Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[F-].[K+].Br.Br.[CH2:22]1[C:24]2([CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23]1>CS(C)=O.CCOC(C)=O>[CH3:7][N:6]1[C:2]([N:26]2[CH2:27][CH2:28][NH:29][CH2:30][C:24]3([CH2:22][CH2:23]3)[CH2:25]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: C1CNCC2(CC2)CN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Br
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1ncc([N+](=O)[O-])c1N1CCNCC2(CC2)C1
Temperature: 65 °C
Yield: 30.4 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (323 mg, 2.0 mmol), triethylamine (0.7 mL, 5.0 mmol) and potassium fluoride (581 mg, 10.0 mmol) in dry DMSO (20 mL) was added 5,8-diazaspiro[2.6]nonane dihydrobromide (686 mg, 2.4 mmol) and the mixture was heated in the microwave at 65° C. for 4 hr. The mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (3×20 mL). The aqueous layer was further extracted with DCM (3×20 mL) and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. The residue was loaded onto an SCX-2 column which was washed with MeOH and eluted with 3% 7M ammonia in MeOH/DCM and concentrated under reduced pressure to give 5-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,8-diazaspiro[2.6]nonane as a yellow gum (153 mg). To a solution of this intermediate in DCM (10 mL) was added di-tert-butyl dicarbonate (157 mg, 0.72 mmol) and DMAP (4 mg, 0.03 mmol) and the mixture stirred at room temperature for 2 hr. The mixture was washed with water (3×10 mL) and the organic layer separated, passed through a phase separation cartridge and concentrated under reduced pressure to give tert-butyl 8-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,8-diazaspiro[2.6]nonane-5-carboxylate as a yellow gum (200 mg, 28% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.02 and 8.00 (2s, 1H), 3.85-3.77 (m, 3H), 3.75-3.67 (m, 2H), 3.47-3.27 (m, 4H), 3.29-2.97 (m, 2H), 1.49 (s, 9H), 0.73-0.55 (m, 2H), 0.47-0.38 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1([F:19])[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[F:11][C:12]1([F:19])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: OC1CCC(F)(F)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
The inside of a reactor was sufficiently dried by vacuum heating, and the atmosphere inside the reactor was replaced with dry nitrogen. The reactor was charged with 2000 ml of dichloromethane and 128.4 ml (1.5 mol) of oxalyl chloride at −78° C. After the dropwise addition of 233 ml (3.0 mol) of DMSO, the mixture was stirred at −78° C. After 10 minutes had elapsed, a dichloromethane (300 ml) solution of 136.1 g (1.0 mol) of 4,4-difluorocyclohexanol was added dropwise to the mixture using a syringe over 10 minutes. After stirring the reaction mixture at −78° C. for 40 minutes and at −45° C. for 40 minutes, N,N-diisopropylethylamine (500 ml) was added to the reaction mixture. After stirring the mixture at 0° C. for 20 minutes, a saturated ammonium chloride aqueous solution (1000 ml) was added to the mixture to terminate the reaction. The mixture was then extracted three times with dichloromethane (3000 ml). The organic layer was washed with 1N hydrochloric acid and a saturated salt solution, and dried over magnesium sulfate. After removing anhydrous magnesium sulfate using a Buchner funnel, the solvent was evaporated. The residue was distilled under reduced pressure (30 mmHg) to obtain 4,4-difluorocyclohexanone (118.9 g (yield: 85%)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[Br:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([NH:1][S:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20])=[CH:11]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cnc2c(Br)cccc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2c(Br)cccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
3-Amino-8-bromoquinoline (300 mg, Production Example 5b) was dissolved in pyridine (5 ml), to which was then added 3-pyridinesulfonyl chloride (254 mg), followed by stirring at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title compound (270 mg).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>CO.COC(COC)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([O:19][CH3:1])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CCC(=O)O)cc1OC
Solvent: COCC(C)OC
Solvent: CO
Product: COC(=O)CCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (20 cc) was added dropwise over 10 minutes with stirring to methanol (400 cc); the resulting solution was added all at once to a magnetically stirred suspension of 3-(3,4-dimethoxyphenyl)propionic acid (500 g, 2.378 moles) in methanol (1.6 1) and 2,3-dimethoxypropane (250 cc). The reaction mixture was stirred overnight at room temperature and then at reflux for 1 hour. After cooling, the solution was evaporated in vacuo to a light yellow syrup; yield: 533 g (100%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
To a solution of compound 288 (0.33 g, 0.581 mmol) in DCM (11.6 mL) was added TFA (0.53 mL, 6.98 mmol, 12 eq.). The reaction mixture was stirred at r.t. for 24 h, concentrated and the residue was purified by Biotage SPI Flash Purification System (eluent a gradient DCM/MeOH/NH4OH, 95/5/0.1 to 9/1/0.2) to afford 289 as a white solid (0.256 g, 0.548 mmol, 94% yield). Characterization of compound 289 is provided in the Table 6.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:40])[N:16]2[C:19]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]([F:35])[C:28]=3[F:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=2[Cl:39])=[C:12]([O:41][CH3:42])[N:11]=1)=O)(C)(C)C.Cl.C(OCC)C>O1CCCC1>[ClH:39].[NH2:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:40])[N:16]2[C:19]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]([F:35])[C:28]=3[F:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=2[Cl:39])=[C:12]([O:41][CH3:42])[N:11]=1
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CNC(=O)OC(C)(C)C)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN)nc32)cc1OCc1c(OC)ccc(F)c1F
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylaminomethyl)-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (36 mg) in tetrahydrofuran (1 mL) was added hydrochloric acid (4 mol/L ethyl acetate solution, 2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 3 hours. To the reaction mixture was added diethyl ether, and the insoluble material was collected by filtration. The collected material was washed with diethyl ether, and dried under reduced pressure to give the title compound (14 mg).
Reaction SMILES: [C:1]([C:5]1[C:6]([C:17]([OH:19])=O)=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH3:4])=[O:2].S(Cl)([Cl:22])=O>>[C:1]([C:5]1[C:6]([C:17]([Cl:22])=[O:19])=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH3:4])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Product: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)ccc2c1O

Procedure:
Concurrently, 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride was prepared from 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid (121 mg, 0.43 mM) by heating to 60° C. in thionyl chloride (4 mL). After 3 hours the crude acid chloride was isolated by distilling away the excess thionyl chloride. The crude 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride (130 mg, 0.43 mM) was then placed in anhydrous tetrahydrofuran (3 mL) at ambient temperature and added via cannula to the 4-(trifluoromethoxy)phenylhydrazine solution. After 30 minutes the reaction mixture was poured into 1.0N hydrochloric acid producing a precipitate. The solid was isolated to yield the title compound (185 mg, 95%) as an off-white solid, mp 346-350° C.; MS 456 (M+H). 1H NMR 12.67 (s, 1H, exchangeable), 10.79 (s, 1H, exchangeable), 8.37 (br s, 1H, exchangeable), 8.13 (d, J=8.61 Hz, 1H), 7.83 (d, J=1.76 Hz, 1H), 7.48 (dd, J=8.61, 1.76 Hz, 1H), 7.21 (d, J=8.50 Hz, 2H), 6.94 (d, J=8.50 Hz, 2H), 3.70 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:32]=[CH:31][C:23]([O:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>CO.[Pd]>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]2[CH:22]=[CH:21][C:20]([C:17]3[N:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[O:19][N:18]=3)=[CH:32][CH:31]=2)[CH:26]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5cccnc5)cc4)no3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc(-c3ccc(Oc4cccnc4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 23 h
Yield: 1.1 %

Procedure:
In a single neck round bottom flask fitted with a condenser, 3-(4-(5-(4-(Benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenoxy)pyridine (224 mg, 531 μmol) was suspended in methanol (5.0 mL) and THF (5.0 mL) and then 10% Pd/C (1.0 mg, 36 μmol) was added. The reaction vessel was sealed and the solution was stirred under H2 at 55° C. for 23 hours. The hot solution was filtered through Celite and the pad was washed with methanol (20 mL). The solvent was removed under reduced pressure. The solid residue was purified by silica gel column chromatography (EtOAc/Hex 1:2) to give the product as a white solid (2 mg, 1%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 7.00 (2H, d, J=9.0 Hz), 7.23 (1H, d, J=9.0 Hz), 7.05 (1H, ddd, J=8.4, 4.8, 0.8 Hz), 7.61 (1H, ddd, J=8.4, 2.8, 1.4 Hz), 8.02 (2H, d, J=9.0 Hz), 8.01 (2H, d, J=9.0 Hz), 8.46 (1H, dd, J=4.7, 1.3 Hz), 8.21 (1H, d, J=2.8 Hz) 10.58 (1H, s). MS (FAB+): 332 (MH+). HRMS for C19H13N3O3 (MH+): calculated: 332.1035; found 332.1013.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[N:2]1.[Cl:28][C:29]1[C:34](Cl)=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:28][C:29]1[C:34]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C@@H:15]4[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]4)=[CH:11][CH:10]=3)=[O:7])=[N:2]2)=[N:33][CH:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4nccnc4Cl)n3)cc2)C1
Reaction time: 16 h
Yield: 41.2 %

Procedure:
(S)-tert-Butyl 2-(4-(1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (90 mg, 0.24 mmol) and 2,3-dichloropyrazine (43 mg, 0.29 mmol) were dissolved in dimethylacetamide (2 ml) and potassium carbonate (67 mg, 0.48 mmol) was added. The reaction mixture was placed on a Büchi shaker for 16 hours at 80° C. To complete the reaction an additional amount of 2,3-dichloropyrazine (10 mg) was added and heating was continued for another 2 h at 120° C. After cooling the mixture, water was added followed by extraction with ethyl acetate twice. The combined organic layers was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 10 g, 25% to 50% EtOAc in heptane) to yield an off-white gum (48 mg, 42%). MS (ISP): 429.3 (100%, [M−tBu+H]+), 485.4 (10%, [M+H]+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]21[CH2:19][CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=1)[CH2:11]2)=[O:4].[N+:24]([O-:27])([O-:26])=[O:25].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]21[CH2:19][CH2:18][C:17]1[C:12](=[CH:13][C:14]([N+:24]([O-:26])=[O:25])=[C:15]([O:20][CH3:21])[CH:16]=1)[CH2:11]2)=[O:4].[F:23][C:2]([F:1])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]21[CH2:19][CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[C:16]=1[N+:24]([O-:27])=[O:25])[CH2:11]2)=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)CCC1(CCCCN1C(=O)C(F)(F)F)C2
Agent: [NH4+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])CC1(CCCCN1C(=O)C(F)(F)F)CC2
Product: COc1ccc2c(c1[N+](=O)[O-])CCC1(CCCCN1C(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 1'-trifluoroacetyl-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine] was dissolved in 150 ml of chloroform. After 1.5 g of ammonium nitrate was suspended in this solution, 9 ml of trifluoroacetic anhydride was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and filtered, after which the solvent was distilled off. The residue was purified by silica gel column chromatography to yield 1.4 g of 1'-trifluoroacetyl-3,4-dihydro-6-methoxy-7-nitrospiro[naphthalene-2(1H),2'-piperidine] and 0.457 g of 1'-trifluoroacetyl-3,4-dihydro-6-methoxy-5-nitrospiro[naphthalene-2(1H),2'-piperidine].
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1)[CH3:2].C(N(CC)C[CH2:20][O:21][C:22]1C=CC=C([N+]([O-])=O)C=1)C.C[OH:34]>[Pd]>[CH3:22][O:21][C:20](=[O:34])[C:12]1[CH:11]=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:14][CH3:15]
Reactant: CO
Reactant: CCN(CC)CCOc1cccc(N)c1
Reactant: CCN(CC)CCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Product: CCN(CC)CCOc1cc(N)ccc1C(=O)OC
Reaction time: 2 h

Procedure:
3-(2-Diethylamino-ethoxy)-phenyl-amine can be prepared by the following procedure. In a Parr pressure bottle, a solution of diethyl-[2-(3-nitro-phenoxy)-ethyl]-amine (2.72 mmol) (from Example 11) in MeOH (10 mL) is added Pd (5% on carbon, 50% wet, 10% weight). The suspension is shaken at 40 psi of H2 for 2 h. The reaction is filtered through celite. The solvent is removed under reduced pressure to afford the title compound in quantitative yield. MS (m/z) (M+1)+ 267.1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]([CH3:26])([CH3:25])[CH2:7][C:8]1[N:9]([CH2:22][CH2:23][CH3:24])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH2:21].C(N(CC)CC)C.Cl>ClCCl.CO>[NH2:21][C:12]1[C:11]2=[N:10][N:9]([CH2:22][CH2:23][CH3:24])[C:8]([CH2:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])([CH3:26])[CH3:25])=[C:20]2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CC(=O)Cl
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(C)=O
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 72.9 %

Procedure:
Acetyl chloride (221 μL, 3.14 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 840 mg, 2.82 mmol) and triethylamine (591 μL, 4.24 mmol) in dichloromethane (25.2 mL). The solution was stirred for 20.5 h at ambient temperature, then was concentrated under reduced pressure to yield a foam that was dissolved in methanol. To the solution was added concentrated hydrochloric acid (2 mL). The solution was stirred at ambient temperature for 90 minutes, then heated at reflux for 40 minutes. After cooling to ambient temperature, the solution was concentrated under reduced pressure and 2 M aqueous sodium carbonate was added until the pH was basic. The solution was extracted with chloroform. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichlormethane (10 mL), then triethylamine (786 mL) and acetyl chloride (300 mL) were added. The reaction was worked up as before, then methanol (20 mL) and concentrated hydrochloric acid (2 mL) were added. The solution was heated at reflux for 30 minutes, left to stand at ambient temperature overnight, then heated at reflux again for 30 minutes. After cooling to ambient temperature, the solution was concentrated under reduced pressure and 2 M aqueous sodium carbonate was added until the pH was adjusted to pH 10-11. The solution was extracted with chloroform three times. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 20-30% CMA in chloroform for the first column; gradient elution with 4-10% methanol in chloroform for the second column). The appropriate fractions were combined and concentrated under reduced pressure to yield a colorless foam that was crystallized from ethyl acetate/hexanes. A white solid was isolated and dried under vacuum at elevated temperature to yield 698 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a white solid, mp 182-183° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1>C1COCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:22])([CH3:23])[CH2:17][C:18]([CH3:20])([CH3:21])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([C:41]3[CH:42]=[CH:43][O:39][CH:40]=3)=[CH:8][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC(C)(C)C1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(-c3ccoc3)cc2)CC(C)(C)C1
Yield: 40.3 %

Procedure:
The procedure described for 28 was utilized using triflate 25 (150 mg, 0.319 mmol), PdCl2 (Ph3P)2 (23 mg, 0.032 mmol), 2 N aqueous Na2CO3 (320 uL, 0.638 mmol), 3-furanylboronic acid (71 mg, 0.638 mmol), and THF (10 mL). The reaction mixture was refluxed for 15 h. Standard work-up followed by purification gave 50 mg (40%) of the title product 29 (40%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.45 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.18-7.12 (m, 4H), 6.96 (app. t, J=8.4 Hz, 2H), 6.68 (s, 1H), 2.0 (s, 2H), 1.96 (s, 2H), 1.30 (s, 2H), 0.94 (s, 6H), 0.93 (s, 6H). LCMS (APCI): m/z 389 (M+H)+.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[N:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]#[CH:24].[Cl-].C(N(CC)CC)C>C(#N)C.[Cu]I.O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]#[C:24][C:2]1[S:15][C:5]2[C:6]3[CH:14]=[N:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Brc1cc2c(s1)-c1cnccc1OCC2
Agent: [Cu]I
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccccc1C#Cc1cc2c(s1)-c1cnccc1OCC2
Temperature: 85 °C
Yield: 81 %

Procedure:
A mixture of 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (140 mg, 0.5 mmol) from Example 72, 1-chloro-2-ethynylbenzene, 18 mg (0.025 mmol) of bistriphenylphosphinepalladium(II) chloride and 1 ml (7.17 mmol) of triethylamine in 4 ml of acetonitrile was degassed. Copper (I) iodide (2.4 mg, 0.012 mmol) was then added and the mixture was heated at 85° C. for 3 hours. The mixture was mixed with 20 ml of water and extracted with 10 ml of ethyl acetate twice. The combined extracts were washed with 1% aqueous ammonia, water, brine and dried over sodium sulfate. The solution was concentrated in vacuum, the residue purified by flash chromatography eluting with 30% ethyl acetate in hexane to give 2-((2-chlorophenyl)ethynyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (137 mg, 81%). MS: (ESI+) 338.1
Reaction SMILES: [Na].[CH3:2][SH:3].C[O-].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19][N:20]=[C:21]([CH2:24]Cl)[CH:22]=[O:23]>CO>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19][N:20]=[C:21]([CH2:24][S:3][CH3:2])[CH:22]=[O:23]
Reactant: CS
Reactant: O=CC(CCl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSCC(C=O)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
9.2 g of sodium was dissolved in 900 ml of methanol. 21.3 g of methanethiol was introduced into the sodium methylate solution thus obtained. Then 110.0 g of 3-chloropyruvaldehyde-1-[2,6-dichloro-4-(trifluoromethyl)-phenyl]hydrazone (produced according to Example 1) was added in portions at 30° to 40° C. The reaction mixture was stirred for 1 hour at 40° C. and then the methanol was distilled off in a water jet vacuum. The residue was mixed with 500 ml of water and extracted three times with 250 ml of dichloromethane each. The combined dichloromethane extracts were dried on sodium sulfate and concentrated by evaporation. The residue was suspended in 200 ml of n-hexane, filtered off and dried in a water jet vacuum. The yield of the product was 92.2 g [content (GC): 94.7 percent]. The melting point of the product was 88° to 90° C.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[N:6]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=[C:7]=[O:8]>ClCCl>[CH:1]1([CH2:4][NH:5][C:7](=[O:8])[NH:6][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: NCC1CC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)NCC2CC2)cc1
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To cyclopropylmethanamine (57.5 mmol, 4.99 ml, 4.09 g) in dichloromethane (40 mL) was added to ethyl 4-isocyanatobenzoate (52.3 mmol, 10 g) in dichloromethane (45 mL) and the reaction stirred overnight. The reaction was then concentrated under reduced pressure to give the title compound (14.7 g).