Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)(C)(C)C.CCOCC.C(OCC)(=O)C.[ClH:54]>>[ClH:54].[ClH:54].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)[C@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3.5 h

Procedure:
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.72 g of tert-butyl 3(R)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3.5 hours. Ether (10 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.50 g of 3(R)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:28]([NH2:30])=[O:29])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH:31]([S:33]([CH:36]=[CH2:37])(=[O:35])=[O:34])=[CH2:32]>CC(O)C>[O:34]=[S:33]1(=[O:35])[CH2:36][CH2:37][N:1]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][O:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)[CH:12]=[C:11]([C:28]([NH2:30])=[O:29])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:32][CH2:31]1
Reactant: NC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1[nH]c1cc(N)ccc12
Reactant: C=CS(=O)(=O)C=C
Solvent: CC(C)O
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A mixture of 7-amino-2-(4-(morpholinomethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (50 mg, 0.125 mmol), vinyl sulfone (0.13 mL, 1 3 mmol) in 2-propanol (3 mL) was stirred at 100° C. overnight. The solvent was removed and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-(1,1-dioxido-4-thiomorpholinyl)-2-(4-(4-morpholinylmethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (6 mg, 10.97 μmol, 8.81% yield). MS (ESI) m/z 520.22 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.22 (1H, s), 8.54 (1H, br. s.), 8.30 (1H, s), 8.22 (2H, d, J=8.24 Hz), 8.09 (1H, d, J=8.55 Hz), 7.82 (1H,s),7.46 (2H, d, J=7.93 Hz), 7.32 (1H, d, J=2.14 Hz), 7.07 (1H, dd, J=8.85, 2.14 Hz), 3.88 (4H, br. s.), 3.58-3.65 (4H, m), 3.55 (2H, s), 3.20-3.27 (4H, m), 2.41 (4H, br. s.).
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 7.9 %

Procedure:
To the solution of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (100 mg, 0.239 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (64.4 mg, 0.287 mmol) in NMP (1 mL) was added K2CO3 (132 mg, 0.957 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (9 mg, 7.85% yield). LCMS: rt=3.54 min, [M+H+]=479
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH2:15]([C@H:17]1[CH2:22][O:21][CH2:20][C@H:19]([CH3:23])[NH:18]1)[CH3:16]>C1COCC1>[CH2:15]([C@@H:17]1[N:18]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:19]([CH3:23])[CH2:20][O:21][CH2:22]1)[CH3:16]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC[C@H]1COC[C@H](C)N1
Solvent: C1CCOC1
Product: CC[C@H]1COC[C@H](C)N1c1nc2c(C(=O)OC)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (750 mg, 3.54 mmol) and (3S,5S)-3-ethyl-5-methylmorpholine (1.00 g, 7.75 mmol) in THF (40 mL) was stirred at ambient temperature overnight. Then the reaction mixture was heated in a 50° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature and most of the THF was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with 0.5 N HCl (25 ml), H2O (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexanes to 10% EtOAc in hexanes) to give methyl 2-((3S,5S)-3-ethyl-5-methylmorpholino)benzoxazole-4-carboxylate (540 mg, 50%), as a colorless oil. 1H NMR consistent.
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].C(C1C=NN2[C:24]([C:25]3[CH:26]=[C:27]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:22]=NC=12)#N.C(OCC)(=O)C>C(O)(=O)C>[CH3:36][N:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:24]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:22][CH:23]=2)[CH:26]=1)[S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(C)(=O)=O
Yield: 83 %

Procedure:
A mixture of 0.1 g (0.52 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.146 g (0.93 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-methanesulfonamide (obtained as described in Example 2) in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 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 178 mg N-methyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-methane-sulfonamide as a yellow solid (yield 83%; m.p.=169-170° C.).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])[CH:24]=2)[CH2:19]1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.O>C(OC(C)C)(=O)C>[CH2:1]([N:3]([C@H:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])[CH:24]=2)[CH2:19]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)[C@@H]1Cc2ccc(SC(C)(C)C(=O)O)cc2C1
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionate (288 g, 0.534 mol) was added a solution of sulfuric acid (535 g, 5.34 mol) in isopropyl acetate (0.7 L) while maintaining the reaction temperature at about 15-20° C. The clear solution was stirred at 15° C. for 1 hour after the addition. To the reaction mixture was added cold water (0.94 L). After removal of the acidic aqueous layer, the isopropyl acetate layer was washed until the pH of the aqueous layer reached 3. The solution was used in the next step without isolation.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:23]([NH2:25])=[NH:24])[S:20][CH:21]=1)=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:28][CH2:29][CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C(N(CC)CC)C>[N+]([O-])([O-])=O.[Ag+].CN(C)C=O>[C:1]([NH:9][C:10]([NH:28][CH2:29][CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[N:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:23]([NH2:25])=[NH:24])[S:20][CH:21]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Nc1nc(CSCCNC(=S)NC(=O)c2ccccc2)cs1
Reactant: NCCc1c[nH]cn1
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)Nc1nc(CSCCN=C(NCCc2c[nH]cn2)NC(=O)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-3-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]thiourea (0.394 g), histamine dihydrochloride (0.276 g), triethylamine (0.20 g), silver nitrate (0.204 g) and dimethyl formamide (20 ml) was stirred at room temperature overnight. After filtration the solution was evaporated to dryness and the residue purified by preparative thin layer chromatography (Merck 60F-254 plates developed with ethyl acetate/ethanol/ammonia (s.g. 0.88) 6:1:1 v/v/v). Isolation of the main band (RF 0.3) gave an oil which crystallized on trituration with acetone to give 1-benzoyl-2-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-3-[2-(imidazol-4-yl)ethyl]guanidine, decomposing at 147°-150° after softening at 115°-117°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:17][C:18]([F:27])([F:26])[C:19]1[N:23]=[C:22]([CH2:24][NH2:25])[O:21][N:20]=1>>[Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:14]([NH:25][CH2:24][C:22]1[O:21][N:20]=[C:19]([C:18]([F:27])([F:26])[F:17])[N:23]=1)=[O:16]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 97%, 448.9532 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=2)[CH:23]=[CH:22][C:21]=1[OH:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:9]1([C:8]2[C:3]([CH2:2][O:32][C:21]3[CH:22]=[CH:23][C:24]([C:26]4[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=4)=[CH:25][C:20]=3[CH3:19])=[C:4]([N:12]3[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]3)[CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: Cn1nnn(-c2cccc(C3CC3)c2CBr)c1=O
Reactant: Cc1cc(-c2ccn(C)n2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-c2ccn(C)n2)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(2-bromomethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 0.30 g, 2-methyl-4-(1-methyl-1H-pyrazol-3-yl)-phenol (described in Reference Preparation example 29) 0.18 g, potassium carbonate 0.18 g and acetonitrile 10 ml was stirred with heating under reflux for four hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was then concentrated. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-[2-methyl-4-(1-methyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 12”) 0.22 g.
Reaction SMILES: NN=C([C:10]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15](N)[C:14]=2[CH:13]=[CH:12][C:11]=1CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:33].[NH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.S(=O)(=O)(O)O.N>O.C(O)C>[ClH:33].[CH2:24]1[C:16]2[N:15]3[C:37]4[CH:38]=[CH:39][N:34]=[CH:35][C:36]=4[C:13]4[CH2:12][CH2:11][CH:10]=[C:20]([C:14]=43)[CH:19]=[CH:18][C:17]=2[CH2:21][CH2:22][CH2:23]1
Reactant: NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N
Reactant: O=C1CCNCC1
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reaction time: 0.67 h

Procedure:
A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz[b,f]azepine) and 14.8 g. of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes and cooled; a solution of 20 g. of concentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 l. of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and 1N hydrochloric acid, and dried in vacuo at 100° to yield 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:16])=[N-]>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-3-nitro-benzoic acid (6 g, 33 mmol) in methanol (20 mL), an ethereal solution of diazomethane gas was added until the staring material is completely consumed. The reaction mixture was then evaporated under reduced pressure. The crude solid obtained was purified by flash column chromatography using 5% ethylacetate & hexane as an eluent, to obtain the required product as a yellow coloured solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and morpholine. Yellow solid. MS (m/e): 341.3 ({37Cl}M+H+, 20%), 339.1 ({35Cl}M+H+, 100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([C:15]#[N:16])[C:9]=1[N+:17]([O-:19])=[O:18].[CH2:20](I)[CH3:21]>CN(C=O)C>[Cl:14][C:12]1[N:11]=[C:10]([C:15]#[N:16])[C:9]([N+:17]([O-:19])=[O:18])=[C:8]([NH:7][CH2:20][CH3:21])[CH:13]=1
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
At room temperature, potassium carbonate (3.06 g) was added by portions to a solution of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (4.0 g) in DMF (60 mL). A solution of ethyl iodide (3.46 g) in DMF (20 mL) was added dropwise to the mixture, then stirred for 24 h at room temperature and concentrated under reduced pressure. The residue was partitioned between water (50 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (3×50 ml), then concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: dichloromethane) to afford the title compound (2.94 g) as yellow crystals (mp=120° C.). 1H NMR (DMSO-d6) δ: 8.67 (br. s, 1H); 7.46 (s, 1H); 3.51 (q, J=8 Hz, 2H); 1.21 (t, J=8 Hz, 3H). MS m/z: 227/229 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1>>[CH2:15]1[O:14][C:13]2[CH:17]=[CH:18][C:10]([CH2:9][N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)=[CH:11][C:12]=2[O:16]1
Reactant: O=C1CCNCC1
Reactant: ClCc1ccc2c(c1)OCO2
Product: O=C1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
1-(3,4-Methylenedioxy)benzyl-4-piperidone is prepared from 4-piperidone and 5-chloromethyl-1,3-benzodioxole essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[CH3:21][O:22][C:23](=[O:41])[C:24]([CH3:40])([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25].[F-].[Cs+]>COCCOC.O>[CH3:21][O:22][C:23](=[O:41])[C:24]([N:26]1[CH:30]=[C:29]([C:17]2[CH:16]=[N:15][C:14]([NH2:20])=[C:13]([O:12][CH:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[Cl:1])[CH3:11])[CH:18]=2)[CH:28]=[N:27]1)([CH3:40])[CH3:25]
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(C)(C)n1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Temperature: 120 °C

Procedure:
To a solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (6.363 g, 14.901 mmol) and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]propionic acid methyl ester (4.6 g, 15.64 mmol) in DME (27 mL) was added a solution of CsF (6.79 g, 44.7 mmol) in water (9.3 mL). The reaction mixture was degassed 3 times with N2. Pd(dppf)CH2Cl2 was added and the reaction mixture was degassed 3 times with N2. The reaction was heated to 120° C. in the microwave (subsequent Pd was added in intervals of 30 minutes until the reaction was complete). Water was added and the reaction was extracted with EtOAc, dried over Na2SO4, and concentrated to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester. The crude product was purified by a silica gel column chromatography with a gradient of 25%-50% EtOAc/hexanes to provide 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid methyl ester (1.46 g, 21% yield) with a Rf 0.11 (50% EtOAc/hexanes).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[S:25][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: COCCOc1cccs1
Product: COCCOc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-(2-methoxy-ethoxy)-thiophene (prepared by cupric oxide-mediated coupling of 2-methoxy-ethanol and 2-iodo-thiophene, J. Am. Chem. Soc. 1953, 3697).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=2[OH:33])[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Reactant: COC(=O)c1ccc(O)c(Br)n1
Product: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)c(OCc3ccccc3)c2)n1
Yield: 65 %

Procedure:
According to the method described in example 4.3, starting from 4.95 g (16.7 mmol) of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid and 3.88 g (16.72 mmol) of methyl 6-bromo-5-hydroxypyridine-2-carboxylate, we obtain 4.38 g of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[Cs+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(COC)OC.ClCCl>[CH3:10][O:9][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-({methyl[(4-bromophenyl)methyl]amino}sulfonyl)acetate (300 mg, 0.9 mmol) in dimethoxyethane (5 ml) was added 4-cyanophenylboronic acid (Preparation 6, 150 mg, 1.0 mmol), caesium fluoride (290 mg), tri-ortho-tolyl phosphine (28 mg, 0.09 mmol) and bis(benzylideneacetone)palladium(0) (25 mg, 0.04 mmol) and the mixture was heated to reflux for 1 hour under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, diluted with dichloromethane (30 ml) and washed with water. The organic layer was dried (Na2SO4), the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1 as eluent) to give the titled compound as a pale yellow low melting solid (230 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([CH3:21])[C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:22]1([C:28]2[N:33]=[N:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]([C:14]1[N:32]3[N:33]=[C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=[CH:30][C:31]3=[N:34][N:35]=1)[CH3:21])=[CH:8][CH:7]=2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cnc2ccc(C(C)c3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.130 g, 0.45 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.17 g, 0.90 mmol), HYDROCHLORIC ACID (0.11 ml, 1.4 mmol), and water (0.2 mL) as solvent. The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 15 min. at 140° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and the solid was collected by filtration. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=97%:3%, Flow=40 mL/min) to afford the desired product as light yellowish solid. MS m/z: 382.3 (M+H). Calc'd. for C23H19N5O—381.43.