3-fluoro-5-trifluoromethylpyridine and 1.3 g (0.004 mol) of 18-crown-6 are added. The reaction mixture is stirred for 48 hours at 140° C. and subsequently distilled by introducing steam. The oil is separated and the aqueous phase is extracted twice with a small amount of ether. The organic phases are purified, dried with a small amount of magnesium sulfate and filtered. Distillation affords 54.8 g (91% of theory) of 2,3-difluoro-5-trifluoromethylpyridine, b.p. 100°-102° C. (980 mbar).
Reaction SMILES: [CH3:1][CH:2]1[CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:1][CH:2]1[CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CCC(C)NC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CCn2c(cc3ccc(C(=O)O)cc32)C(=O)N1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
To a solution of ethyl 3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (120 mg, 0.42 mmol) in ethanol (10 mL) is added 1M NaOH solution (1.0 mL, 1.0 mmol). The reaction mixture is heated at 80° C. for 2 h. Acetic acid (3 mL) is and water (60 mL) are added and the mixture is concentrated. The residue is purified by preparative HPLC to afford the title compound (63 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C:16]#[C:17][C@@H:18]([OH:33])[C@@H:19]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>O1CCCC1.O.C(O)C>[CH2:1]([O:8][C@@H:9]([CH:16]=[CH:17][C@@H:18]([OH:33])[C@@H:19]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC[C@H](OCc1ccccc1)[C@H](O)C#C[C@@H](CC(OC)OC)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC[C@H](OCc1ccccc1)[C@H](O)C=C[C@@H](CC(OC)OC)OCc1ccccc1
Reaction time: 0.3 h
Yield: 81.9 %

Procedure:
A solution of 654 mg (1.44 mM) of (3R,6R,7S) 3,7-dibenzyloxy-1,1-dimethoxydodeca-4-yn-6-ol [3b] described above in 10 ml of anhydrous tetrahydrofuran was dropwise added at 0° C. to a suspension of 115.7 mg (3.02 mM) of lithium aluminum hydride in 5 ml of anhydrous tetrahydrofuran, the mixture was stirred for 18 minutes under reflux. After completion of the reaction, ethyl acetate, ethanol, water and 0.1 N hydrochloric acid were added in sequence. Then, the aqueous phase was extracted with diethyl ether 3 times. The extracts were combined and washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and 538 mg (1.18 mM) of (3R,6R,7S) 3,7-dibenzyloxy-1,1-dimethoxydodeca-4-en-6-ol [5] was obtained from the fraction eluted with diethyl ether : hexane=1:3. Yield, 82%.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([N:9]1[CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[CH2:11][CH2:10]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cccc2c1CCNCC2
Solvent: c1ccncc1
Product: CC(=O)N1CCc2cccc(Cl)c2CC1

Procedure:
A solution of 1.5 g. of 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine, 2.0 g. of acetic anhydride and 20 ml. of pyridine was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue washed with 3N hydrochloric acid, then water, to yield 3-acetyl-6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine melting at 64°-66°. This amide was reduced in ether with a 50% excess of lithium aluminum hydride at reflux for 6 hours. Upon decomposition of excess reducing agent, the reaction mixture was filtered and the ethereal filtrate dried over magnesium sulfate. The filtrate was treated with ethereal hydrogen chloride solution to precipitate 6-chloro-3-ethyl-2,3,4,5-tetrahydro-1H -3-benzazepine as the hydrochloride salt which melted at 274°-275° from absolute alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C1COCC1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]([CH2:14][OH:15])[CH2:11][C:12]2=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(F)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(CO)CN1c1ccc(F)cc1

Procedure:
A 500 mL round-bottomed flask was charged with methyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate 52 (7.50 g, 31.6 mmol), sodium borohydride (1.32 g, 34.8 mmol), and 100 mL of THF. After being heated to reflux, 15 mL of MeOH was slowly added. After 1 h at reflux, the reaction was concentrated, 100 mL of water was added, and the mixture was extracted with DCM. The combined extracts were dried and concentrated to give 1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one 53.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C@H:13](O)[CH2:12]2)[C:7]1=[O:25].CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][C@H:13]1[C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:15][CH2:16][N:11]([CH:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:2]([F:1])[CH:3]=3)[C:7]2=[O:25])[CH2:12]1
Reactant: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)cc4)[C@H](O)C3)C2=O)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1F
Reaction time: 1 h
Yield: 7.8 %

Procedure:
To a solution of (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.7 mmol) in DCM (20 mL) was added DAST (0.5 mL, 3.5 mmol) and the reaction mixture was stirred under nitrogen for 1 h. The reaction was then quenched by the addition of 100 mL of a saturated sodium bicarbonate solution and the mixture was diluted with 100 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was subjected to preparative HPLC (method B) to yield 22 mg of (±)-rel-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one as a mixture of 4 diastereomers. LCMS (method P) RT 1.64 min; m/z=401.0 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@H:9]([CH3:10])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:10][C@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1 h

Procedure:
Methanol (2.0 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and bicyclic alcohol (110) (45 mg, 0.162 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1 hour then filtered through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with diethyl ether (3×3 mL) to obtain the crude (3R,3aR,6S,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (109) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1c(Br)cnn1C
Yield: 63.6 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-(trifluoromethoxy)phenyl isocyanate (0.025 g, 18.4 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 19 (0.032 g, 0.07 mmol, 58%) as a white solid, LCMS m/z (%)=485 (M+H79Br, 92), 487 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.19 (s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.51 (s, 1H), 7.45 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.9 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: CO[C:3](OC)([N:5]([CH3:7])[CH3:6])C.[C:10]([O:13][C@@H:14]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:25][S:24][C@H:15]1[O:16][C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:12])[CH3:11]>C(O)C>[CH3:3][N:5]([CH3:7])[CH:6]=[N:23][C:18]1[C:17]([O:16][C@@H:15]2[S:24][CH2:25][C@@H:26]([O:32][C:33](=[O:35])[CH3:34])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:14]2[O:13][C:10](=[O:12])[CH3:11])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1N
Reactant: COC(C)(OC)N(C)C
Solvent: CCO
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1N=CN(C)C
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
0.31 g (2.6 mM) of 1,1-dimethoxy-N,N-dimethylethanamine (N,N-dimethylformamide dimethylacetal) is added to a solution of 1 g (2.6 mM) of 2-amino-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside (Preparation 1) in 10 ml of ethanol. The mixture is heated, in a microwave-compatible container, with stirring at 120° C. for 20 minutes in a microwave oven. The reaction mixture is subsequently concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with ethyl acetate. The desired product is obtained in the form of a white solid with a yield of 46%.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:19]([O:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc(C(C)O)on1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
5.55 g of ethyl 5-(1-hydroxyethyl)-isoxazole-3-carboxylate was dissolved in 30 ml of N,N-dimethylformamide, and 2.38 g of imidazole and 5.28 g of t-butyldimethylsilyl chloride were then added. The mixture was stirred at room temperature for 10 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 8.95 g of ethyl 5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazole-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.Cl.C(=O)([O-])[O-]>O1CCOCC1.COCCO.C(OCC)C.C(Cl)Cl.C(Cl)Cl.CO>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1ccc2c(c1)CCN(C[C@@H](O)C(F)(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: COCCO
Solvent: CO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](O)C(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
(R)-3-(7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (82 mg, 0.30 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (81 mg, 0.27 mmol), and 4.00 M of Hydrogen chloride in 1,4-Dioxane (0.20 mL) were combined in 2-Methoxyethanol (2.5 mL) and heated at 120° C. After two hours, the mixture was cooled to room temperature, then diluted with 10 mL ethyl ether. A mixture of solids and gum formed, which was intractable, so the mixture was further diluted with 10 mL DCM and Macroporous carbonate resin (3.16 mmol/g loading; 0.64 g, 2.0 mmol) was added and stirred for 4 h, then filtered and concentrated in vacuo to afford a white solid, which was dissolved in DCM/MeOH, and chromatographed (ISCO, 2×12 g, 0-5% MeOH:DCM) to afford 2-{5-Chloro-2-[3-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (72 mg, 49%) as a white solid. m.p.=188-191° C.; LCMS (m/e) 535 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.07 (s, 1H), 8.65 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.43 (dd, 1H, J=7.8, 8.0 Hz), 7.28 (m, 2H), 7.09 (dd, 1H, J=7.4, 7.7 Hz), 7.03 (d, 1H, J=8.1 Hz), 6.88 (s, 1H), 4.40 (br m, 1H), 4.05 (m, 1H), 3.04 (d, 3H, J=4.8 Hz), 2.85 (m, 8H), 2.7 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:40][CH2:41][CH3:42])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[O:30])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:39])[CH3:2]>C(O)C.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[NH:15][C:8]2([CH2:28][C:29]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[O:30])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH:4]([O:40][CH2:41][CH3:42])[O:3][CH2:1][CH3:2])[C:7]2=[O:39])=[CH:24][CH:23]=1
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc([N+](=O)[O-])cc2)c2ccccc21)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(N)cc2)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A suspension of 0.62 g of (RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N′-(4-nitrophenyl)ureido)indolin-2-one and 20 mg of 5% Pd/C in 100 ml of ethanol was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through Cerite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 0.33 g (57%) of the title compound.
Reaction SMILES: [Na].[CH2:2]([N:9]1[C:13](=[O:14])/[C:12](=[C:15](/[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)\[CH3:16])/[C:11]([CH2:25][C:26]([O:28]C)=O)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CC(O)C>[CH2:2]([N:9]1[C:13](=[O:14])[C:12]2=[C:15]([CH3:16])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:26](=[O:28])[CH:25]=[C:11]2[NH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CC1=NN(Cc2ccccc2)C(=O)/C1=C(\C)NCc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: Cc1c2c(=O)n(Cc3ccccc3)[nH]c2cc(=O)n1Cc1ccccn1
Yield: 97 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.017 g, 0.713 mmol, 1 equiv) in i-PrOH (16 ml), was treated with methyl [(4E)-1-benzyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (0.270 g, 0.713 mmol, 1 equiv.). The reaction mixture was refluxed for 1 h, then cooled and neutralized to pH 7 by addition of 0.12 ml of a 20% aqueous HCl solution. 15 ml of i-PrOH were removed in vacuo and 10 ml of H2O were added before placing the flask in the fridge overnight. The white precipitate formed was filtered off, washed with water (2×3 ml), then with cyclohexane and dried in vacuo. 0.240 g of pure product 2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione was obtained. Yield 97%. 1H NMR (500 MHz, DMSO-d6, ppm) 2.78 (s, 3H), 4.81 (s, 2H), 5.37 (s, 2H), 5.59 (s, 1H), 7.31-7.26 (m, 5H), 7.36 (m, 2H), 7.76 (td, J 7.6, 1.9 Hz, 1H), 8.46 (dt, J 4.2, 1.6 Hz, 1H), 10.34 (s, 1H); MS (ESI+1)=347.2.
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9](N(OC)C)=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[CH3:15][Li]>CCOCC>[C:9]([C:5]12[CH2:8][N:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2)(=[O:10])[CH3:15]
Reactant: [Li]C
Reactant: CON(C)C(=O)C12CCCN(CC1)C2
Solvent: CCOCC
Product: CC(=O)C12CCCN(CC1)C2
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of (±) 1-azabicyclo[3.2.1]oct-5-yl-N-methyl-N-methoxycarboxamide (D3) (22.0 g; 0.11 mole) in dry ether (500 ml) was cooled to -30° C. under nitrogen and treated dropwise with methyl lithium (80.0 ml of a 1.4 M solution in diethyl ether; 0.11 mole). The rate of addition was controlled to ensure that the temperature of the reaction remained below 0° C. After stirring for 1 h at -10° C. the reaction was quenched by the addition of excess glacial acetic acid, while maintaining the temperature below -10° C. The ether solution was washed with a saturated solution of potassium carbonate. After extraction of the aqueous phase with chloroform (3×200 ml) the combined organic layers were dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:6]
Reactant: N=C(N)COCCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc(Cl)cc1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(4-chloro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(4-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as yellow oil. MS: m/e=388.1 [M+H+].
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:32])([CH3:31])[CH2:9]/[CH:10]=[CH:11]/[C@H:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@@H:13]2[CH2:18][CH2:19][S:20][C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH:1]1([CH2:7][C:8]([OH:32])([CH3:31])[CH2:9]/[CH:10]=[CH:11]/[C@H:12]2[CH2:16][CH2:15][C:14](=[O:17])[C@@H:13]2[CH2:18][CH2:19][S:20][C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1csc(SCC[C@H]2[C@@H](O)CC[C@@H]2/C=C/CC(C)(O)CC2CCCCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(SCC[C@H]2C(=O)CC[C@@H]2/C=C/CC(C)(O)CC2CCCCC2)n1
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of the compound 51 (242 mg) in dimethylsulfoxide (2.0 mL)/ethyl acetate (4.0 mL) were added diisopropylethylamine (0.70 mL) and sulfur trioxide-pyridine complex (320 mg) at 10° C. and the solution was stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed 1N hydrochloric acid, water and brine, anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=7:3) to give the title compound (154 mg) having the following physical data.