Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Cl:10])=[O:4].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][Br:19])=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)cc1Cl
Yield: 61 %

Procedure:
A mixture of 3-Chloro-5-methyl-thiophene-2-carboxylic acid methyl ester (4.4 g, 23.1 mmol), NBS (5.1 g, 28.85 mmol), and ACHN in CCl4 (40 ml) was refluxed in a pressure tube over the weekend. The reaction mixture was cooled and evaporated. The residue was purified by column (0-5% EtOAc in hexane) to give 3.8 g (61%) yellow solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:9]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[N:19](C)C)[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.N>O1CCOCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=2)[C:9]2[CH:16]=[C:15]3[C:12](=[CH:11][N:10]=2)[C:13]([NH2:14])=[N:19][CH:18]=[CH:17]3)=[CH:28][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(/C=C/N(C)C)c(C#N)cn2)cc1
Agent: N
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N)c3cn2)cc1
Temperature: 90 °C
Reaction time: 138 h

Procedure:
A mixture of crude 4-4 (9.40 g, <19.3 mmol), ammonia (7 M in methanol; 150 mL, 1050 mmol), and 1,4-dioxane (50.0 mL) was placed in a 350 mL sealed tube. The resulting mixture was stirred at 90° C. for 138 hours and cooled to ambient temperature. The reaction mixture was concentrated under reduced pressure to give 10.9 g of 4-5 as a brown oil. The crude product was used for next step without further purification.
Reaction SMILES: C(N1C=C([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)C=N1)C.Br[C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:22]=1>>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:22]=2)[O:9]1
Reactant: FC(F)(F)Cn1cc(Br)cn1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1(C)OB(c2cnn(CC(F)(F)F)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole.
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])=[CH:22][CH:21]=1.[K+].[Br-]>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][CH:22]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)cc4)c3c2s1
Yield: 80 %

Procedure:
Prepared from VII and 4-aminophenol. Flash chromatography eluent (EtOAc). Yield: 80%; orange solid; mp 236° C.; IR (KBr) νmax/cm−1 3072, 2225, 1641, 1615, 1577, 1503, 1464, 1378, 1350, 1307, 1230, 1212, 1159, 1097, 972, 832; 1H NMR (300 MHz, DMSO-d6) δ 8.48 (d, 1H, J=8.7 Hz), 8.08 (m, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.15 (m, 2H), 6.79 (m, 2H); HRMS calcd for C16H10N5OS (M+H+): 320.0606, found 320.0619.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH3:21].C1(O)C=CC=CC=1.[ClH:36]>CC(C)=O.C(O)C>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CN(C)CCCCCCN
Agent: Cl
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCCCN(C)C)c2n1

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 1.5 g. of dimethylaminohexylamine and 6.5 g. of phenol is stirred and heated on a steam bath for 3 hours. The mixture is cooled, 20 ml. of ethanol are added and the dark solution is poured into a mixture of 200 ml. of acetone and 2.5 ml. of concentrated hydrochloric acid. The mixture is cooled in ice. The solid is collected, air-dried and recrystallized from 3A alcohol:acetone (50:50), giving the desired product as yellow crystals, mp. 243°-244° C. (dec.).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.Br>O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccc(F)cc1
Agent: Br
Agent: Cl
Solvent: O
Product: Oc1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccc(F)cc1
Yield: 92 %

Procedure:
A solution of 22.3 parts of 1-[(4-fluorophenyl)methyl]-5-methoxy-2-(4-piperidinylmethyl)-1H-benzimidazole dihydrochloride.monohydrate in 75 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 18 hours. The whole was slightly cooled and evaporated. The residue was dissolved in water. The solution was treated with an ammonium hydroxide solution. The product was extracted three times with trichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated, yielding 15.7 parts (92%) of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazol-5-ol; mp. 210° C. (78).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](OC(C)(C)C)=[O:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[Al]>C1COCC1.O.CO>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To the solution of tert-butyl 4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)picolinate (420 mg, 1.14 mmol) under argon in 50 ml of THF was added 1 M LAH solution in THF (3.41 ml, 3.41 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The crude reaction mixture was worked up by carefully adding methanol (5 ml), then 6M NaOH (5 ml), and water (5 ml) with stirring at room temperature. The aluminum salts were allowed to precipitate out. Ethyl acetate (200 ml) was added and the organic layer was decanted off from salts. The salts were washed again with ethyl acetate (100 ml) and decanted. The organic layers were combined and washed with brine (2×50 ml), dried with Na2SO4, filtered and concentrated. The resulting solid residue was purified by silica gel column chromatography, eluted with (5% methanol 95% DCM) and concentrated in vaccuo to give (4-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yloxy)pyridin-2-yl)methanol as solid (157 mg). ES/MS m/z 370.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([C:34]4[CH:33]=[CH:32][C:31]5[O:26][CH2:27][CH2:28][O:29][C:30]=5[CH:35]=4)[OH:40])[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccc2c(c1)OCCO2
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2ccc3c(c2)OCCO3)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.253 mmol), 1-(1,4-benzodioxan-6-yl)-2-(methylamino)ethanol (Preparation 13, 79 mg, 0.38 mmol), and diisopropylethylamine (66 μL, 0.38 mmol) in dry DMF (5.5 mL) was stirred at room temperature for 18 hours. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo at 60° C. to provide the titled compound (105 mg) as an off white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[C:10]([F:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][C:31]#[N:32])[C:15]=2[C:14]2[C:9]1=[C:10]([F:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A mixture of 9-benzyl-8-fluoro-9H-carbazol-4-ol (1.0775 g, 0.0037 mol), potassium carbonate (0.6284 g, 0.0046 mol), bromoacetonitrile (0.6 mL, 0.0086 mol) and DMF (12 mL) is stirred at room temperature for 4 h. The mixture is then partitioned between water and dichloromethane. The aqueous layer is also washed with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to a residue, which is then partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated to a residue. The resulting residue is chromatographed on silica gel (100 mL) using ethyl acetate/hexane (20/80) followed by dichloromethane (100 %). The solids are recrystallized from ethyl acetate/heptane to give 0.8869 g (73%) of the title compound; mp 134-134.25° C.; MS (ESI+) for C21H15FN2O m/z 353.1 (M+Na)+; IR(drift) 1578, 1500, 1458, 1439, 1369, 1344, 1335, 1323, 1278, 1235, 1144, 1080, 793, 739, 695 cm−1; 1H NMR (CDCl3) δ5.05, 5.71, 6.75, 7.16, 7.24, 7.41, 8.07. Anal. Calcd for C21H15FN2O: C, 76.35; H, 4.58; N, 8.48. Found: C, 76.15; H, 4.63; N, 8.35.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([OH:25])=O)[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH2:26]([N:28]([CH2:49][CH3:50])[CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>ClCCl>[CH2:49]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)[C:23](=[O:25])[CH2:22][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:21])[CH:20]=[C:11]1[CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:50]
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2ccccc21
Reactant: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCN(CC)CCN(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-acetic acid (Int. E2) (0.26 g, 1 equiv), N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine (Int. A2) (0.265 g, 1 equiv), HATU (0.28 g, 1.2 equiv) and diisopropylamine (0.32 ml, 2.4 equiv) in dichloromethane (15 ml) was stirred at room temperature overnight, then washed with aqueous ammonium chloride and aqueous sodium bicarbonate. The organic layer was dried and evaporated, and the product purified by column chromatography (silica, 2% [2M ammonia in methanol] in dichloromethane). Product fractions were evaporated to an off-white foam (0.201 g). Trituration with ether gave the title compound as a white solid (0.476 g). 1H-NMR (d6-DMSO, ca 2:1 rotamer mixture) δ 0.93 (6H, 2×t), 2.38–2.80 (4H, m), 2.90–3.05 (4H, m), 3.45 (2H, m), 4.30–4.95 (4H, m), 5.23–5.58 (2H, m), 6.06 (1H, 2×s), 7.14–7.38 (7H, m), 7.50–7.95 (7H, m), 8.16 (1H, m); MS (APCI+) found (M+1)=676. C39H38F5N3O2 requires 675.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=C([Cl:20])C=CC=1OC.COB(OC)OC>>[Cl:20][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: COB(OC)OC
Product: COc1ccc(Cl)cc1B(O)O
Yield: 77 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-chloroanisole (2.00 g, 9.0 mmol, 1.0 equivuiv), η-BuLi (2.5M in hexanes; 3.62 mL, 9.0 mmol, 1.0 equivuiv), and trimethylborate (3.0 mL, 26 mmol, 2.9 equivuiv) to afford 1.30 g (77%) of crude 5-chloro-2-methoxyphenylboronic acid as a white semi-solid. This compound was used in the next reaction with no further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: Nc1ccccc1B(O)O
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Nc1ccccc1-c1cccc(C(=O)O)c1
Yield: 95.2 %

Procedure:
The general procedure described in Example 3 was used with 3-chlorobenzoic acid (157 mg, 1.00 mmol), 2-aminophenylboronic acid (205 mg, 1.50 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 12 h, 100° C. The product was isolated as a white solid (203 mg, 95%). Mp=170° C. (lit.=173-175° C.) 1H NMR (400 MHz, d4-MeOH) δ: 8.07 (m, 1H), 7.99 (d, 1H, J=7.6 Hz), 7.65 (d, 1H, J=8.0 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.13 (td, 1H, J=1.6 Hz, J=7.6 Hz), 6.84 (d, 1H, J=8.0 Hz), 6.77 (t, 1H, J=7.6 Hz). 13C NMR (125 MHz, d4-MeOH) δ: 169.9, 145.1, 141.7, 134.8, 132.6, 131.4, 131.4, 130.1, 129.9, 129.5, 128.3, 120.0, 117.6.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[C:13]([C:15]([CH3:21])([CH2:18][CH2:19][CH3:20])[CH2:16][OH:17])#[N:14]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:17][CH2:16][C:15]([C:13]#[N:14])([CH3:21])[CH2:18][CH2:19][CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCC(C)(C#N)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(C)(C#N)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a round-bottomed flask, 1.35 mg (10.6 mM) of (-)-2-cyano-2-methylpentanol was dissolved in 2.52 g of dry pyridine. The mixture was placed on an ice bath, and 2.22 g (11.7 mM) of p-toluenesulfonyl chloride was added, followed by 6 hours of stirring at room temperature. After the reaction, 10 ml of 6N-hydrochloric acid was added, followed by 3 times of extraction with 15 ml of diethyl ether. The extract was dried overnight on anhydrous sodium sulfate, followed by distilling-off of the solvent and purification by column chromatography by using 80 g of silica gel and a dichloromethane/benzene (2/1) solvent to obtain (-)-2-cyano-2-methylpentyl p-toluenesulfonate. Yield: 2.57 g (9.1 mM), 86%
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([C:26](Cl)=[O:27])[CH:25]=1)[O:22][CH2:21][CH2:20][CH2:19]2>C(C(C)=O)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][NH:14][C:26]([C:24]2[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]3[C:23]=2[O:22][CH2:21][CH2:20][CH2:19]3)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NCC1CCCN1CC1=CCCCC1
Reactant: O=C(Cl)c1cc(Cl)cc2c1OCCC2
Solvent: CCC(C)=O
Product: O=C(NCC1CCCN1CC1=CCCCC1)c1cc(Cl)cc2c1OCCC2
Temperature: 5 °C

Procedure:
101 g of 1-cyclohexenylmethyl-2-aminomethylpyrrolidine and 200 ml of methyl ethyl ketone were introduced into a 2-liter round-bottomed flask. The contents were cooled to 5° C. and a solution of 109 g of 6-chlorochroman-8-carbonyl chloride in 500 ml of methyl ethyl ketone was added dropwise, while maintaining the temperature between 0° and 5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH2:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH:23]=[CH2:24]>>[CH2:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]
Reactant: C=CCN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Product: C=CCN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 39 %

Procedure:
Using the procedure of Example 7, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one was reacted with 1-allyl-piperazine to obtain a 39% yield of 11-[3-(4-allyl-1-piperazinyl)-propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 205°-207° C. after crystallization from ethanol.
Reaction SMILES: NCC[NH:4][C:5](=S)[NH:6][C:7]1[C:15](C)=C2C(C=CN2)=CC=1.[N:18]([C:21]1[C:29]([CH3:30])=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=C=S.C(N)CN>C1(C)C=CC=CC=1>[CH3:30][C:29]1[C:21]([NH:18][N:6]2[CH2:7][CH2:15][N:4]=[CH:5]2)=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][CH:26]=[CH:25]2
Reactant: Cc1c(N=C=S)ccc2cc[nH]c12
Reactant: Cc1c(NC(=S)NCCN)ccc2cc[nH]c12
Solvent: Cc1ccccc1
Solvent: NCCN
Product: Cc1c(NN2C=NCC2)ccc2cc[nH]c12

Procedure:
6-[-N′-(2-Aminoethyl)thioureido]-7-methylindole. A solution of 6-isothiocyanato-7-methylindole (0.85 g, 4.52 mmol) in 25 mL of toluene is added to a solution of ethylenediamine (1.06 mL, 15.8 mmol) in 50 mL of toluene. The milky white mixture is stirred for 30 minutes as the desired product precipitates. The reaction is filtered to yield 1.1 g of 6-[-N′-(2-aminoethyl)thioureido]-7-methylindole as a flaky white solid (99% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:18][N:19]2C(=O)C4C(=CC=CC=4)C2=O)[CH2:10]3)=[CH:5][CH:4]=[N:3]1.NN>CO.O1CCCC1>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc2c(c1)CN([C@H](CN)Cc1cc(F)cc(F)c1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
The product of Step D (0.72 g, 1.41 mmol) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). To the resulting solution was added hydrazine (2 mL, 60 mmol). The solution was stirred at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by combi-flash chromatography eluting with MeOH/EtOAc (20-60%). The product was further purified by prep.-LC/MS (pH=10). The purification afforded 210 mg (39.0% yield) of the final product as a white solid. LC/MS found: 383.1 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ: 7.9 (d, J=13.8 Hz, 2H), 7.58 (dd, J1=7.9 Hz, J2=1.1 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 6.96 (m, 3H), 6.45 (d, J=1.9 Hz, 1H), 4.47 (s, 2H), 4.41 (m, 1H), 3.86 (s, 3H), 3.04 (dd, J1=14.3 Hz, J2=4.8 Hz, 1H), 2.89 (dd, J1=14.0 Hz, J2=3.9 Hz, 1H), 2.85 (d, J=6.80 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:9][C:10]=2[Cl:12])[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:9][C:10]=2[Cl:12])[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.12 g, 0.38 mmol) with boron tribromide (0.75 mL of 1N solution, 0.75 mmol) according to method D to yield 0.10 (86%) of which was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 172-174° C. (dec.); 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.54 Hz), 7.36 (1H, d, J=8.90 Hz), 7.65 (2H, d, J=8.56 Hz), 7.88-7.91 (2H, m), 8.10 (1H, d, J=1.63 Hz), 9.69 (1H, s), 10.64 (1H, s); MS (ESI) m/z303/305/307 (M−H)−.Anal. for C16H10Cl2O2 0.25H2O Calc'd: C: 62.98H: 3.30 Found: C: 61.80H: 3.08
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([CH2:74][C:75]2[CH:82]=[CH:81][C:78]([CH:79]=O)=[CH:77][CH:76]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:78]3[CH:77]=[CH:76][C:75]([CH2:74][N:71]4[CH2:70][CH2:69][N:68]([CH3:67])[CH2:73][CH2:72]4)=[CH:82][CH:81]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CN1CCN(Cc2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 20.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and 4-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.14 mmol, 31 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (15 mg, 21%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.16 (s, 3H, CH3), 2.34-2.38 (m, 8H, 2× piperazine N(CH2)2), 2.62 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 3.62 (s, 2H, NCH2), 3.70 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.6, 4.6 Hz, 1H, pyridine H-5), 7.45 (d, J=8.4 Hz, 2H, phenyl H-3 & H-5), 7.79 (dt, J=7.7, 1.8 Hz, 1H, pyridine H-4), 8.13 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.47 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ccc(Cl)nc1
Product: Nc1ccc(-c2ccccc2F)nc1
Yield: 31 %

Procedure:
Obtained (0.210 g, yield 31%) following the procedure described in Intermediate 39, starting with 6-chloropyridin-3-amine (3.50 mmol, 0.45 g), 2-fluorophenylboronic acid (6.94 mmol, 0.97 g).