Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2([CH3:30])[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=[CH:21][C:22]=3[OH:23])[CH2:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>CN(C=O)C>[CH3:30][C:11]1([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:20]=[CH:21][C:22]=3[O:23][C:14]2=[O:16])[O:15][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CN(c2cc(-c3ccccc3)ccc2O)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2c(=O)oc3ccc(-c4ccccc4)cc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
A mixture of 5-(2-chloro-4-nitroimidazol-1-ylmethyl)-3-(4-hydroxybiphenyl-3-yl)-5-methyloxazolidin-2-one prepared in Example 548 (1.23 g, 2.88 mmol), sodium hydride (127 mg, 3.16 mmol) and DMF (10 ml) was stirred at 100° C. for 4 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was washed with water and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-5-phenyl-3H-benzoxazol-2-one (172 mg, yield 15%) as a yellowish brown powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27][N:28]1[C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[CH:32]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[NH:31][CH2:30][C:29]1=[O:46]>C(N(CC)CC)C.O1CCCC1>[CH3:27][N:28]1[C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[CH:32]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:31]([C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:30][C:29]1=[O:46]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN1C(=O)CN(C(=O)CNC(=O)OCc2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 0.33 h
Yield: 90 %

Procedure:
2.8 g. (13.4 mmoles) of benzyloxycarbonyl-glycine are suspended in 27 ml. of dry ether, and 3 g. (15 mmoles) of phosphorous pentachloride are added in portions to the suspension at 0° C. The mixture is stirred for 20 minutes, and thereafter a solution of 2.86 g. (10 mmoles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 15 ml. of dry tetrahydrofuran containing 9 ml. of triethylamine is added dropwise to the obtained solution. The reaction mixture is stirred in an ice bath for 6 hours, and evaporated to dryness under reduced pressure. The oily residue is dissolved in 100 ml. of chloroform, the chloroform solution is washed with 3×50 ml. of water, 1×50 ml. of sodium bicarbonate solution and with water again, dried, and evaporated to dryness under reduced pressure. The oily residue is covered with ether, upon which is solidifies. 4.28 g. (90 %) of 1-methyl-4-(N-benzyloxycarbonyl-aminoacetyl)-5-phenyl- 7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 158°-160° C. (after recrystallization from ethanol), Rf2 = 0.60. Analysis: Calculated for C26H24O4N3Cl (M = 477.93): C: 65.2 % H: 5.1 % N: 8.8 % Found: C: 65.5 % H: 4.9 % N: 8.9 %
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:10][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH3:24])=[C:4]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:5]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)[CH3:9])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1-c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)OS(C)(=O)=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-chloro-N-ethyl-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxamide (185 mg, 0.523 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol), followed by methanesulfonyl chloride (0.061 mL, 0.78 mmol). The reaction was stirred at rt for 10 min, quenched by pouring onto iced water, and extracted with dichloromethane. The combined organic layers were washed with aq. sodium bicarbonate, dried over magnesium sulfate, and evaporated to dry. The residue was used directly in next step (0.226 g, 100%). LCMS calculated for C19H21ClF2NO4S (M+H)+: m/z=432.1; Found: 432.1.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([O:12]C)[C:7]([O:10]C)=[CH:8][CH:9]=1)[CH2:2][CH3:3].C(O)(=O)C.Br>O>[CH2:1]([C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:8][CH:9]=1)[OH:10])[CH2:2][CH3:3]
Reactant: CCCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A mixture of 15.0 g (83 mM) of 4-propylveratrole, 53.0 g (882 mM) of acetic acid and 159.4 g (926 mM) of 47% hydrobromic acid was heated under reflux for 2 hours with stirring. After cooling to the room temperature, the reaction mixture was added with 140 ml of water and extracted three times with each 150 ml of ether. The extracted solution was successively washed with 150 ml of water, 150 g of 5% aqueous sodium thiosulfate solution and then twice with each 150 ml of water. The resulting solution was dried with anhydrous sodium sulfate, distilled off ether and vacuum distilled to obtain 10.5 g (69 mM) of 4-propylcatechol as a light yellow liquid having a boiling point of 119° C./3 mmHg.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][C:9](=[O:16])[C:8]2=[O:17].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1Br.[Mg].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:8]1([OH:17])[C:7]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][CH3:3])[CH:6]=2)[NH:10][C:9]1=[O:16]
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N2
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3cc(OC)c(OC)cc32)c(OC)c1
Reaction time: 1 h

Procedure:
293 mg of 60% sodium hydride was added under ice cooling and a nitrogen gas flow to a suspension of 1.38 g of 5,6-dimethoxy-1H-indol-2,3-dione in 30 mL of tetrahydrofuran, and the reaction mixture was stirred for 1 hour at the same temperature. A Grignard's reagent generated in 20 mL of tetrahydrofuran using 3.61 g of 2,4-dimethoxybromobenzene and 486 mg of magnesium was added dropwise over a period of 3 minutes to the reaction mixture under ice cooling, after which the reaction mixture was stirred for 13 hours at room temperature. 20 mL of saturated aqueous ammonium chloride and 40 mL of ethyl acetate were added to the reaction solution, and the reaction mixture was stirred for 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (20 mL×2), the combined organic layer was washed with saturated brine and dried with magnesium sulfate, and the drying agent was then filtered off and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain 1.37 g of the titled compound (brown solid).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=3[C:13](O)=[O:14])[CH2:8]2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.[NH2:31][C:32]1([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=3[C:13]([NH:31][C:32]3([C:35]4[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=4)[CH2:34][CH2:33]3)=[O:14])[CH2:8]2)=[CH:4][C:3]=1[C:26]([F:28])([F:27])[F:29]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(C(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)c(C(F)(F)F)c4)C3)CC2)cc1
Yield: 34.3 %

Procedure:
The title compound (D176) (52 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(4-fluoro-3-(trifluoromethyl)phenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D125) (108 mg, 0.254 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (57.95 mg, 0.254 mmol).
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2].C(O)C.[BH4-].[Na+].C(O)(=O)C>O>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(CC(=O)O)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCN(CC(=O)O)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
(a-2) To a stirred solution of 47.8 parts of ethyl N-(4-formyl-2-nitrophenyl)glycine in 280 parts of ethanol were added in small portions 3.8 parts of sodium tetrahydroborate. The whole was stirred for 30 minutes at room temperature. The reaction mixture was decomposed by a solution of 12 parts of acetic acid in 50 parts of water. The mixture was concentrated. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 34.1 parts (70.6%) of ethyl N-[4-(hydroxymethyl)-2-nitrophenyl]glycine (int. 30).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(c2nc3cc(C(=O)O)ccc3s2)CC1
Reactant: C1CCNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2nc3cc(C(=O)N4CCCC4)ccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carboxylic acid (530 mg, 1.75 mmol), pyrrolidine (149 mg, 2.10 mmol) and DIEA in THF (7.3 mL) was stirred for 30 min at rt. Then PyBOP was added and the reaction mixture was stirred at rt overnight. The mixture was concentrated and the residue was neutralized with an aqueous solution of Na2CO3 to pH 7. Then the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified with preparative HPLC to give 490 mg (78%) of (2-(4-isopropylpiperazin-1-yl)benzothiazol-5-yl)(pyrrolidin-1-yl)methanone as a trifluoroacetate salt.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:12]=1)(=O)=O.[N:21]1([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[C:17]([O:16][C:14]([NH:13][C:10]1[N:9]=[CH:8][C:7]([CH2:6][N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:26][CH2:25]2)=[CH:12][CH:11]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)cn1
Yield: 96 %

Procedure:
A mixture of (6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl methanesulfonate (102; 1.30 g, 5.4 mmol), benzyl piperazine-1-carboxylate 103; (1.42 g, 6.5 mmol), K2CO3 (2.30 g, 16.1 mmol) and NaI (0.08 g, 0.54 mmol) in DMF (20 mL) was stirred at 60° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water (30 mL) was added and the mixture was filtered. The collected solids were washed further with water and dried to afford benzyl 4-((6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate 104 (2.20 g, 96%).
Reaction SMILES: [CH:1]1([CH:6]([OH:9])[CH:7]=[CH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[CH:18]([F:20])[F:19].C([O-])(O)=O.[Na+].O>CN1C(=O)CCC1>[CH:1]1([C:6](=[O:9])[CH2:7][CH2:8][C:15]2[CH:14]=[CH:13][C:12]([CH:18]([F:20])[F:19])=[C:11]([F:10])[CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cc(Br)ccc1C(F)F
Reactant: C=CC(O)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(CCc1ccc(C(F)F)c(F)c1)C1CCCC1
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A mixture of 1-cyclopentyl-2-propen-1-ol (34 g, 0.266 mol), 2-fluoro-4-bromo-difluoromethyl benzene, (40 g, 0.177 mol, 1.5 equiv), and NaHCO3 (17.8 g, 0.212 mol, 1.2 equiv) in anhydrous NMP (200 mL) was heated to 140° C. for 1 h, resulting in complete conversion by TLC. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. After the removal of the solvent, the residue was purified by column chromatography using hexanes/ethyl acetate, and the product-containing fractions combined and concentrated. The residue was fractionally distilled through a Vigreux column to give 16 g (33%) of the desired product (bp 100° C./0.2 Torr). 1H NMR (CDCl3) d 1.57 (m, 8H), 2.81 (m, 4H), 3.09 (m, 1H), 6.86 (t, 1H, J=57 Hz), 6.95 (m, 2H), 7.51 (t, 1H, J=7.5 Hz). MS (APCI) calcd for C15H17F3O, 270.29; found [M−19(−F)]: 251.02 m/z.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.O>ClCCl>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([NH:29][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])[CH3:28])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine trifluoroacetate (115 mg, 0.28 mmol) and triethylamine (0.117 ml, 0.83 mmol) were dissolved in 5 ml of dichloromethane. Cyclopropanecarbonyl chloride (0.043 ml, 0.46 mmol) was added at 0° C. and the reaction mixture was stirred for 3 hours during which it warmed to room temperature. Following addition of water, the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 63 mg (62%), M+H+: 369.25.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]2[O:23][C:24]([CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:25][N:26]=2)=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:29]([O:28][CH2:27][C:24]1[O:23][C:22]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:26][N:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(CCCCCCOc1ccc(OCc2ccccc2)cc1)c1nnc(COCc2ccccc2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCCCCCOc1ccc(O)cc1)c1nnc(COCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 73.2 (50 mg, 0.1 mmol) and Pd/C (10 mg) in AcOEt (5 mL) was stirred vigorously under hydrogen overnight at room temperature. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The crude material was purified through a column of silica gel, eluting with 45% ethyl acetate-petroleum ether to give 74.2 as a white solid in 75% yield (31 mg).
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:30][NH2:31].CO.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]I>[CH3:30][NH:31][C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1cccc2c1CCn1cc(-c3ccccc3)nc1C2OC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (276 mg, 0, 55 mmole) in dimethylformamide (5 mL) in a screw-capped vial are added a 3M solution of methylamine in methanol (2.8 mL, 5.5 mmoles), copper(I) iodide (100 mg, 0, 52 mmole) and cesium carbonate (250 mg, 0.77 mmole). The vial is evacuated and filled with argon. The reaction mixture is stirred at 100° C. for 36 hours. Water and ammonia are added to the reaction mixture, and the aqueous phase is extracted three times with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 11% (B) to 21% (B) in 10 minutes) to afford methyl-[4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-8-yl]-amine melting at 189° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC[O-]
Reactant: N#Cc1ccnc(C2CC2)n1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1ccnc(C2CC2)n1
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbonitrile (600 mg, 4.13 mmol) in ethanol (10 mL) was added sodium ethoxide (561.9 mg, 8.27 mmol). After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 2-cyclopropylpyrimidine-4-carbimidate (400 mg) as a pale yellow liquid. The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)- thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[N-].[BrH:14].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:14][CH2:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1
Reactant: Br
Reactant: [N-]=[N+]=CC(=O)Cc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CBr)Cc1ccc(I)cc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
1-Diazo-3-(4-iodophenyl)propan-2-one (13) (1.27 g, 4.43 mmol) was dissolved in acetic acid (20 mL) and cooled to 0° C. To this was added 47% hydrobromic acid (1.55 mL, 13.3 mmol) and stirred for an hour after warming to room temperature. After neutralization by adding saturated aqueous solution of sodium bicarbonate, the product was extracted with ethyl acetate (×3) and the organic layer was washed sequentially with saturated aqueous solution of sodium bicarbonate (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=7/1) to give 1-bromo-3-(4-iodophenyl)propan-2-one (16) as a colorless solid (1.42 g, 4.18 mmol, 94.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(#N)C>[N:14]1([CH:9]2[CH2:10][CH:11]3[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([CH2:13][CH2:12]3)[CH2:8]2)[CH2:19][CH2:18][C:17]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][CH2:20]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(C(=O)OC(C)(C)C)Cc1ccccc13)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
The crude tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H -spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b (3.641 g) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 45 min, then concentrated under reduced pressure. The oil obtained was re-dissolved in acetonitrile, re-concentrated under reduced pressure, treated with 2 N NaOH (25 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were washed with saturated NaHCO3, saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2.55 g crude ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 5c as a pale yellow oil, which solidified upon standing overnight at room temperature. LC/MS m/z [M+H]+ 384.2 retention time 1.34 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.0 Hz, 1H), 7.29 (t, J=7.3 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.06 (br s, 2H), 4.37 (br s, 2H), 4.25 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.47 (m, 3H), 3.24 (m, 2H), 2.93 (m, 2H), 2.53 (m, 2H), 1.96 (m, 8H), 1.71 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).