Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[Cl:9][CH2:10][CH2:11][CH2:12]Cl>CN(C=O)C>[Cl:9][CH2:10][CH2:11][CH2:12][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:8]
Reactant: ClCCCCl
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCCl
Temperature: 25 °C
Yield: 95 %

Procedure:
To a mechanically stirred, room temperature suspension of NaH (0.305 mole, hexane washed) in 50 mL of DMF under N2, was added 2-oxazolidinone (0.287 mole) portion wise. After stirring the resulting gelatinous mixture overnight, 1,3-dichloropropane (0.643 mole) was added and the mixture stirred 4 days at room temperature. The volatiles were then removed in vacuo and the resulting white residue taken up in CH2Cl2 and washed with H2O and brine, and dried over MgSO4. After filtration, the material was passed through a short column (SiO2 : EtOAc/Hex) to give (XVI) as a clear oil in 95% yield: 1H NMR (CDCl3) δ4.22 (t, 2H, J=6.6 Hz), 3.47 (m, 4H), 3.24 (t, 2H, J=7.0 Hz), and 1.98 (p, 2H, J=6.5 Hz); 13C NMR (CDCl3) δ158.5, 61.8, 45.0, 42.0, 41.8, and 30.2. Anal. Calcd for C6H10ClNO2 : C, 44.05; H, 6.16; N, 8.56. Found: 41.17; H, 5.77; N, 8.26.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH:19](C)C)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC1[S:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][N:33]=1>CC#N>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:19]2[S:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][N:33]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1nnc(Br)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC(C)C)cc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(Cl)c21
Temperature: -30 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a solution of ethyl 2-(4-chloro-1-hydroxy-6-isopropoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (400 mg, 1.48 mmol) in MeCN (5 mL) was added anhydrous K2CO3 (414 mg, 3 mmol) and the mixture was cooled to −30° C. To this mixture was added 2-bromo-5-nitro-1,3,4-thiadiazole (420 mg, 2 mmol). The reaction mixture was stirred at −30° C. for 5 h. The reaction was quenched by addition of ice and the mixture was extracted with EtOAc (3×5 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil (430 mg). MS (ESI) m/z=400 [M+H]+.
Reaction SMILES: CI.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(O)cccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC2=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Methyl iodide (69 ml) is added dropwise over a period of 15 minutes to a stirred mixture of 4-hydroxy-1-indanone (150 g) and anhydrous potassium carbonate (154 g) dissolved in DMF (1.5 liter) cooled to 0° C. under nitrogen. The reaction mixture is stirred at RT for 24 hours and partitioned between methylene chloride and water. The methylene chloride fraction is washed with water and 2% aqueous NaOH and dried over Na2SO4. The dried extract is filtered, concentrated in vacuo and the residue dissolved in hot methanol which upon cooling forms a precipitate. The precipitate is filtered and recrystallized from methanol yielding the methoxy product as a solid, M.P. 104°-106° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:12])=[CH:9][N:10]=1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[S:7][C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][N:10]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCCNc2ncc(C(=O)c3ccccc3C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone was dissolved in dichloromethane and triethylamine and toluene-4-sulfonyl chloride added. The mixture was stirred overnight at room temperature, poured into 1 M pH4 phosphate buffer (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic phases were dried over magnesium sulfate and evaporated. The oily residue was purified by column chromatography on silica gel (13:7 hexane/acetone eluant), using a small amount of dichloromethane to apply the mixture to the column. The title compound was isolated as an off-white solid. MS (m/e): 428.3 (M−H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: N#CC(=Cc1cccnc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Product: N#CC(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
This intermediate (64 g.) was prepared using the procedure described in Example 12b except using 80 g. (0.3 mole) of 2-(4-chlorophenyl)-3-(3-pyridyl)acrylonitrile, and 14 g. (0.36 mole) of sodium borohydride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]#[C:12][Si](CC)(CC)CC)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[F-].[K+]>CO>[C:11]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[CH2:8][C:9]#[N:10])#[CH:12]
Reactant: CC[Si](C#Cc1ccc(F)cc1CC#N)(CC)CC
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(F)cc1CC#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
2-(5-Fluoro-2-((triethylsilyl)ethynyl)phenyl)acetonitrile (1.044 g, 3.82 mmol) is dissolved in methanol (38.2 ml), and potassium fluoride (0.887 g, 15.27 mmol) is added. The yellowish solution is stirred at RT for 48 hours. The solvent is subsequently removed in vacuo, and the residue is taken up with water (30 ml). The usual extraction and drying method described under 1) gives 606 mg of the title compound in quantitative yield. (3.81 mmol);
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:67])[O:48][CH2:49][C:50]2([C:56](=[O:66])[NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[Cl:65])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:42][CH:41]=1)[CH3:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:67])[O:48][CH2:49][C:50]2([C:56](=[O:66])[NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[Cl:65])[CH2:55][CH2:54][N:53]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:52][CH2:51]2)=[CH:42][CH:41]=1)[CH3:39]
Reactant: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of Boc-Gly-OH (54 mg, 0.31 mmol, 1.2 equiv.) in DMF (1 mL) were added HATU (120 mg, 0.31 mmol, 1.2 equiv.), followed by addition of (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate hydrochloride (120 mg, 0.26 mmol, 1 equiv.) and DIEA (89 μL, 0.51 mmol, 2 equiv.) at rt The reaction mixture was stirred for 3 h and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-(tert-butoxycarbonyl)aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (127 mg, 84%). LRMS (M-Boc+H+) m/z 487.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[N:24]=[C:23]([O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N=C(N)Nc1ccc(-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N=C(N)Nc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-(3′-hydroxy-biphenyl-4-yl)guanidine (550 mg), 2,4-dichloropyrimidine (146 mg) and potassium carbonate (196 mg) in DMF (8 ml) is stirred at rt for 20 h. This mixture is purified by preparative HPLC (gradient of water, 0.1% TFA/acetonitrile, 0.1% TFA from 80/20 to 0/100 on Nucleosil 100-10 C18 column). The fractions containing product are basified with 1 N NaOH to pH 8, evaporated and dried under reduced pressure. The residue is stirred in ethanol, the solvent is evaporated and dried under reduced pressure to afford crude N-[3′-(2-chloro-pyrimidin-4-yloxy)biphenyl-4-yl]-guanidine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][N:9]=[C:10]([C:14]2[C:15](=[O:23])[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=2[OH:20])[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:23][C:15]1[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19](=[O:20])[C:14]=1[C:10](=[N:9][O:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH3:13])(=[O:32])[CH3:31]
Reactant: CCCC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C)(C)CC1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=NOCc1ccc(Cl)s1)C1=C(OC(C)=O)CC(C)(C)CC1=O
Temperature: 0 °C

Procedure:
To a reaction mixture containing 3.6 gms (0.01 mol) of 2-{1-[(5-chlorothien-2-ylmethoxy)imino]butyl}-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one and 0.87 gm (0.011 mol) of pyridine in 20 mls of methylene chloride stirred at 0° C. is added 0.89 gm (0.011 mol) of acetyl chloride. The mixture is then stirred at room temperature for 2 hours. The mixture is then worked up by washing with water, drying with anhydrous magnesium sulfate, and filtered. The filtrate is evaporated under vacuum affording 3-acetyloxy-2-{1-[(5-chlorothien-2-ylmethoxy)imino]butyl}-5,5-dimethylcyclohex-2-en-1-one.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(O)(=O)CC>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[C:16]3[NH:12][C:13]([C:8]([C:7]4[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)=[C:13]4[N:12]=[C:16]([C:8]([C:7]5[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=5)=[C:13]5[NH:12][C:16](=[C:8]([C:7]6[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][CH:10]=6)[C:13]6[CH:14]=[CH:15][C:16]=2[N:12]=6)[CH:15]=[CH:14]5)[CH:15]=[CH:14]4)=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: CC(C)c1ccc(-c2c3nc(c(-c4ccc(C(C)C)cc4)c4ccc([nH]4)c(-c4ccc(C(C)C)cc4)c4nc(c(-c5ccc(C(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1

Procedure:
Under the conditions of example 4a, 14.82 g (100 mmol) of 4-isopropylbenzaldehyde is reacted with 6.92 ml (100 mmol) of pyrrole in 300 ml of propionic acid. The solution is evaporated to dryness in a vacuum. The residue is heated with 200 ml of ethanol quickly to boiling. It is left to cool slowly, the title compound is suctioned off, washed with a little ethanol and dried at 50° C. in a vacuum.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(-c3csc(C)n3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(-c3csc(C)n3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 105.4 mg of (2S,4R)-1-acetyl-2-methyl-4-{[4-(2-methylthiazol-4-yl)phenyl]amino}-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 74.9 mg (75.5%, cis:trans=10:1) of the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C(#N)C.CO.[OH-].[Pd+2].[OH-]>[O:32]=[S:27]1(=[O:31])[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=[C:20]1[CH2:33][O:34][CH2:35][CH3:36]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 28 h
Yield: 58.1 %

Procedure:
A mixture of 7-(benzyloxy)-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (4.6 g, 9.04 mmol) and palladium hydroxide (1.5 g) in acetonitrile (50 mL) and methanol (75 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) for 28 hours. The mixture was filtered through CELITE filter agent, which was rinsed afterwards with 40% methanol in acetonitrile (600 mL). The filtrates were combined and concentrated under reduced pressure to yield a yellow solid that was triturated with acetonitrile and isolated by filtration to afford 2.2 g of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and butyryl chloride. m.p.: 157-158° C. 1H-NMR (CDCl3) δ: 9.96 (1H, br s), 8.29 (1H, d, J=8.8 Hz), 8.17 (1H, br s), 7.78 (1H, dd, J=1.5, 1.8 Hz), 7.70-7.59 (2H, m), 7.51 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=1.1 Hz), 7.11 (1H, dd, J=1.8, 8.8 Hz), 2.47 (2H, t, J=7.3 Hz), 1.88-1.75 (2H, m), 1.05 (3H, t, J=7.5 Hz)
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:21][CH2:20]4)[C:13]=3[C:12]([C:22]([C:24]3[C:25]([F:39])=[N:26][C:27]([NH:30][C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:28][CH:29]=3)=[O:23])=[CH:11]2)(=O)=O)C=CC=CC=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:19]1([C:18]2[C:13]3[C:12]([C:22]([C:24]4[C:25]([F:39])=[N:26][C:27]([NH:30][C:31]5[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[CH:28][CH:29]=4)=[O:23])=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(Nc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(C5CC5)c34)c(F)n2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(C(=O)c3c[nH]c4ncnc(C5CC5)c34)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To (7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone (78, 0.235 g, 0.432 mmol) in 10.0 mL of tetrahydrofuran, tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is added. The reaction is stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fraction are combined and concentrated under vacuum to provide the desired compound (P-4022, 104.5 mg). MS (ESI) [M+H+]+=405.0.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CC(C)=O>[N:13]1([C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1[nH]c2ncnc(N3CCCc4ccccc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (4 equivalents, Fluka, Buchs, Switzerland). M.p: 263-264° C.; FAB-MS: (M+H)+ =279 (corresponds to C17H18N4); Rf value (toluene-acetone--(4:6))=0.29.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4](OC)[CH:3]=1.[OH-].[Na+].[CH3:15]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)[O-]
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-fluoro-2-methoxybenzoate (10.0 g, 58.8 mmol) in methanol (50 mL) was slowly added 6 M NaOH solution (30 mL). White solid immediately precipitated and the mixture was stirred for another hour at room temperature before it was re-dissolved in H2O and acidified with 6 M HCl solution until precipitation occurred. The white solid was collected by vacuum filtration and dried on vacuum oven overnight to afford 4-fluoro-2-methyl benzoic acid (44, 9.2 g, 85%) 1H NMR (300 MHz, CDCl3) δ 8.21 (dd, J=9.0 Hz, 6.9 Hz, 1H), 6.82-6.88 (m, 1H), 6.79 (dd, J=7.8 Hz, 2.1 Hz, 1H), 4.07 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=3)[N:13]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH2:43](Cl)Cl.CO.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CC(O)=O>[F:1][C:2]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:17][CH2:18][N:19]([CH3:43])[CH2:20][CH:21]=3)[N:13]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:23])=[O:24])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: ClCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCNCC2)n3S(=O)(=O)c2ccccc2)c1F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCN(C)CC2)n3S(=O)(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,6-difluoro-N-(1-(phenylsulfonyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (15 mg, 0.024 mmol) in 5:1 CH2Cl2/MeOH (6 mL) was treated with 37% aqueous formaldehyde (100 μL) and a drop of AcOH. After 5 minutes, the mixture was treated with sodium triacetoxyborohydride (26 mg, 5 eq.), and the reaction mixture was stirred for 16 hours at ambient temperature. The mixture was treated with MeOH (1 mL), concentrated under reduced pressure, and purified by silica gel chromatography (eluting with 10% MeOH/CH2Cl2) to afford 2,6-difluoro-N-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide.
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:5]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:16][O:15][C:9]1[N:8]=[C:7]2[C:6]([C:17]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)=[CH:5][N:4]([CH2:3][CH2:2][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:12]2=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: C1COCCN1
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
Stir bisazaindole iodide 18 (52 mg, 0.0862 mmol), morpholine (1.10 equiv., 8.26 mg, 8.3 μL, 0.0948 mmol) and K2CO3 (13 mg, 0.0942 mmol), with heating at 60° C. in CH3CN (6 mL) under N2, for 24. LC-MS shows that the reaction is only 50% complete. Add extra morpholine (17 μL) and continue stirring at 60° C. After 48 h, the reaction medium is concentrated under vacuum and the residue is submitted to flash chromatography to give 19 (48 mg, 99%) as a white solid: 1H NMR (CDCl3) δ 8.38 (dd, 1H, J=4.5, 1.2 Hz), 7.75 (dd, 1H, J=4.5, 1.2 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.62 (s, 1H), 7.14 (m, 2H), 7.05 (d, 2H, J=8.4 Hz), 7.02 (s, 1H), 4.28 (t, 2H), 4.05 (s, 3H), 4.0 (s, 3H), 3.74 (m, 4H), 2.90 (t, 2H), 2.55 (m, 4H), 2.29 (s, 3H). TLC (MeOH at 4%/CH2Cl2, 0.25% of NH3) Rf=0.65, m/z obs.=562.15 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.CS(C)=[O:41]>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH2:29][OH:41])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)CO)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 mm Erlenmeyer flask containing 50 mm of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of six 300 mm Erlenmeyer flask containing 50 mm of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-[6-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-(4-methylphenyl)-4-pyrimidinyl]-4-(tert-butyl)benzenesulfonamide (EP 0658548B1) dissolved in 0.5 mm of dimethylsulfoxide was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 3 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.