Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[CH:24][C:23]=1[F:38]>O1CCCC1>[C:33]([C:29]1[CH:28]=[C:27]([O:26][C:25]2[CH:36]=[CH:37][C:22]([NH:21][C:7]([C:1]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]3)=[O:9])=[C:23]([F:38])[CH:24]=2)[CH:32]=[CH:31][N:30]=1)(=[O:34])[NH2:35]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)O)CC3)c(F)c2)ccn1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of 1,1-cyclopropanedicarboxylic acid (3.12 g) in tetrahydrofuran (90 ml) was added dropwise triethylamine (2.43 g) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 1.5 hr. To the reaction mixture, was then added thionyl chloride (1.75 ml), followed by stirring at the same temperature for 30 min. To the reaction mixture were added 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (2.97 g) and triethylamine (2.43 g) in this order while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 70 min. The reaction mixture was partitioned after addition of tert-butyl methyl ether (30 ml) and a 1N aqueous solution of sodium hydroxide (90 ml). The aqueous layer was partitioned with tert-butyl methyl ether (30 ml) again, and the separated aqueous layer was treated with 1N hydrochloric acid to precipitate a solid. The solid was collected by suction filtration and washed with water (10 ml, four times). Drying under reduced pressure at 50° C. provided 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (1.90 g, 44%). After the filtrate was stood overnight, further precipitated solid was collected by suction filtration and washed with water (10 ml, twice). Drying under reduced pressure provided additional 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (758 mg, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.O>CN(C=O)C.C(OCC)(=O)C>[CH:11]([N:8]1[C:6]2[N:7]=[C:2]([O:1][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CN1CCC(Br)CC1
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OC2CCN(C)CC2)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in DMF and K2CO3 (1.5 equiv.) and 4-bromo-1-methylpiperidine (1.5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, water was added to it and extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [Li].C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[C:22]12[CH2:33][O:32][CH2:31][C:30]1=[CH:29][C:28]1[CH2:27][O:26][CH2:25][C:24]=1[CH:23]=2.O>O1CCCC1>[CH3:33][C:22]1[C:30]([CH2:31][OH:32])=[CH:29][C:28]2[CH2:27][O:26][CH2:25][C:24]=2[CH:23]=1
Reactant: c1c2c(cc3c1COC3)COC2
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1CO)COC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
To a mixture of lithium powder (15 g, 2.1 mol), 4,4′-di-tert-butylbiphenyl (5.0 g, 0.021 mol) and tetrahydrofuran (200 mL) was added a mixture of 5,11-dioxatricyclo[7.3.0.0^{3,7}]dodeca-1,3(7),8-triene (35 g, 0.21 mol) described in Production Example 1-4 and tetrahydrofuran (100 mL) at −78° C., followed by stirring at that temperature for 4 hours. Water (10 mol) was added at that temperature to the reaction mixture, and thoroughly stirred. The reaction mixture was allowed to warm to room temperature, and extracted with ethyl acetate after addition of a 2 N aqueous solution of hydrochloric acid (500 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound (10 g, 30% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([NH2:30])=[C:19]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:20]=3)[C:12]([CH:31]=O)=[N:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:33][NH2:34].[Na]>CO.ClCCl.ClCCl.CO>[NH2:30][C:18]1[N:17]=[CH:16][C:15]([C:13]2[C:12]([CH2:31][NH:34][CH3:33])=[N:11][N:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[CH:14]=2)=[CH:20][C:19]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CN
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CNCc1nn(C2CCN(C(C)=O)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Over a period of 5 minutes, a solution of 1-(1-acetylpiperidin-4-yl)-4-(6-amino-5-(1,3-benzoxazol-2-yl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (132 mg) in MeOH/dichloromethane (1:1) that had been cooled to 0° C., was added to a stirred solution of methylamine (0.153 ml, 0.31 mmol) dissolved in dichloromethane (6 ml) and methanol (6 ml). The resulting solution was stirred at 0° C. for 20 minutes. Sodium triacetoxyhydroborate (78 mg) was added at 0° C. to the mixture and stirred at 0° C. for 5 hours. The mixture was evaporated. A saturated solution of sodium bicarbonate was added and the mixture was extracted with methylene chloride, dried over magnesium sulphate, filtered and evaporated under reduced pression. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 micron silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness, tritured with hot acetonitrile, filtered and dried under reduce pressure to afford 1-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methylaminomethyl)pyrazol-1-yl]-1-piperidyl]ethanone (23 mg) as a solid. NMR Spectrum: (CDCl3) 1.86-2.11 (m, 2H), 2.15 (s, 3H), 2.13-2.24 (m, 1H), 2.24-2.33 (m, 1H), 2.60 (s, 3H), 2.73-2.84 (m, 1H), 3.21-3.32 (m, 1H), 3.96 (s, 2H), 3.97-4.06 (m, 1H), 4.31-4.42 (m, 1H), 4.70-4.85 (m, 1H), 6.97 (bs, 2H), 7.32-7.41 (m, 2H), 7.54 (s, 1H), 7.57 (dd, 1H), 7.73 (dd, 1H), 8.32 (s, 1H), 8.42 (s, 1H); Mass spectrum: M+H+ 446;
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=O.C([NH2:20])C1C=CC=CC=1.ClCCl.CO.[OH-].[NH4+]>>[OH:1][CH2:2][C:3]1([NH2:20])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Typical procedure from fructose: 18.0 g (100 mmol) of D-(−)-fructose was treated at 0° C. with freshly distilled benzyl amine (3-8 equiv.). The reaction mixture was allowed to warm to room temperature and was then heated at 40° C. for 20 h. The TLC (dichloromethane:methanol:ammonium hydroxide 2:1:1) showed the disappearance of the starting material. The excess of benzyl amine was removed by repeated washings with petroleum ether according to the following method: 150-500 mL of petroleum ether was added into the reaction mixture and subsequently cooled to between −25 and −20° C. (dry ice-alcohol bath) until the carbohydrate-rich phase was frozen. The organic layer was then decanted, and the procedure was repeated 4-5 times. The obtained crude fructosyl amine was diluted with methanol (200-300 mL) and treated with glacial acetic acid (15-20 mL) at room temperature for 2-4 h. TLC (dichloromethane:methanol:ammonium hydroxide 20:4:0.5) showed consumption of the ketosylamine and the formation of N-benzyl-2-amino-2-deoxy-D-mannose together with N-benzyl-2-amino-2-deoxy-D-glucose in a ratio of 2:8-4:6 as the main products. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (dichloromethane:methanol:ammonium hydroxide 20:4:0.5) to give N-benzyl-2-amino-2-deoxy-D-mannose as an amorphous solid (4.1-8.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[CH2:15]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][O:41][CH3:42].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:17][C:16](=[O:32])[CH2:15]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH2:40][O:41][CH3:42])[CH3:2]
Reactant: COCCl
Reactant: CCOc1cc(C2CC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C2CC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1OCOC
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a mixture of 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyridin-2(1H)-one (Compound 1, see Example 1) (200 mg, 0.47 mmol) and potassium carbonate (130 mg, 0.93 mmol) in DMF (5 mL) was added chloro(methoxy)methane (75 mg, 0.93 mmol) at 25° C. and then the mixture was stirred at the same temperature for 2 hours. The mixture was poured into water and a standard aqueous/EtOAc workup was followed to give product (200 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[CH2:6][C:5]2=[O:13].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:13])[CH:6]([N+:14]([O-:16])=[O:15])[C:7]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c(cc1C)C(=O)CC2=O
Solvent: CCOCC
Product: Cc1cc2c(cc1C)C(=O)C([N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended in anhydrous ether (5 ml.) was stirred at 10° C during the dropwise addition of fuming nitric acid (1.0 ml.). After the addition was complete the mixture was stirred at ambient temperature for 1 hr. and the precipitated yellow solid filtered. m.p. (water, hydrochloric acid) 111°-113° C. (Found: C, 60.11; H, 4.10; N, 6.14; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: C([O:8][C:9]1[C:35]([O:36][CH3:37])=[CH:34][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([F:32])=[CH:26][C:25]=1[Cl:33])C1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.[Pd]>[Cl:33][C:25]1[CH:26]=[C:27]([F:32])[C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:15]1[C:14]2[C:19](=[CH:20][C:11]3[CH:10]=[C:9]([OH:8])[C:35]([O:36][CH3:37])=[CH:34][C:12]=3[CH:13]=2)[N:18]=[CH:17][C:16]=1[C:21]#[N:22]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCc5ccccc5)c(OC)cc4cc23)c(Cl)cc1F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2cc3c(Nc4cc(OC)c(F)cc4Cl)c(C#N)cnc3cc2cc1O
Reaction time: 15 h
Yield: 95.7 %

Procedure:
A mixture of 8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[g]quinoline-3-carbonitrile (1.88 g, 3.70 mmol) and 280 mg of 15% Pd on carbon in a mixture of 50 mL of methylene chloride and 70 mL of N,N-dimethylformamide is hydrogenated at 50-40 psi for 15 hours. The mixture is filtered through Celite and concentrated in vacuo to a small volume. The yellow solid is collected by filtration to provide 1.50 g (95%) of 4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, mp 239-242° C. dec.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.O.[NH2:18][NH2:19]>C(O)C>[N:18]1[NH:19][C:14](=[O:16])[CH2:13][CH:3]2[CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=12
Reactant: NN
Reactant: O=C(O)CC1CCCc2ccccc2C1=O
Solvent: O
Solvent: CCO
Product: O=C1CC2CCCc3ccccc3C2=NN1

Procedure:
A mixture of the compound of formula (Dc), 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid, (5.7 g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20 mL of ethanol was refluxed for 2 h, cooled and filtered (washed with small amount of EtOH) to give the compound of formula (Dd), 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one, as a white solid (4.7 g, 84%); 1H NMR (300 MHz, CDCl3) δ: 8.61 (bs, 1H), 7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58 (dd, J=15.3, 16.8 Hz, 1H), 2.31 (dd, J=12.0, 16.8 Hz, 1H), 1.96-1.59 (m, 4H); LC-MS: purity: 100%; MS (m/e): 215 (MH+).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:36]([O:38][CH3:39])=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH:30]=[CH:29][C:28]2=[O:33])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:33]=[C:28]1[CH:29]=[CH:30][C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]([C:36]([O:38][CH3:39])=[O:37])[NH2:8])=[CH:12][CH:13]=1)=[O:35])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
To a solution of #251 (800 mg, 1.47 mmol, 1 eq.) in dichloromethane (16 mL) was added TFA (4.8 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and filtered. The filtrate was lyophilized to afford #252 (800 mg, 97.5%) as a white solid. HPLC (Protocol Q3) [M+H+] 445.4, retention time=0.90 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[CH:10][CH2:11]Cl.[CH2:13]([N:15]([CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:14]>O>[Cl-:1].[CH2:23]([N+:15]([CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH:10]=[CH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:24]
Reactant: ClCC=CCc1ccccc1Cl
Reactant: CCCCCCCN(CC)CC
Solvent: O
Product: CCCCCCC[N+](CC)(CC)CC=CCc1ccccc1Cl
Product: [Cl-]

Procedure:
Combine 1.00 g (4.76 mmole) 1-chloro-2-(4-chloro-2- butenyl)benzene and 1.77 g (4.76 mmole) N,N-diethylheptanamine and heat at 100° C. ca. 20 hrs. Follow the progress of the reaction by TLC on silica gel (acetonitrile: ammonium hydroxide, 9:1). At the completion of the reaction, decant off the top layer of the two phase reaction mixture. Dissolve the bottom layer in 50 ml H2O. Extract with 3×100 ml hexane, 1×25 ml CH2Cl2. Dry CH2Cl2 over MgSO4 and treat with activated charcoal. Evaporate the solvents to provide the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]([N:39]3[CH2:38][CH2:37][N:36]([CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:41][CH2:40]3)=[O:26])[O:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2noc(C(=O)N3CCN(C4CCN(C)CC4)CC3)n2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.07 mmol), 1-(1-methylpiperidin-4-yl)piperazine (26 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=1)[CH2:19]2.C(C(O)=O)(F)(F)F.C(N)CN>C(Cl)Cl.C([O-])(O)=O.[Na+]>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=1)[CH2:19]2
Reactant: COC(=O)c1ccc2c(c1)CC1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COC(=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-methyl 2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate from Step B (3.65 g, 8.60 mmol) in CH2Cl2 (80 mL) was added CF3CO2H (40 mL, 52 mmol) and the resulting mixture was stirred at ambient temperature for 18 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and treated with ethylene diamine (2.3 mL, 34.4 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then diluted with saturated aqueous NaHCO3 (50 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×100 mL). The combined organic layers were washed with brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—97:3, to give methyl 2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate as a tan solid. This solid was dissolved in MeOH (22 mL) and 1 N sodium hydroxide (25.4 mL, 25.4 mmol) was added. The reaction mixture was heated at 60° C. for 18 h then allowed to cool. The mixture was acidified by addition of 6 N HCl, and the resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=281 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][CH:47]([N:50]5[CH2:51][CH2:52][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:54][CH2:55]5)[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 34.9 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (0.050 g, 0.11 mmol), 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 236, Step B) (0.041 g, 0.11 mmol) and para-toluenesulfonic acid (0.049 g, 0.26 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 20 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.031 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 9.42 (br. s., 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=5.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.34-7.55 (m, 3H), 7.17-7.29 (m, 2H), 6.95-7.06 (m, 1H), 6.77 (s, 1H), 6.51 (d, J=5.2 Hz, 1H), 3.80 (s, 3H), 3.05-3.17 (m, 6H), 2.88 (s, 3H), 2.59-2.73 (m, 6H), 2.38-2.46 (m, 1H), 2.16 (s, 3H), 1.81-1.90 (m, 2H), 1.53-1.68 (m, 2H). MS (M−H, ES−) 806.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(Cl)Cl>[C:39]([N:7]([CH:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:27][CH3:28])[CH2:24][CH2:25]2)[CH2:9]1)[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:41])[CH3:40]
Reactant: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(NC3CCCCC3)CC2c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C(C)=O)C3CCCCC3)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(RS and SR)-(cyclohexylamino)-3-(SR)-((4-(N-(benzyloxycarbonyl)-N-(ethyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (prepared as in Example 43A) in methylene chloride (2 mL) was added acetic anhydride (0.17 mL, 1.67 mmol) and pyridine (0.17 mL, 2 mmol). The reaction was stirred at rt for 16 h. It was then diluted with methylene chloride and quenched with 1N NaOH. The mixture was washed with 1N NaOH and brine, dried over sodium sulfate and evaporated to dryness. The sample was purified by HPLC and the fractions containing the title compound by HPLC/MS were combined and evaporated.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10].C(O)(C)C>[Cl-].[Zn+2].[Cl-].CCOCC>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCCS1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
To a mixture of 221 g of 5,6-dihydro-2-(methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1950) and 1 g of zinc chloride at about 100°, 202 g of methyl nitroacetate (S. Zen et al., Kogyo Kagaku Zasshi, 74, 70 (1971)) was added dropwise over a 30-minute period. The resulting mixture was heated for 4 hours at 95°-105°. 200 ml of isopropyl alcohol then was added to the hot mixture, then 400 ml of ether was added. The resulting mixture was filtered to give methyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)-acetate (1A), as a pale yellow solid, m.p.: 107°-108° C.