Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:7][CH2:6]1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[S:27])[NH2:26])=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]2[S:27][CH:2]=[C:3]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:7][CH2:6]3)[N:26]=2)=[CH:22][CH:23]=1
Reactant: NC(=S)Cc1ccc(Cl)cc1
Reactant: C=CCOC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CCO
Product: C=CCOC(=O)N1CCC(c2csc(Cc3ccc(Cl)cc3)n2)CC1

Procedure:
A mixture of allyl 4-(bromoacetyl)piperidine-1-carboxylate (547 mg) and 2-(4-chlorophenyl)ethanethioamide (366 mg) in ethanol (15 ml) was refluxed for 5 hours. The reaction mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with methanol/dichloromethane (2:98) to give allyl 4-[2-(4-chlorobenzyl)-1,3-thiazol-4-yl]piperidine-1-carboxylate. Yield 698 mg. NMR (CDCl3): 1.65 (m, 2H), 2.25 (m, 2H), 2.95 (m, 2H), 3.2 (m, 1H), 4.3 (m, 2H), 4.55 (m, 4H), 5.3 (m, 2H), 6.0 (m, 1H), 6.95 (s, 1H), 7.35 (m, 4H).
Reaction SMILES: [O:1]=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:17][C:18]([CH3:23])([CH2:21]O)[CH2:19][OH:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:17][C:18]1([CH3:23])[CH2:19][O:20][C:2]([CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:1][CH2:21]1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)CSCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CSCC1(c2ccccc2)OCC(C)(C)CO1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Ethyl [(2-oxo-2-phenylethyl)thio]acetate (10.8 g, 45.3 mmol) was dissolved in toluene (250 ml). 2,2-Dimethyl-1,3-propanediol (37.6 g, 0.36 mol) and p-toluene sulfonic acid (cat., 500 mg) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for two hours and at room temperature overnight. The mixture was concentrated under reduced pressure. The crude oil was purified by flash-chromatography (hexane:EtOAc-7:1) to give 11.2 g (70%) of the title compound as a colourless oil. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2-1.3 (t, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.2 (s, 2H), 3.5 (s, 4H), 4.1-4.2 (q, 2H), 7.3-7.6 (m, 5H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[OH:14]>ClCCl>[Cl:6][C:7]1[C:8]([OH:14])=[CH:9][C:10]([CH3:13])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(Cl)c(O)c1
Solvent: ClCCl
Product: Cc1cc(O)c(Cl)cc1S(=O)(=O)Cl
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 120 mg (7.1%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([NH:20][C:2]2[C:3]3[CH:13]=[CH:12][NH:11][C:4]=3[N:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.182 g, 0.921 mmol) in DMF (5 mL) was added cyclohexylamine (0.55 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for about 2 h. The solvent was removed under reduced pressure and EtOAc (100 mL) and water (20 mL) were added. The layers were separated and the organic layer was washed with water (3×25 mL) and brine (20 mL), dried over anhydrous MgSO4, filtered, and concd to give N-cyclohexyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (0.20, 57%) as a brown residue: LC/MS (Table 1, Method c) Rt=1.53 min; MS m/z 261 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]=1[C:40]([F:43])([F:42])[F:41]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][C:30]=2[C:40]([F:41])([F:43])[F:42])[N:8]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.29 g, 5.78 mmol) in THF (30 ml) was added 1.0M lithium bis(trimethylsilyl)amide in THF (5.66 ml, 5.66 mmol) at ambient temperature under nitrogen. The solution was stirred at ambient temperature for 30 min. To the solution was added a solution of ethyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate (for a preparation see Intermediate 20)(1.6 g, 5.14 mmol) in THF (20 ml). The mixture was stirred for 3.5 h at ambient temperature under nitrogen. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The phases were separated and the aqueous phase washed with ethyl acetate (25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a pale yellow oil (2.8 g). The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.68 g); LCMS: (System 4) MH+=454, tRET=3.15 min.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:19])=[NH:16])=[CH:10][CH:9]=1.[CH3:31][C:32]([CH3:34])=O>>[ClH:3].[NH2:16][C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[C:32]([CH3:34])([CH3:31])[N:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:17]=1
Reactant: CCCCCCCCCCNC(=N)NC(=N)Nc1ccc(OC)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N(c2ccc(OC)cc2)C(N)=N1

Procedure:
50 ml of methanol, 40 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 1.5 g (3.6 mmol) of N1-(4-methoxyphenyl)-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1)). The eluate was dissolved in 80% aqueous acetonitrile, and the solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 0.92 g of a pale yellow resinous solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])OC)=[CH:5][CH:4]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][C@H:20]([CH3:23])[CH2:19][N:18]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:18]2[C@@H:17]([CH3:16])[CH2:22][N:21]([C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)=[O:13])[C@H:20]([CH3:23])[CH2:19]2)=[CH:25][C:26]=1[O:32][CH3:33])#[N:29]
Reactant: COC(=O)Nc1ccc(C(F)(F)F)nc1
Reactant: COc1cc(N2C[C@@H](C)NC[C@@H]2C)ccc1C#N
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(N2C[C@@H](C)N(C(=O)Nc3ccc(C(F)(F)F)nc3)C[C@@H]2C)ccc1C#N
Temperature: 100 °C
Yield: 45.7 %

Procedure:
Into 5 ml of toluene were dissolved 500 mg of methyl 6-(trifluoromethyl)pyridin-3-ylcarbamate and 557 mg of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-methoxybenzonitrile, and then 0.03 ml of DBU was added thereto, followed by heating to 100° C. and 8 hours of stirring. The reaction solution was concentrated and the residue was subjected to silica gel column chromatography to obtain 450 mg of the title compound from an eluate using chloroform-methanol (96:4, v/v).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH:13]([CH3:17])[C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][C:13]([CH3:17])=[C:14]2[CH3:15])=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)C(C)CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1C
Yield: 66.4 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]-3-methylpentane-1,4-dione (110 mg, 0.41 mmol), 4-bromoaniline (71 mg, 0.41 mmol), and p-toluenesulfonic acid (10 mg) in toluene (3 mL) was heated at reflux temperature using Dean-Stark apparatus. After cooling down, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/3) to give the subtitle compound (110 mg, 67% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.I[CH:35]([CH3:37])[CH3:36]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:35]([CH3:37])[CH3:36])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Reactant: CC(C)I
Product: CC(C)Oc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-iodopropane (0.17 mL) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-isopropoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (35 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1([F:25])[CH2:22][CH:21]1[CH2:23]Br.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:23][CH:21]2[CH2:22][C:20]2([F:25])[F:19])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: FC1(F)CC1CBr
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(OCC2CC2(F)F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.6 g 2-Chloro-4-fluoro-5-nitrophenol was dissolved in dimethylformamide and treated with potassium carbonate. The mixture was stirred at room temperature for one hour and then 3.3 g 2,2-difluorocyclopropylmethyl bromide added. It was the heated at 80° C. for 2 hours and added to water. The mixture was extracted with methylene chloride and the organic phase washed with saturated brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using a mixture of 3 parts hexane and 1 part ethyl acetate. There was obtained 5 g (=93% of theory) of yellow crystals whose nmr spectrum is as follows: δ=1.1-2.4 ppm (m) 3H, δ=4.15 ppm (d 7 Hz,tr 1.5 Hz) 2H, δ=7.35 ppm (d 10 Hz) 1H, δ=7.5 ppm (d 7 Hz) 1H.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a stirred solution of 6.65 g (0.0265 mol, 1 eq.) of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 25 ml of DMF at 0° C. were added 1.23 g of NaH (55% in oil, 0.0282 mol, 1.05 eq). After 30 minutes, 4.31 g (0.0282 mol, 1.05 eq.) of bromo-acetic acid methyl ester were added and the temperature raised to RT, and stirring was continued overnight. The reaction was quenched by the addition of aq.HCl 0.1 M, and the product was extracted with EtOAc and the combined organic phases dried over Na2SO4. Recrystallisation in Et2O/Heptane afforded 6.90 g (80%) of [6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid methyl ester as white crystals.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C@H:16]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[CH:18]([CH2:19][CH2:20][C:21]3[C:22]4[C@:30]([CH3:38])([CH2:31][CH2:32][C:33]=32)[C@@H:25]([C@H:26]([CH3:29])[CH:27]=O)[CH2:24][CH:23]=4)[C:17]1([CH3:40])[CH3:39].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:41]1([CH2:29][C@H:26]([C@@H:25]2[C@:30]3([CH3:38])[C:22]([C:21]4[CH2:20][CH2:19][C@@H:18]5[C@:34]([C:33]=4[CH2:32][CH2:31]3)([CH3:37])[CH2:35][CH2:36][C@H:16]([OH:15])[C:17]5([CH3:40])[CH3:39])=[CH:23][CH2:24]2)[CH3:27])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CN1CCCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reaction time: 2 h

Procedure:
38 mg sodium tris(acetoxy)borohydride were added to a solution of 42 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al and 10 μl piperidine in 3 ml tetrahydrofuran at room temperature. The mixture was stirred for two hours, poured into saturated sodium bicarbonate solution, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 15 mg (20S)-20-[(piperidin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#N)=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.C[Si](C)(C)N[Si](C)(C)C.[H-].C([Al+]CC(C)C)C(C)C.CC[O:46]C(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([CH:16]=[O:46])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O

Procedure:
An oven dried three-necked 250 mL 14/20 standard taper round bottom flask was equipped with a magnetic stir bar and a rubber septum, a glass stopper, and a reflux condenser in each of the three necks. A piece of vacuum tubing from a Firestone valve was connected to a tubing adapter placed at the top of the condenser. The flask was then charged with a suspension of 10.473 g (30.7 mmol) of 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (prepared in similar fashion to Step B Example 1) in 35 mL toluene, the atmosphere in the reaction vessel was replaced with nitrogen by cycling the Firestone valve, and finally hexamethyldisilazane (6.40 mL, 30.7 mmol) was added via syringe. The reaction mixture was stirred and gently refluxed for 2.5 h, then cooled and stirred at −40° C. using an external dry ice-acetone bath and diisobutylaluminum hydride (31.0 mL, 46.0 mmol) was then slowly added by syringe. The reaction mixture was stirred at −40° to −30° C. for 3 h at which point LC/MS analysis of an acid-quenched aliquot indicated that the reduction was complete. The cooling bath was removed and the reaction was quenched by dropwise addition of 40 mL of 2 N HCl. After gas evolution had ceased, the reaction mixture was transferred to a 1 L Erlenmeyer flask using 100 mL THF to rinse the solids. Additional 2 N HCl was added (200 mL), and the two phase mixture was stirred and heated for 30 min on a hot plate to ensure complete hydrolysis of the intermediate imine. EtOAc (200 mL) was added and the reaction mixture was stirred and heated until the solids had dissolved. The organic layer was separated, evaporated to dryness, then redissolved in EtOAc. The aq layer was adjusted to pH=7 with 6 N sodium hydroxide solution, then added back to organic layer. The layers were again heated and magnetically stirred to dissolve all the solids, then separated. The aq layer was washed with additional hot EtOAc, the organic layers were combined and then washed with water, brine, then dried (MgSO4), filtered and slowly evaporated. The product was crystallized from the EtOAc solution during the evaporation process and collected by vacuum filtration. The yellow crystalline solid was dried in vacuo to afford the title compound. HPLC/MS: 344.1 (M+1), 346.1 (M+3); Rt=3.17 min.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)(C)C.S(=O)(O)[O-].[Na+].[NH2:20][C:21]1[CH:22]=[C:23]([C:34]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:45]([NH2:56])[CH:44]=2)([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.C(O)C>[F:36][C:35]([F:37])([F:38])[C:34]([C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:20][C:21]=2[CH:22]=1)([C:43]1[CH:48]=[CH:47][C:46]2[N:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:56][C:45]=2[CH:44]=1)[C:39]([F:40])([F:41])[F:42]
Reactant: C[Si](C)(C)C#Cc1cccc(C=O)c1
Reactant: Nc1cc(C(c2ccc(Nc3ccccc3)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C#Cc1cccc(-c2nc3cc(C(c4ccc5c(c4)nc(-c4cccc(C#C)c4)n5-c4ccccc4)(C(F)(F)F)C(F)(F)F)ccc3n2-c2ccccc2)c1

Procedure:
The exact procedure described above (high dilution and dropwise addition) was repeated for 26.0 g of the aldehyde (VI), 110 g of sodium bisulfite, and 30.0 g of the tetramine (V) in a total volume of 4.5 L of 1:5 water-ethanol. At the end, the powdery end product (VIII) was fractionated by Soxhlet extraction into an ether-insoluble portion (high oligomers) and an ether-soluble portion (20.0 g, 46.9%). The latter material, when tested on the Kofler hot bench at 250° C., showed a gel time of about 3 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([Br:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3Br)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (45 mg, 0.157 mmol), NBS (56 mg, 0.314 mmol) in DMF (0.5 mL) was stirred at room temperature for 1.5 h. Following solvent removal, product (20 mg, 34.8%) was collected through silica gel column purification (CHCl3:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, acetone-d6) 7.51 (bs, 2H), 7.21 (s, 1H), 6.98 (s, 1H), 6.06 (s, 2H), 4.13 (s, 2H); MS m/z 366.0 (M+H)+.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[CH:17][N:16]([CH:27]([CH3:29])[CH3:28])[C:12]=2[N:13]=[CH:14][N:15]=1>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([CH:23]([OH:24])[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:25][CH:26]=3)=[CH:17][N:16]([CH:27]([CH3:29])[CH3:28])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CC(C)n1cc(-c2ccc(C=O)cc2)c2c(N)ncnc21
Reactant: Cl[Mg]c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)n1cc(-c2ccc(C(O)c3ccccc3)cc2)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Phenylmagnesium chloride (1.5 ml of a 2M solution in THF) was added dropwise with stirring under nitrogen to a solution of 4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzaldehyde (0.25 g) in toluene/THF (1:1, 16 ml) at minus 78° C. under nitrogen. After the addition the mixture was allowed to warm 0° C. and maintained at this temperature for 40 minutes. The reaction was quenched by the dropwise addition of saturated ammonial chloride solution (4 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stood overnight at this temperature. The solvent was removed under reduced pressure and the solid residue obtained was washed with water and filtered. The residue was triturated with hot ethyl acetate, collected by filtration and identified by LCMS as ∝-[4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]benzyl alcohol, m.p. 279-281° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2)(=O)C.[NH4+].[OH-]>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.150 g, 2.01 mmol) in MeOH (100 mL) was added 28% aq. NH4OH solution (0.7 mL). The mixture was stirred at RT for 20 h. The solid was collected via filtration and dried under vacuum to give tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.800 g, 1.51 mmol, 75%). HPLC retention time 6.57 mins.