Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2].ClC1C=C2C(=CC=1)[NH:22]C=C2C1CCNCC1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([NH2:22])=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1csc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Nitro-3-benzothiophencarboxylic acid 1b (20 g) was converted into the corresponding carboxylic acid chloride as in Example 2. The acid chloride was dissolved in THF (200 ml) and added dropwise to a solution of 5-chloro-3-(4-piperidinyl)-1H-indole, 9a (19 g) and triethylamine (10 ml) in THF (200 ml) at 0-5° C. The mixture was stirred overnight at room temperature. THF was evaporated. Water was added to the remaining oil. Extraction with dichloromethane (2×100 ml) and work-up of the organic extracts afforded the crude 5-nitro-3-benzothiophencarboxylic acid amide, which was subsequently purified by column chromatography on silica gel (eluted with ethyl acetatelheptane 1:1). Yield 6.6 g, mp: 243-250° C. All of the amide was dissolved in 90% ethanol at reflux. Fe-powder (5 g) and concentrated aqueous HCl were added successively in small portions during 10 minutes. The mixture was refluxed for another 2.5 hours. Inorganic salts were filtered off and ethanol evaporated in vacuo. Water was added to the remaining oil and pH was adjusted to >9 by addition of diluted aqueous NH4OH. Extraction with dichloromethane (2×100 ml) and subsequent work-up of the organic phase yielded 4 g of the 5-amino-3-benzothiophencarboxylic acid amide as an oil. All of this oil was dissolved in methanol (100 ml). 0.5 g of Mg turnings were added. By heating to 35° C. an exothermic reaction started. Mg turnings were added in small portions (3×0.5 g) while keeping the temperature below 45° C. The mixture was finally poured into an aqueous NH4Cl solution and concentrated aqueous HCl (1 ml) was added. Extraction with dichloromethane (2×50 ml) and work-up of the organic extracts as above afforded 2 g of the 5-amino-2,3-dihydrobenzothiophen-3-carboxylic acid amide as an oil. To a suspension of LiAIH4 (0.6 g) in dry THF (50 ml) was added dropwise a solution of all of the carboxamide in THF (50 ml). The mixture was gently refluxed for 2 hours. After cooling to 10° C. water (2.4 ml ) and a 15% aqueous NaOH solution were cautiously added to destroy excess LiAIH4. Inorganic salts were filtered off and washed extensively with THF. The combined THF solutions were evaporated leaving 1.9 g of 3-[1-(5-amino-213-dihydrobenzothiophen-3-ylmethyl)piperidin-4-yl)-5-chloro-1H-indole as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:14]([O:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzylpiperazine is reacted with 2-benzyloxyacetyl chloride in dichloromethane in the presence of triethylamine to give 2-benzyloxy-1-(4-benzyl-piperazin-1-yl)-ethanone which is then hydrogenated over a palladium on carbon catalyst in a methanol/hydrochloric acid mixture to remove the benzyl group and give the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1)[NH2:17]
Reactant: COc1nc(C)nc(F)c1C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1nc(C)nc(NN)c1C(F)(F)F

Procedure:
Next, a reaction flask was loaded with 4-fluoro-6-methoxy-2-methyl-5-(trifluoromethyl)-pyrimidine (22 g) and ethanol (40 ml), followed by dropwise addition of hydrazine monohydrate (10.5 g) to the flask in one hour with stirring. Then, after stirring for one hour, the reaction mixture was filtrated to give 4-hydrazino-6-methoxy-2-methyl-5-(trifluoromethyl)pyrimidine. By GC/MS analysis, a molecular ion peak of 222 was confirmed for this compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[C:7]([OH:15])=[N:8][O:9][C:10]=1[CH2:11][S:12][CH2:13][CH3:14]>C1C=CC=CC=1>[Cl:5][C:6]1[C:7](=[O:15])[N:8]([C:1]([Cl:4])=[O:2])[O:9][C:10]=1[CH2:11][S:12][CH2:13][CH3:14]
Reactant: CCSCc1onc(O)c1Cl
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CCSCc1on(C(=O)Cl)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.5 ml of phosgene in 5 ml of benzene was added to 581 mg of 4-chloro-3-hydroxy-5-ethylthiomethylisoxazole, and then the mixture was stirred at room temperature for 5 hours, after which the solvent and excess phosgene were distilled off, to produce 4-chloro-2-chlorocarbonyl-5-ethylthiomethyl-4-isoxazolin-3-one. This was dissolved, without purification, in 30 ml of benzene and an equimolar mixture of the calculated amount of dimethylamine with triethylamine in 5 ml of benzene was added, with stirring, at room temperature. The mixture was stirred for a further 30 minutes and then washed, in turn, with 0.1N sulphuric acid (twice, 10 ml each time) and then water (3 times, 10 ml each time). The benzene layer was dried over anhydrous sodium sulphate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a 25:1 by volume mixture of benzene and acetone. The solvent was distilled from the eluate, to give 661 mg (yield 83.2%) of the title compound in the form of an oil having a refractive index, nD22 =1.5454.
Reaction SMILES: [C:1]([C:3]1([N:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg+].[Br-].C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[OH:22][CH:19]1[CH2:20][CH2:21][N:16]([C:3]2([CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(N2CCC(O)CC2)CC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a stirred solution of tert-butyl 4-cyano-4-(4-hydroxy-1-piperidyl)piperidine-1-carboxylate (5.8 g, 18.74 mmol) in THF (40 mL) was added a 1.4 M solution of MeMgBr in toluene/THF (26.8 mL, 37.48 mmol) at 0° C., and the mixture was stirred at room temperature for 12 h. The reaction was then quenched with saturated aqueous ammonium chloride and the mixture was extracted with dichloromethane (2×30 mL). The combined extracts were concentrated in vacuo to afford (5.42 g, 97%) the title compound, which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c([N+](=O)[O-])c4)c3c2s1
Yield: 60 %

Procedure:
Prepared from VII and 4-amino-2-nitrophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 60%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3334, 3081, 2926, 2225, 1627, 1591, 1569, 1525, 1465, 1419, 1395, 1305, 1237, 1171, 1132, 1070, 966, 930, 834, 819; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H, J=8.7 Hz), 8.28 (m, 1H), 8.03 (m, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.61 (m, 1H), 7.15 (d, 1H, J=9.0 Hz); HRMS calcd for C16H9N6O3S (M+H+): 365.0457, found 365.0441.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[C:4]=1[CH3:21]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 59.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 1-bromo-4-(trifluoromethyl)benzene (506 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 389 mg (yield 40%). Melting point was 186 to 187° C. (hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CN(C=O)C.CC[O-].[Na+]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[N:13]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:12]2=[O:17])=[CH:2]1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1NC(Cc2c[nH]c3ccccc23)C(=O)N1CCCN1CCC(c2ccccc2)CC1
Reaction time: 10 h

Procedure:
A mixture of 5-(indol-3-ylmethyl)hydantoin (6.4 g, 0.028 mole), 1-(3-chloropropyl)-4-phenylpiperidine (6.6 g, 0.028 mole) and 200 ml of DMF in 200 ml of anhydrous C2H5OH and 0.028 mole of NaOC2H5 was heated under reflux with stirring for 10 hours. The mixture was filtered and the filtrate was diluted with H2O. The solid was collected and twice recrystallized from aqueous C2H5OH, yield 2.0 g, mp 179°-80°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[C:9]=2[CH:10]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][C:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Cc1cc2c(CC(=O)O)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1cccc2[nH]c(C)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylindole-4-acetic acid (53 g) in N,N-dimethylformamide (500 ml) was added dropwise allyl bromide (31 ml), and added anhydrous potassium carbonate (59 g). The mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into a mixture of 2N hydrochloric acid—ethyl acetate and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane—ethyl acetate) to give the title compound (43.5 g) having the following physical data.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[OH:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O>CO>[NH2:4][C:3]1[O:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:2]=1[C:1]#[N:5]
Reactant: O=C(CO)c1ccc(F)cc1
Reactant: N#CCC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1c(-c2ccc(F)cc2)coc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of malononitrile (0.31 g, 4.65 mmol) and triethylamine (0.65 ml, 4.65 mmol) in methanol (5 ml) was added drop-wise to a stirred suspension of 2-hydroxy-4′-fluoroacetophenone (0.65 g, 4.22 mmol) in methanol (16 ml) under a nitrogen atmosphere at ambient temperature. When the addition was complete, the mixture was stirred for 18 hr at ambient temperature. The solvent was then removed in vacuo, water (50 ml) was then added to the residue and the mixture was extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 2-amino-4-(4′-fluorophenyl)-3-furonitrile which was partially purified by flash chromatography (silica) eluting with dichloromethane and ethyl acetate (1:1). This gave a 3.5:1 mixture of the product and 2-hydroxy-4′-fluoroacetophenone (0.60 g), which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[Na+].[Na+].O>CO>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
13.2 g of p-cyanobenzylamine, 28.6 g of sodium persulfate, 10 ml of water, and 100 ml of methanol were mixed and allowed to react at 50° C. for 40 minutes while stirring. After cooling the reaction mixture to room temperature, methanol was distilled off to precipitate solids. To the resulting suspension was added dichloromethane for extraction. The organic layer was washed twice with saturated aqueous sodium bicarbonate solution and then twice with water, and then magnesium sulfate was added thereto. The residue after distilling off dichloromethane was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=5/1), and hexane and ethyl acetate were distilled off. The resultant crude product concentrated to dryness was recrystallized from cyclohexane, the crystals were filtered, and dried to obtain 7.7 g (yield: 58%) of p-cyanobenzaldehyde. The obtained p-cyanobenzaldehyde had a purity of 99% by the analysis of high performance liquid chromatography.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(C(CC)C(N)=O)C.O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2ncccn2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: CCC(CC)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ncccn2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in di ethyl acetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2-pyrimidylsulfonyl)aniline (0.59 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A dark colored precipitate was formed that was filtered, washed with water and dried. The crude material was preabsorbed onto silica gel and chromatographed on silica gel eluting with 70-80% ethyl/acetate/hexane. Evaporation of product-containing fractions and crystallization from methylene chloride/methanol/hexane gave the title compound (0.33 g, 34%) as a white solid; mp 209°-210° C. 1H-NMR (300 MHz, d6 -DMSO):6.46(t, J=54.06 Hz, 2H, HCF2), 7.78 (t, J=4.8 Hz, 1H, ArH), 7.95-7.98(m, 3H, ArH, OH), 8.02-8.06(m, 2H, ArH), 9.01 (d, J=5.01 Hz, 2H, ArH), 10.58 (s, 1H, NH). MS(CI):394(M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])[CH2:14][CH2:13]3)[C:9]3=[CH:26][C:27]([CH3:29])=[CH:28][N:8]3[CH2:7][C:6]=2[CH:30]=1.[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])[CH2:16][CH2:17]3)[C:9]3=[CH:26][C:27]([CH3:29])=[CH:28][N:8]3[CH2:7][C:6]=2[CH:30]=1
Reactant: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2N1CCN(CC(C)(C)C(=O)O)CC1
Temperature: 70 °C
Yield: 97.8 %

Procedure:
To a suspension of methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (28.0 g, 65.27 mmoles) in a mixture of isopropyl alcohol (150 mL) and water (150 mL) add sodium hydroxide (3 equiv; 7.83 g, 195.82 mmoles) and heat at 70° C. for 4 h to give a clear solution. Heat at 70° C. for a further 1 h then cool slightly. Add 5M hydrochloric acid to give pH 8 and precipitate a white solid. Add further 5M hydrochloric acid to give a pH between 6.5 and 7. Reduce the volume of solvent by half and then chill the flask in a fridge for 0.5 h. Collect the resulting white solid by filtration and dry overnight in a vacuum oven at 40° C. over phosphorus pentoxide to give 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoic acid (26.5 g, 98% yield). MS (m/z): 415.3 (M+1). DSC melting point=246.5° C. (onset).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15]Br>C(Cl)Cl>[Br:15][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:11]
Reactant: CCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(C)Br)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 1-(4-methyl-3-nitrophenyl)propan-1-one (6.6 g, 34.1 mmol) in CH2Cl2 (200 mL) is added bromine (34.1 mmol) dropwise over 20 minutes. The reaction is stirred for 4 hours at room temp. and then washed with sat. aqueous NaHCO3 (100 mL), organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness to afford 9.0 g (97%) of the title compound as an orange oil: Rf 0.53 (1:1 CH2Cl2:hexanes).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
Imidazole (0.816 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.011 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.22 g, 56%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C:24]([CH3:28])([CH3:29])[C:25]([NH2:31])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(=O)O)cc1OCC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
To a solution of 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid (96 mg, 0.24 mmol) in DMF (3 mL) was added HATU (184 mg, 0.48 mmol), ammonium chloride (39 mg, 0.72 mmol) and triethyl amine (100 μL, 0.72 mmol) and the reaction mixture stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water, extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield 429 as a white solid (38 mg, 38%). LCMS: RT=7.36 min, [M+H]+=398; 1H NMR (400 MHz, d6-DMSO) 8.99 (1H, s), 8.11 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.16 (1H, s), 6.89 (1H, s), 6.37 (1H, s), 5.89 (1H, sept, J=6.6 Hz), 4.59-4.42 (4H, m), 1.54 (6H, s), 1.44 (6H, d, J=6.6 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=C(O)c1ccsc1
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NC(=O)c2ccsc2)c1
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.1 eq, 0.17 mmol) was added to a solution 3-thiophenecarboxylic acid (20 mg, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.16 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 17 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (10 mg, 0.03 mmol, 17%). LCMS: [M+H]+=337, Rt=1.58 min, 100% purity.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCCCCCCCCCCCCCO
Agent: P
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of methyl 15-hydroxypentadecanoate (4.2 g, 15.6 mmol, 1.0 eq) and carbon tetrabromide (5.7 g, 17.1 mmol, 1.1 eq) in dichloromethane (15 mL) cooled to 0° C., was added triphenyl phosphine (4.3 g, 17.1 mmol, 1.1 eq) in portions over 30 min with vigorous stirring. Upon addition of the phosphine, the colourless solution turned a pale brown colour and was stirred for an additional 2 hours at room temperature. The mixture was concentrated in vacuo (using a rotary evaporator attached to a diaphragm pump) to a brown oil. Hexane (200 mL) was quickly added and the resulting mixture was stirred for 15 minutes. The resultant white precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (20:1 hexane:ethyl acetate), yielding methyl 15-bromopentadecanoate (4.6 g, 90%) as a colourless solid.