Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH2:14])[C:8]2=[CH:7][N:6]=1.[CH3:20][C:21]([CH3:23])=O.C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH:14][CH:21]([CH3:23])[CH3:20])[C:8]2=[CH:7][N:6]=1
Reactant: Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a room temperature slurry of 6-(2,4-Difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-ylamine (170 mg, 0.646 mmol), acetone (0.95 mL, 12.9 mmol) acetic acid (0.037 mL) and THF (6.5 mL) was added NaBH(OAc)3 (547 mg, 2.58 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to room temperature and diluted with ether. This mixture was washed with water and brine, then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed through silica (10%-50% EtOAc in hexanes) to give 105 mg of [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-isopropyl-amine, MP=211.3-214.4° C., MS(M+H)=306.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[NH:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1)#[N:2].O.[NH2:15]N>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:12][CH:13]=1)[C:7](=[O:8])[NH:15][NH:9][C:10]2=[O:11])#[N:2]
Reactant: N#Cc1ccc2c(c1)C(=O)NC2=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Cyanophthalimide (80 g) was suspended in 1000 ml of ethanol, followed by the addition of 25 ml of hydrazine monohydrate. The obtained mixture was stirred at room temperature for 5 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3](=[O:27])[CH2:4][O:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[NH:8][N:7]=1.F[C:31]1C=CC(C2C(OCC(=O)C(C)(C)C)=NNC=2C)=C[CH:32]=1>O>[CH2:31]([N:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([O:5][CH2:4][C:3](=[O:27])[C:2]([CH3:29])([CH3:28])[CH3:1])=[N:7]1)[CH3:32]
Reactant: Cc1[nH]nc(OCC(=O)C(C)(C)C)c1-c1ccc(F)cc1
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Solvent: O
Product: CCn1nc(OCC(=O)C(C)(C)C)c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1

Procedure:
The desired compound was prepared according to the method of Example 27, substituting 3,3-dimethyl-1-[(5-(4-(methylsulphonyl)phenyl)-4-phenyl-1H-pyrazol-3-yl)oxy]butan-2-one, prepared according to the method of Example 32B, in place of 1-[(4-(4-fluorophenyl)-5-methyl-1H-pyrazol-3-yl)oxy]-3,3-dimethylbutan-2-one (yield: 145 mg, 94%). MP 158-161° C.; MS (APCI+) m/z 441 (M+H)+; (APCI−) m/z 475 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ1.20 (m, 12H), 3.30 (s, 3H), 3.80 (q, J=7 Hz, 2H), 5.25 (s, 2H), 7.19 (m, 5H), 7.62 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H); Anal. calc. for C24H28N2O4S.0.25 H2O: C, 64.76; H, 6.45; N, 6.29. Found: C, 64.72; H, 6.60; N, 6.13.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Yield: 66.5 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (140 mg, 0.437 mmol) was reacted with 3-chloropropane sulfonyl chloride (58 uL, 0.480 mmol) in the presence of diisopropylethyl amine (305 uL, 1.75 mmol) and DMAP (53 mg, 0.437 mmol) in dichloromethane (5 mL) to give the title compound (134 mg, 77%)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH:32]1[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33]1.O.[OH-].[Cs+]>CN(C)C=O>[CH3:37][C:34]1([CH3:38])[O:33][CH:32]([CH2:31][N:2]2[C:3]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)=[CH:4][CH:5]=[N:1]2)[CH2:36][O:35]1
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC1(C)OCC(CBr)O1
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccnn2CC2COC(C)(C)O2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.104 mmol) in N,N-dimethylformamide (0.5 mL) was added 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (20.2 mg, 0.104 mmol) and cesium hydroxide hydrate (17.4 mg, 0.104 mmol). The mixture was stirred for 16 hours at ambient temperature, filtered, washing with methanol and ethyl acetate, and concentrated under a stream of nitrogen. The resulting material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The isolated product (22.5 mg) was a 7:3 mixture of two regioisomers, N-(1-((1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-5-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and N-(1-((1-(2,3-dihydroxypropyl)-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide. This material was continued to the next step as a mixture.
Reaction SMILES: [OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:23])[F:22])=[CH:15]\[C:16]([O:18]CC)=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11].[OH-].[Na+].Cl>O.O1CCCC1>[OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:22])([F:23])[F:24])=[CH:15]\[C:16]([OH:18])=[O:17])[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11]
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=CC(=O)CC(C)(C)C1(O)C#C/C(=C\C(=O)O)C(F)(F)F
Temperature: 25 °C
Yield: 33.3 %

Procedure:
In a round-bottom flask, ethyl (2E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)pent-2-en-4-ynoate (130 mg, 0.38 mmol) was dissolved in a mixture of water and tetrahydrofuran, and sodium hydroxide (38 mg, 0.94 mmol) was then added. The resulting reaction mixture was stirred under reflux for 2 h and, after cooling to room temperature, acidified with aqueous hydrochloric acid. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), (2E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)pent-2-en-4-ynoic acid (40 mg, 32% of theory) was obtained in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 10.14 (br. s, 1H, OH), 6.70 (s, 1H), 5.92 (s, 1H), 2.61 (d, 1H), 2.43 (d, 1H), 2.30 (br. s, 1H, OH), 2.16 (s, 3H), 1.28 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>C(Cl)Cl.N1C=CC=CC=1>[O:12]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16])[CH3:11]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: Nc1nc2ccccc2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2nc3ccccc3s2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2-amino-1,3-benzthiazole (700 mg, 4.7 mmol) in methylene chloride (20 ml) and pyridine (800 μl) was treated with 2,4-dimethoxybenzoyl chloride and stirred at 25° C. for 30 minutes. After this time, the reaction was treated with HCl (10 ml of 5 wt %) and the resulting precipitated collected by filtration. The solid was recrystallized from methanol to give 2-(2,4-dimethoxylbenzamido)-1,3-benzthiazole as colorless needles. (1.185 mg, 80% yield)
Reaction SMILES: Cl[C:2]1(OC)[CH:10]=[CH:9][C:8]2[N:7]([C:11](=O)[C:12]([CH3:14])=C)C(C(O)=O)C[C:4]=2[CH2:3]1.[C:21](SCC(C)C(N1C2C(=CC(Cl)=CC=2)CC1C(O)=O)=O)(=O)[C:22]1C=CC=C[CH:23]=1>>[CH:11]1([NH:7][CH:8]2[CH2:4][CH2:3][CH2:2][CH2:10][CH2:9]2)[CH2:12][CH2:14][CH2:23][CH2:22][CH2:21]1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccc(Cl)cc2CC1C(=O)O
Reactant: C=C(C)C(=O)N1C2=C(CC1C(=O)O)CC(Cl)(OC)C=C2
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
By substituting 5-chloro-2,3-dihydro-5-methoxy-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid in the procedure of Example 25, 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-5-chloro-2,3dihydro-1H-indole-2-carboxylic acid, dicyclohexylamine was obtained. The latter salt was then treated with 5% aqueous potassium hydrogen sulfate as in Example 15 to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7](=O)[CH2:8][CH3:9])[CH:3]=1.[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1>>[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:7](/[C:4]2[CH:3]=[C:2]([Cl:1])[S:6][CH:5]=2)\[CH2:8][CH3:9])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1csc(Cl)c1
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1csc(Cl)c1
Yield: 26.4 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(5-chlorothiophen-3-yl)propan-1-one (1.5 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.2 eq) to give 0.8 g desired product (45% yield, E).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)#[CH:11]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:11]#[C:10][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:4][N:3]=1
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Reactant: Nc1ncc(I)c(N)n1
Product: COc1cc(C#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 89.9 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 5-Ethynyl-1,2,3-trimethoxybenzene (384 mg) as per the general procedure to afford 2,4-Diamino-5-(2-(3,4,5-trimethoxyphenyl)ethynyl)pyrimidine as a white powder (270 mg, 90%): Rf=0.28 (9:1, CHCl3:MeOH); mp=202-204° C.; 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 6.90 (s, 2H), 6.37 (s, 2H), 3.79 (s, 6H), 3.67 (s, 3H); 13C NMR (DMSO-d6) δ 163.4, 162.2, 159.4, 159.2, 152.8, 137.6, 118.6, 108.3, 108.2, 94.7, 89.8, 83.4, 60.2, 60.1, 56.0, 55.9; Anal. (C15H16N4O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[Br:25]Br>C(Cl)Cl>[Br:25][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1

Procedure:
To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) in CH2Cl2 containing CHCl3 (1.0 mL) and Cl4 (1.0 mL) was added bromine (0.614 g). After shining light for 1 h, the reaction was quenched with Na2S2O4, extracted with CH2Cl2, dried over Na2SO4 and evaporated to yield the title compound which was used as such for the next step (1.10 g).
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=O)[CH:4]=1.[CH:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)(=O)C>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[C:12](\[CH2:13][CH2:14][CH2:15][CH3:16])/[CH:11]=[O:17])[CH:4]=1
Reactant: CCCCCC=O
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCC/C(C=O)=C\c1cccnc1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
6.0 g (0.15 mol) of sodium hydroxide were added to a solution of 160.5 g (1.5 mol) of pyridine-3-carbaldehyde in 750 ml of methanol. Thereafter, 150.0 g (1.5 mol) of hexanal were added dropwise in the course of 3 hours at room temperature. Stirring was carried out for 1 hour, the pH was brought to 6 with acetic acid and the solvent was then evaporated under reduced pressure. The residue was taken up in a water/dichloromethane mixture and the organic phase was washed with water, dried over sodium sulfate and evaporated down under reduced pressure. Distillation gave 190 g (67% of theory) of E-2-(3-pyridylmethylidene)-hexanal as a yellow oil of boiling point 132°-134° C./2 mbar.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1)#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(CC#N)cc2)cs1
Temperature: 25 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
NaCN (115 mg), KI (130 mg) and water (1.8 ml) were combined, and then a solution of N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (230 mg) in DMF (7 ml) was added dropwise to the mixture at 0° C. The reaction mixture was stirred at r.t. for 19 hours, poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-(4-{2-[4-(cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (149.1-mg) as a colorless solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]([CH3:28])([CH3:27])[CH2:8][C:9]1[N:10]([CH2:23][CH2:24][O:25][CH3:26])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22]>C(OCC)(=O)C>[NH2:22][C:13]1[C:12]2=[N:11][N:10]([CH2:23][CH2:24][O:25][CH3:26])[C:9]([CH2:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:28])[CH3:27])=[C:21]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Solvent: CCOC(C)=O
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NS(C)(=O)=O
Yield: 59.4 %

Procedure:
Using the method of Example 66, methanesulfonyl chloride (399 mg, 3.48 mmol) was reacted with 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (1.09 g, 3.48 mmol, prepared as described in Example 590). The crude product was purified by IFC (40M cartridge eluting with a gradient of 15 to 35% CMA in chloroform) to provide a white foam. The foam was refluxed with 35% ethyl acetate in hexanes (50 mL), ethyl acetate was added until a free flowing white solid appeared, and then the mixture was cooled on ice. The solid was isolated by filtration and dried to provide 809 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, mp 211-213° C. MS (ESI) m/z 392 (M+H)+; Anal. Calcd for C18H25N5O3S: C, 55.22; H, 6.44; N, 17.89. Found: C, 55.05; H, 6.38; N, 17.98.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C(CBr)N1CCCC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), 2-bromo-1-pyrrolidin-1-yl-ethanone (3 g, 20 mmol) and cesium carbonate (19.5 g, 60 mmol) in dimethylformamide (16 mL) was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.8 g (25%) 5-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:19](OC)=[O:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].CO>C1COCC1>[CH2:1]([NH:8][C@H:9]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl N-benzyl-O-[tert-butyl(dimethyl)silyl]-D-serinate (1 eq.) in THF (0.4 M) at rt were added 2M LiBH4 in THF (1.2 eq.) and MeOH (1.2 eq). The mixture was stirred at rt for 16 hrs and quenched by the slow addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was used as such for the next step.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12]C)=O.[NH3:14].O>CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: N
Reactant: COC(=O)c1cc2cccnc2[nH]1
Solvent: O
Solvent: CO
Product: NC(=O)c1cc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1) (880 mg, 5.0 mmol) in MeOH (2 mL) was added NH3.H2O (6 mL). The reaction was heated at 80° C. overnight. After being cooled to room temperature, the mixture was concentrated in vacuo to afford the title compound (805 mg) as a yellow solid, which was used for the next step without further purification. MS (m/z): 162 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([F:21])[C:17]=2[C:19]#[CH:20])[C:12](=[O:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([F:21])[C:17]=2[C:19]#[CH:20])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]1
Reactant: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(-c3ccc(F)cc3F)c12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)cc3F)c12
Yield: 90.3 %

Procedure:
1.17 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 9 ml of glacial acetic acid, 0.75 ml of water and 0.2 ml of concentrated sulphuric acid. The solid which has crystallised out at room temperature is filtered off with suction and dried. 0.98 g of 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of theory).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[C:19]#[N:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl.N>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[C:19]#[N:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of N-benzoyl 2-cyano-4-nitroaniline (3.38 g, 12.6 mmol) and tin (II) chloride (14.3 g, 63.2 mmol) were heated in ethyl acetate (200 ml) at reflux for 2.5 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature, concentrated aqueous ammonia (20 ml) added and the reaction was then filtered. Evaporation of the organic layer in vacuo yielded N-benzoyl 2-cyano-4-aminoaniline (2.64 g, 88% yield) as a yellow solid:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.CCCCCC>[Cl:17][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1
Temperature: -78 °C

Procedure:
To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyllithium (472 mL, 1.18 mol) in hexane while maintaining the temperature below −65° C. Upon completion of the addition the reaction mixture was maintained at −78° C. for an additional 45 minutes, after which time a solution of hexachloroethane (279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. The reaction mixture was maintained for an hour at −78° C., warmed to −20° C. and then quenched with water (1 L). The reaction mixture was extracted with methylene chloride (4×500 mL); the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride as eluent to afford the title product compound as a yellow oil (160 g).
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-].[Cl-].[Cl-].C1([Zr+3:26])C=CC=C1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]1([Zr:26])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [Zr]c1cccc2c1C=C1C2=Nc2ccccc21
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum. Yield of complex 10: 16.5 g. The 1H NMR spectrum is consistent with the proposed structure:
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:11]([CH2:17][CH3:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>>[CH2:17]([C:11]1[NH:8][C:2]2[C:7]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:18]
Reactant: NNc1ccccc1
Reactant: CCC(=O)CCC(=O)O
Agent: Cl
Product: CCc1[nH]c2ccccc2c1CC(=O)O
Yield: 10 %

Procedure:
Reaction was conducted in the same manner as Reference Example 86, except that phenylhydrazine hydrochloride was used instead of 3-tolylhydrazine hydrochloride and 4-oxohexanoic acid was used instead of levulinic acid, to obtain the title compound (10% yield).