Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:13]([O-])=O.[Cl-].[NH4+]>C(O)C.CN(C)C=O.[Fe]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[NH2:13]
Reactant: COc1cc2ncccc2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2ncccc2cc1N
Yield: 84.9 %

Procedure:
A mixture of 7-methoxy-6-nitro-quinoline (5 g, 24.0 mmol), iron powder (9.8 g, 172 mmol) and ammonium chloride (9.1 g, 172 mmol) in a mixture of ethanol and water (3/1, 160 mL) was heated at reflux overnight. The resulting mixture was filtered through a CELITE™ pad, the filtrate was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc) to afford 3.551 g of 7-methoxy-quinolin-6-ylamine as a grey solid.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[NH:32][C:31]=2[CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH:35]3[CH2:36][CH2:37][N:38]([CH2:20][C:19]4[CH:22]=[CH:23][C:16]([C:7]5[C:8]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)=[CH:9][N:4]6[N:3]=[C:2]([CH3:1])[N:24]=[C:5]6[N:6]=5)=[CH:17][CH:18]=4)[CH2:39][CH2:40]3)[NH:32][C:31]=2[CH:41]=1
Reactant: Fc1ccc2nc(C3CCNCC3)[nH]c2c1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccc(F)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
200 mg (0.64 mmol)-4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 184 mg (0.76 mmol) 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After stirring at room temperature for five days and the usual workup und purification 142 mg of the desired compound have been obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:5][C:6]=1[C:7](OCC)=[O:8].C([O-])(=O)C.[NH4+].[CH:24]([NH2:26])=O>O>[C:16]([O:15][CH2:14][CH2:13][CH2:12][C:4]1[S:3][C:2]2[N:1]=[CH:24][NH:26][C:7](=[O:8])[C:6]=2[CH:5]=1)(=[O:18])[CH3:17]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(CCCOC(C)=O)sc1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)OCCCc1cc2c(=O)[nH]cnc2s1
Temperature: 145 °C
Yield: 73.6 %

Procedure:
A mixture of ethyl 2-amino-5-(3-acetyloxypropyl)-thiophene-3-carboxylate (2.6 g, 9.7 mmole), ammonium acetate (0.74 g, 9.7 mmole) and formamide (8.64 ml, 19.2 mmole), was stirred under reflux at 145° C. for 12 hours. It was then cooled, diluted with water (20 ml), extracted with ethyl acetate (3×25 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(3-Acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A26) (1.8 gm, 75%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cn1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cn3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(4-fluorophenyl)-2-pyridinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)=[CH:14][CH:13]=1>ClCCCl>[CH3:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: CSc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: CSc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
Phenyl isocyanate (0.79 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2[-4-(methylthio)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.8 g) in 1,2-dichloroethane (25 cc). The solution obtained is heated to 80° C. for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in acetonitrile, (5RS, 6SR)-2-[4-(methylthio)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1 g), m.p. 170° C., is obtained.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][CH3:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][CH3:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: COc1ccccc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccccc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(chloromethyl)-2-methoxybenzene and isolated as colorless gum (6.6 mg, 40%). MS (m/e): 403.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[NH:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([N:26]5[CH2:30][CH2:29][CH2:28][CH:27]5[CH:31]5[CH2:36][CH2:35][N:34]([CH:37]6[CH2:42][CH2:41][O:40][CH2:39][CH2:38]6)[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: C1CNC(C2CCN(C3CCOCC3)CC2)C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCCC4C4CCN(C5CCOCC5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (200 mg, 0.516 mmol), 4-(pyrrolidin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine hydrochloride (354 mg, 1.29 mmol), Pd(PtBu3)2 (20 mg, 0.04 mmol), Na2OtBu (148 mg, 1.55 mmol) in toluene (5.0 ml) in a seal tube was degassed with N2 for three times. The mixture was stirred at 110° C. for 120 min. The solid was filtered through Celite. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to give racemic 254 (13 mg, 4.6% yield). LCMS (ESI): RT=2.00 min, m/z: 546.4 [M+H+]. 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 6.47 (dd, J=9.5 Hz, 2.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.95-5.92 (m, 1H), 4.48-4.36 (m, 4H), 4.05 (d, J=8.5 Hz, 1H), 3.85-3.75 (m, 1H), 3.41-3.24 (m, 6H), 2.41 (s, 4H), 2.02-1.74 (m, 14H), 1.56 (d, J=6.5 Hz, 7H)
Reaction SMILES: [ClH:1].[CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:25])[CH:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH3:15])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(#N)C>[ClH:1].[C:26]([O:25][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([S:5][CH:2]([CH3:4])[CH3:3])=[CH:7][CH:8]=1)[CH:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH3:15])(=[O:28])[CH3:27]
Reactant: CCCCCCCCNC(CC)C(O)c1ccc(SC(C)C)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC#N
Product: CCCCCCCCNC(CC)C(OC(C)=O)c1ccc(SC(C)C)cc1

Procedure:
To 20 ml of acetonitrile, 5 gr (13 mmol) of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-butanol hydrochloride and 5.3 g (52 mmol) of acetic anhydride are added successively. The mixture is refluxed for 2.5 hours. When cooling, it abandons a white solid. The latter is filtered off and twice recrystallised from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[C:24](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=2[Cl:18])=[CH:6][C:5]2[NH:19][C:24]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1N
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Yield: 74 %

Procedure:
A solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (120 mg, 0.37 mmol), pentafluoropropanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath. Then the mixture was quenched with water (100 ml), pH adjusted to 7 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (124.4 mg, 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[NH:24][N:23]=2)[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][NH2:39])[CH2:33][CH2:32]1>C(O)CCC.CO>[CH:27]([C:25]1[NH:24][N:23]=[C:22]([NH:21][C:4]2[CH:3]=[C:2]([NH:39][CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[N:7]=[C:6]([NH:8][CH2:9][C:10]3[O:14][N:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=3)[N:5]=2)[CH:26]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1cc(Nc2cc(Cl)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Reactant: CN1CCN(CCN)CC1
Solvent: CCCCO
Solvent: CO
Product: CC(C)c1cc(Nc2cc(NCCN3CCN(C)CC3)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Temperature: 180 °C
Yield: 29.5 %

Procedure:
A mixture of 6-chloro-N4-(5-isopropyl-1H-pyrazol-3-yl)-N2-(3-phenylisoxazol-5-ylmethyl)-pyrimidine-2,4-diamine (250 mg, 0.611 mmol) and 2-(4-methylpiperazin-1-yl)-ethylamine (500 mg, 3.50 mmol) in 1-butanol (2 mL) was heated to 180° C. in a 50 mL sealed tube. The mixture was heated for 1 h, then cooled to room temperature and diluted with methanol (10 mL). The mixture thus obtained was purified via preparative reverse phase HPLC to give the desired product (93 mg, 29%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[CH:4][CH:3]=1.[Cl-].N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>ClCCCl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([S:12]([N:15]=[C:23]=[O:24])(=[O:13])=[O:14])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1c(Cl)cccc1S(N)(=O)=O
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cccc1S(=O)(=O)N=C=O
Temperature: 55 °C

Procedure:
100 g of methyl 6-chloro-2-aminosulfonyl-benzoate were suspended in 300 ml of 1,2-dichloroethane, 123 g of thionuyl chloride were added with stirring, and the mixture was slowly heated to the reflux temperature. After it had been stirred for 5 hours under reflux, it was cooled to 55° C., 1.5 ml of pyridine were added and the mixture again heated to the reflux temperature, while introducing phosgene. After 4 hours' treatment with phosgene gas, the reaction mixture was concentrated under reduced pressure and flushed with nitrogen. The oil which remained (105 g) was used, without further purification, for the subsequent stages.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.Cl>>[Br:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Br)CC1
Agent: Cl
Product: CN1CCC(Nc2cc(N)ncc2Br)CC1
Yield: 99.4 %

Procedure:
N-(5-Bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (526 mg, 1.075 mmol) in 6M HCl (10 mL, 60.0 mmol) was heated by microwave irradiation to 105° C. for 1.5 hr. After cooling the volatiles were removed in vacuo. The residue was purified by ion exchange on Isolute SCX II acidic resin, washing with MeOH and then with 2M NH3 in MeOH. The basic fractions were concentrated to give crude 5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (290 mg, 1.069 mmol, 100% yield) as a cream powder. LCMS (4) Rt=0.56 min; m/z (ESI+) 271/273 (MH+). Di-tert-butyl dicarbonate (73.6 μl, 0.317 mmol) dissolved in the minimum amount of dichloromethane was slowly added to an ice-cooled solution of 5-bromo-N4-(piperidin-4-yl)pyridine-2,4-diamine (86 mg, 0.317 mmol) in triethylamine (134 μL, 0.951 mmol) and dichloromethane (2.44 mL). The mixture was stirred at 0° C. for 30 min followed by 1 hr at r.t. Solvents were removed in vacuo and the crude material was purified by preparative thin layer chromatography, eluting with 7% MeOH, 1% NH3 in dichloromethane, to give tert-butyl 4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (91 mg, 0.245 mmol, 77%) as a colourless foam.
Reaction SMILES: CC([O-:5])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Cl)[C:13]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1>O1CCOCC1>[Cl:7][C:8]1[C:13]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:12]([OH:5])[CH:11]=[N:10][CH:9]=1
Reactant: Clc1cncc(Cl)c1COC1CCCCO1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Oc1cncc(Cl)c1COC1CCCCO1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
Potassium tert-butylate (1.77 g, 15.80 mmol) was added to a stirred solution of 3,5-dichloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (825 mg, 3.16 mmol) in dioxane. After stirring for 3 d at 100° C. the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 243.8 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:19])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:19])=[C:8]2[C:13]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:33][CH:32]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CO
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CO
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of compound 16B (84 mg, 0.30 mmol), 4-phenoxyaniline (72 mg, 0.39 mmol) and triethylamine (0.083 mL, 0.60 mmol) in THF (2.5 mL) was heated at 70° C. for 30 min. After cooled to room temperature, the reaction was concentrated to about 0.5 mL, diluted with MeOH (2 mL) and filtered. The solid was washed with MeOH and dried to give compound 16C as a yellow solid (118 mg, 92%). HPLC: 92% at 2.12 min (retention time) (PrimeSphere 5u C18-HC column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; mL/min, monitoring at 220 nm). MS (ES): m/z 429.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15](CCCCN)[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.Cl[CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[C:27]#[N:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28])[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: NCCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1
Reactant: CC(C)(C#N)CCCl
Product: CC(C)(CN)CCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
The intermediate 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(4-amino-3,3-dimethylbutyl)piperazine was prepared analogous to the method described for 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(4-aminobutyl)piperazine (Intermediate 11b) using 4-chloro-2,2-dimethylbutyronitrile.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH3:14][N:15]([CH3:26])[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>>[CH3:26][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[NH:2][C:4]3[C:13]([C:21]=2[CH2:20]1)=[C:8]1[C:9]([CH3:12])=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3
Reactant: CN(C)CCCN1CCC(=O)CC1
Reactant: Cc1csc2ccc(NN)cc12
Agent: Cl
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCN(C)C)CC4

Procedure:
The compound is formed analogously to that described in Example 5, from 5-hydrazino-3-methylbenzothiophene hydrochloride and 8.5 ml of 1-(3-dimethylaminopropyl)-4-piperidone. Melting point: 184° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][F:35])[CH2:24][C:25]([CH2:30][O:31][CH3:32])([CH3:29])[CH2:26][O:27][CH3:28])[CH3:19])([OH:15])[CH2:6][CH2:5]2.CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:13])[CH3:14])[C@@:7]([O:15][C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]([CH2:33][CH2:34][F:35])[CH2:24][C:25]([CH2:26][O:27][CH3:28])([CH3:29])[CH2:30][O:31][CH3:32])[CH3:19])[CH2:6][CH2:5]2
Reactant: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(OC(=O)C(C)C)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 398 mg of (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ol and 0.44 mL of NEt3 in 8 mL of DCM 0.25 mL of isobutyrylchloride was added at 0° C. The mixture was stirred for 25 min at 0° C. and then for 3 h at rt. It was quenched with sat. aqueous NaHCO3 and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude was purified by CC using EtOAc/Hept 3/1 as eluant to yield 411 mg of isobutyric acid (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl ester as orange oil.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH3:25].[H-].[Na+]>C1C=CC=CC=1>[CH2:25]([O:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=[CH:13][CH2:12][CH:11]=[CH:10][CH2:9][CH3:8]
Reactant: O=C1C=CCS1
Reactant: CCC=CCC=CCC=CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC=CCC=CCC=CCCCCCCCCOc1cccs1
Reaction time: 24 h

Procedure:
A mixture of 20.0 g (0.2 mole) of 3-thiolen-2-one [R. T. Hawkins, J. Heterocyclic Chem., 11 291-4 (1974)] 65.5 g (0.2 mole) of 1-bromo-9,12,15-octadecatriene, and 4.8 g (0.2 mole) of sodium hydride in benzene is refluxed with stirring for 24 hours after which the solvent is removed, and the product distilled to give 2-(9,12,15-octadecatrienyloxy)thiophene.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[N:40][N:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:38][CH:39]=[N:40][N:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1nncs1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2nncs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-bromo-[1,3,4]thiadiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=2[CH:18]=1.B.O1CCCC1>CO>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH2:15][OH:16])=[CH:12][C:11]=2[CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2cc(Cl)ccc2o1
Reaction time: 24 h
Yield: 46.6 %

Procedure:
To a tetrahydrofuran solution (12 mL) of 5-chlorobenzofuran-2-carboxylic acid (620 mg, 3.15 mmol), borane-tetrahydrofuran complex (7.88 mL, 7.88 mmol, tetrahydrofuran solution) was added at 0° C. and the resultant solution was stirred at room temperature for 3 hours, at 60° C. for 1 day, and at room temperature for 1 day. After completion of the reaction, concentration under reduced pressure was carried out three times with adding methanol to the reaction solution and the concentrated solution was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1 (v/v)) to obtain the title compound (268 mg, yield 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH:28]=[C:27]([C:30](O)=[O:31])[O:26][C:25]=2[CH:33]=1>>[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH:28]=[C:27]([C:30]([N:9]3[CH2:10][CH2:11][N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:3]=4[O:2][CH3:1])[CH2:7][CH2:8]3)=[O:31])[O:26][C:25]=2[CH:33]=1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Product: COc1ccc(CN2CCN(C(=O)C3=COc4ccc(O)cc4O3)CC2)c(OC)c1OC
Yield: 73 %

Procedure:
That compound is obtained in a yield of 73% starting from 1-(2,3,4-trimethoxybenzyl)piperazine and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.