Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][CH:7]([NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:15]([NH:14][CH:7]1[CH2:8][C:9]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)[CH2:6]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCc1cc2c(cc1CC)CC(NC(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc2c(cc1CC)CC(NCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 6 h

Procedure:
N-(5,6-Diethyl-indan-2-yl)-benzamide (3.30 g) is dissolved in dry THF (100 mL). Lithium aluminium hydride, 1M in THF (22.52 ml) is then added dropwise. The reaction mixture is stirred at 50° C. The reaction is shown to be complete by TLC after 6 hours. The reaction mixture is allowed to cool, poured slowly into ice-water (200 mL) and extracted with diethyl ether (2×105 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 2:1 Rf=0.20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12]>CN(C)C=O.C(OCC)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 10 gm (57.8 mMol) 3-bromophenol in 25 mL dimethylformamide was added dropwise to a mixture of 2.8 gm (70 mMol) sodium hydride (60% suspension in mineral oil) in 30 mL dimethylformamide. The reaction mixture was stirred for one hour after the addition was complete. To the reaction mixture was then added 9.7 mL (64.5 mMol) bromoacetaldehyde diethyl acetal and the resulting mixture was stirred at 153° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature and was diluted with 300 mL diethyl ether. This mixture was then washed with two 150 ml portions of water, washed with 50 mL saturated aqueous sodium chloride, dried over magesium sulfate and concentrated under reduced pressure to provide about 17 gm of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=O.O.[NH2:22][NH2:23]>CCO>[CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:23][N:22]=1
Reactant: NN
Reactant: Cc1cc(C)c(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2n[nH]c(=O)c3ccccc23)c(C)c1
Reaction time: 0.17 h

Procedure:
A mixture of 2-(2,4,6-trimethylbenzoyl-benzoic acid (5.0 g, 18.7 mmol) and hydrazine hydrate (2 mL) in 15 mL of EtOH was stirred at reflux for 8 hours. The solvent was then removed from the mixture. The residue was heated to melt for about 10 minutes and then solidified by cooling. The resulting yellow solids were triturated with ether and filtered. The solid was washed with 1 N NaOH and water, and dried to give 1.8 g of titled compound as yellow solids, m.p. 259-62° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc32)cc1
Reaction time: 72 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO is added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 4-cyanophenylboronic acid (4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture is stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture is concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 4-[5-(5-Nitro-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile.
Reaction SMILES: N1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:14])=O.O[CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[Cl:14][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reaction time: 0.17 h

Procedure:
24 ml (0.3 mole) of pyridine, 400 μl of dimethylformamide and 21.6 ml (0.3 mole) of thionyl chloride are added to a solution of 103 g (0.2 mole) of benzhydryl 3-hydroxymethyl-7β-phenylacetamido-3-cephem-4-carboxylate (prepared, for example, in accordance with Helv. Chim. Acta 57, 2044 (1974)) in 3.5 l of absolute tetrahydrofuran, while cooling with ice. After 10 minutes, the mixture is concentrated on a rotary evaporator, the residue is taken up in 2 l of ethyl acetate and the mixture is extracted by shaking twice with sodium bicarbonate solution and once with water. The organic phase is extracted by stirring with 50 g each of kieselguhr and active charcoal and the extract is filtered with suction over a frit covered with silica gel. The filtrate is then dried over magnesium sulphate and concentrated, the residue is taken up in 200 ml of methylene chloride and the product is precipitated with petroleum ether.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].CN(C)C(N(C)C)=N.[F:39][C:40]([F:47])([F:46])[C:41](OCC)=[O:42]>CO>[CH2:2]([C:4]1[CH:5]=[C:6]([C@@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)[C@@H:11]([NH:13][C:41](=[O:42])[C:40]([F:47])([F:46])[F:39])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)c1

Procedure:
(1R,2S)-1-(3-ethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (50 mg, 0.12 mmol), 1,1,3,3-tetramethylguanidine (100 μl, 0.79 mmol) and ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5 mL) was stirred at r.t. for 1 h. The reaction mixture was concentrated by evaporation, the residual material was purified by HPLC. Yield 41 mg (72%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[CH:12]=[CH:13]3)=[CH:4][CH:3]=1.CCCCC.[C:22]1([P:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[Si](C)(C)C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[CH:11]12[CH2:16][CH:14]([CH:13]=[CH:12]1)[CH2:15][CH:10]2[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([P:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(OCC2CC3C=CC2C3)cc1
Reactant: C[Si](C)(C)P(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: CCCCC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C1=CC2CC1CC2COc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Yield: 14.7 %

Procedure:
Bis(acetonitrile)dichloropalladium(II) (1 mmol) was placed in a Schlenk flask, stoppered with a septum and evacuated and purged with nitrogen three times. To this flask was then added a solution of 8 (0.038 mol) in 100 mL of anhydrous toluene and 9.6 g of diphenyl(trimethylsilyl)phosphine. The resulting deep purple solution was heated at 70° C. overnight, then cooled to room temperature and the solvent evaporated under reduced pressure. The residue was chromatographed on a column of silica gel using first hexane and then 9:1 hexane ethyl acetate as eluent to collect the product. After evaporation of the solvent, the product 9 (10 g), a mixture of endo and exo isomers, was obtained as white gummy material. Addition of 50 mL of hot pentane to this compound resulted in the separation of white crystalline compound (2.1 g). 1H NMR (500 MHz, 25° C., CDCl3): δ (endo isomer, ˜85%) 7.30 (m, 12H, Ar—H), 6.88 (m, 2H, Ar—H), 6.18 (m, 1H, olefinic), 5.98 (m, 1H, olefinic), 3.72 (m, 1H, nor-CH2), 3.57 (m 1H, nor-CH2), 3.04 (br s 1H), 2.88 (br s, 1H), 2.53 (m, 1H), 1.92 (m, 1H), 1.51 (d, |J|=8.0 Hz), 1.32 (d, |J|=8.2 Hz, 1H), 0.65 (m, 1H); (exo isomer, partial) 6.92 (m, 2H, Ar—H), 4.05 (m, 1H), 3.88 (m, 1H). 31P {1H} NMR (200 MHz, 25° C., CDCl3): δ −6.57
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](=C)[CH2:12][C@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[OH:23]>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](=[O:23])[CH2:12][C@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)C1
Reactant: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a solution of (±)-trans-1-t-butyldimethylsilyloxymethyl-4-methylene-2-phenylcyclopentane from Step B1 (2.2 g, 7.3 mmol) in methanol (100 mL) cooled in a dry ice/acetone bath was bubbled ozone until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to rt over 2 h. The volatiles were removed in vacuo and the residue was purified by FC (15-30% ethyl acetate in hexanes) to give the title compound (1.9 g) which was the same as in Method A.
Reaction SMILES: [CH3:1][CH:2]([C@@:4]12[C@@H:19]([OH:20])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1.CCCCCC>N1C=CC=CC=1>[CH3:3][CH:2]([C@@:4]12[C@@H:19]([OH:20])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:1].[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:6])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@@H]2O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 30 h

Procedure:
Triptolide (100 mg) in 10 ml of pyridine was treated with succinic anhydride (150 mg) at room temperature. The reaction was carried out at 85° C. for 30 hours under a nitrogen atmosphere. Hexane (50 ml) was added to the resultant mixture to precipitate a crude product, which was collected by filtration and washed with hexane. The crude product was recrystallized from ether/hexane to yield 90 mg (70%) of triptolide succinate (YM-262), m.p. 111-113° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:17])(OC)[CH:12]=C=O)#[N:2].[OH-:28].[Na+].O.Cl.[CH2:32]([OH:34])C>>[C:32]([C:11]([CH3:12])([CH3:17])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)=[CH:4][C:3]=1[C:1]#[N:2])([OH:34])=[O:28]
Reactant: CCO
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C=C=O)OC)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N)C(=O)O
Temperature: 50 °C

Procedure:
To a solution (6.4 ml) of ethyl 1-(3-cyano-4-(2-methyl-2-methoxy-carbonylpropoxy)phenyl)pyrazole-4-carboxylate (0.64 g) obtained in Example 39 in ethanol was added 2 N aqueous sodium hydroxide solution (2.15 ml) with stirring, and the mixture was heated at 50° C. for 8 hours. After the completion of the reaction, the reaction mxture was poured into water and neutralized with 1 N hydrochloric acid (3.8 ml). The precipitated crystals were recrystallized from a mixed solvent of ethyl alcohol and water to give 0.26 g of 1-(4-(2-carboxy 2-methylpropoxy)-3cyanophenyl)pyrazole-4-carboxylic acid, melting point 230-233° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O.CCOC(C)=O>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCF
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of 2-fluoroethanol (1.92 g, 29.97 mmol) in dry pyridine (15 ml) under an atmosphere of argon at 0° C. was added p-toluenesulphonyl chloride over 15 min, maintaining the temperature below 5° C. The reaction mixture was then stirred at 0° C. for 4 h, then at room temperature for 12 h. The reaction mixture was cooled to 0° C. and ice (15 g) was added followed by water (40 ml) and EtOAc (50 ml). The organic extract was washed with water (30 ml), 1 M HCl (until aqueous extracts were acidic), 10% sodium carbonate (2×30 ml), brine (40 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (5.10 g, 78%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Cl:21])=[CH:18][CH:17]=1)=[CH2:15]>CCOCC>[Cl-:21].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N+:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:1])[CH3:13])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCCCCCCCCCN(C)C
Solvent: CCOCC
Product: C=Cc1ccc(C[N+](C)(C)CCCCCCCCCC)cc1
Product: [Cl-]
Reaction time: 12 h
Yield: 17 %

Procedure:
Dimethyl decyl amine (9.30 g, 50 mmol) and 4-vinylbenzylchloride (7.63 g, 50 mmol) were added to ether (20 mL) and were allowed to stir for 12 hours. A yellow solid precipitated and was subsequently collected by filtration resulting in 3 g (17% yield). The ether was removed and the remaining solution was allowed to react neat for 24 hours giving a near quantitative yield after washing with ether. Subsequent reactions were performed neat. 1H-NMR (90 MHz, CDCl3, δ): 7.68-7.38 (dd, 4H); 6.87-6.56 (dd, 1H); 5.89-5.70 (d, 1H); 5.41-5.29 (d, 1H); 5.09 (s, 2H); 3.51 (bs, 2H); 3.31 (s, 6H); 1.81 (bs, 2H) 1.25 (bs, 14H); 0.92-0.81 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]3[C:14]([OH:19])=[CH:15][C:16](=[O:18])[O:17][C:5]=3[C:4]=2[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]3[C:14]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[C:16](=[O:18])[O:17][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)c2c(O)cc(=O)oc2c2cc(Cl)ccc21
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(O)c([N+](=O)[O-])c(=O)oc2c2cc(Cl)ccc21
Temperature: 20 °C

Procedure:
0.02 Mole 9-chloro-5,6-dihydro-6-methyl-2,5-dioxo-2H-pyrano[3,2-c]quinoline-4-ol from Example 7 (5.6 g) is suspended in 25 ml of glacial acetic acid. 4 ml of nitric acid (d=1.40) are added dropwise at 25° C., while stirring, and the magma-like reaction batch is then heated for 60 minutes to 95° C. It is then cooled to 20° C. During cooling, 36 ml of a mixture of water and isopropanol (1:1) is added. The whole is then filtered. The filter residue is washed with water to neutrality and after washing with isopropanol and petroleum ether, it is dried. 5.5 g (85% of the theory) of a crystalline residue are obtained, the crystals of which have a melting point of 241°-243° C. (decomp.) after recrystallization from a mixture of isobutanol and dimethylformamide.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[H-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([O:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CCCc1c(C=O)ccc(OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(C=O)ccc(OC)c1OC(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 3-hydroxy-4-methoxy-2propylbenzaldehyde (36.6 g) in dry dimethylformamide (50 ml) was added to a suspension of sodium hydride (4.5 g) in dry dimethylformamide (20 ml) in a nitrogen atmosphere. The mixture was stirred at 20° for 30 mins followed by the addition of acetyl chloride (13.5 ml) dropwise over a period of 15 min. The mixture was stirred at 20° for 24 hours.
Reaction SMILES: [CH2:1]([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:11][CH2:12][CH2:13][N:14]([C:16]3[CH:17]=[C:18]([CH3:26])[C:19]4[N:25]=[C:41]([C:40]5[C:35]([Cl:34])=[N:36][CH:37]=[CH:38][C:39]=5[I:43])[NH:22][C:20]=4[CH:21]=3)[CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (330:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (55 mg, 9%). 1H NMR (CDCl3) δ 1.22-1.36 (2H), 1.49-1.84 (6H), 1.95-2.59 (6H), 2.59 (s, 3H), 2.94-3.45 (6H), 6.82 (s, 1H), 6.87 (s, 1H), 7.16-7.33 (5H), 7.72 (d, J=6 Hz, 1H), 7.99 (d, J=6 Hz, 1H). ESI-MS m/z 612 (MH+).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:11][CH:10]=1
Reactant: OCc1ccc(-n2cccn2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of alcohol (III) (10.5 g, 59.9 mmol) in CH2Cl2 (150 ml), SOCl2 (36 g, 22 ml, 299.6 mmol) was added and the resulting reaction mixture was stirred at room temperature for a period of between 12 to 18 hours. The excess SOCl2 was quenched with saturated aqueous NaHCO3. The resulting mixture was extracted with CH2Cl2 and washed with brine. Removal of solvent gave a compound of formulae (11.15 g, 95% yield) as a white solid. MS-ESI=194.06, 196.06, 1H NMR (ppm): 8.59(H3′, d), 8.43(H6, d), 8.03(H2, d), 7.89(H3, dd), 7.78(H5′, s), 6.50(H4′, t), 4.65(—CH2-).
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:13][N:4]1[C:5]2[CH2:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][C:10]=2[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:3]1
Reactant: Cn1nc(I)c2c1CC(C)(C)CC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC(C)(C)C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
To a solution of 3-iodo-1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazole (0.150 g, 0.49 mmol) in THF (3 mL) at 0° C. was slowly added isopropylmagnesium chloride (2.0 M in THF) (0.30 mL, 0.59 mmol). The reaction mixture was stirred at 0° C. for 20 min then tributylchlorostannane (0.16 mL, 0.59 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 10% EtOAc/hexanes (0.5% Et3N) to afford 116 mg (52%) of 1,6,6-trimethyl-3-tributylstannanyl-4,5,6,7-tetrahydro-1H-indazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.74 (s, 3H), 2.49 (t, J=6.4 Hz, 2H), 2.30 (s, 2H), 1.45-1.61 (m, 8H), 1.25-1.41 (m, 6H), 1.04-1.13 (m, 6H), 1.01 (s, 6H), 0.89 (t, J=7.2 Hz, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc(N5CCN(C)CC5)nc4)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=468.0.