Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC2C3C4C=CN=CC=4C(=O)C=3C(=O)NC=2C=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:39]3[C:38]4[CH:37]=[N:36][CH:35]=[CH:34][C:33]=4[C:32](=[O:40])[C:31]=3[C:30](=O)[NH:29][C:28]=2[CH:42]=1.P(Cl)(Cl)([Cl:45])=O>>[Cl:45][C:30]1[C:31]2[C:32](=[O:40])[C:33]3[CH:34]=[CH:35][N:36]=[CH:37][C:38]=3[C:39]=2[C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:42][C:28]=2[N:29]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccncc1-3
Agent: COc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1cnccc1-3
Product: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccncc1-3
Temperature: 60 °C
Reaction time: 72 h

Procedure:
The mixture of 3-methoxy-5H-5,9-diaza-benzo[c]fluorene-6,7-dione and 3-methoxy-5H-5,10-diaza-benzo[c]fluorene-6,7-dione (8.77 g) obtained above was suspended in phosphorus oxychloride (359 g) and stirred at 60° C. for three days. Excess phosphorus oxychloride was evaporated under reduced pressure. The residue was treated with ice water and saturated sodium hydrogen carbonate to adjust the pH to about 7. Black ppt was collected with suction and washed water. The ppt was purified by silica gel column chromatography developed by dichloromethane-methanol-trifluoroacetic acid (200:2:1) and by dichloromethane-methanol-trifluoroacetic acid (200:4:1). This chromatography gave two yellow bands. The first band was collected and evaporated. The residue was treated with methanol to give a less polar isomer (1.72 g), 6-chloro-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one (Example 1c-1) as a yellow powder. The second band was collected and evaporated. The residue was treated with methanol to give a more polar isomer (1.86 g), 6-chloro-3-methoxy-5,9-diaza-benzo[c]-fluoren-7-one (Example 1c-2) as a yellow powder.
Reaction SMILES: [OH:1][C@@H:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:3]([NH:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=O)[CH3:4]>C1COCC1.Cl>[C:8]12([CH2:6][NH:5][C@H:3]([CH3:4])[C@H:2]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[OH:1])[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2
Reactant: C[C@@H](NC(=O)C12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H](NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A stirred solution of N-((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)adamantane-1-carboxamide (3.07 g, 9.8 mmol) in dry THF (50 mL) was cooled in an ice bath and 1M BH3 in THF (50 mL, 50 mmol) was added. The ice bath was allowed to melt and the mixture was stirred over the weekend at rt. The mixture was poured into 5% aq HCl (50 mL). The mixture was concentrated on the rotary evaporator to leave a white solid which was taken up in 5% aq HCl (75 mL) and washed with ether (150 mL). The aqueous layer was made strongly basic by addition of NaOH and extracted with EtOAc (2×100 mL). The combined EtOAc extracts were dried over MgSO4 and concentrated to afford (1S,2R)-2-(1-adamantylmethylamino)-1-phenylpropan-1-ol (2.28 g, 77%) as an oil. LC-MS (3 min) tR=1.32 min, m/z=300.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13]C(=O)C)=[C:5]([F:17])[CH:4]=1)#[N:2].Cl>CCO>[NH2:13][C:6]1[C:5]([F:17])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1F
Agent: Cl
Solvent: CCO
Product: N#Cc1cc(F)c(N)cc1C(F)(F)F
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of compound 24 (800 mg, 3.25 mmol) in EtOH (10 mL) was added concentrated HCl solution (12N, 5 mL). The mixture was heated at reflux for 1 h, cooled to room temperature, concentrated in vacuo. The resulting white solid was dissolved in EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated to give compound 25 (660 mg, 99%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ7.40 (d, 1H, J=7.2 Hz), 7.09 (d, 1H, J=10.0 Hz), 4.48 (br s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20](O)=[O:21])[CH2:3][CH2:2]1.Cl.Cl.[CH3:25][C@H:26]1[C@H:31]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH2:29][NH:28][CH2:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:28]2[CH2:29][CH2:30][C@H:31]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[C@@H:26]([CH3:25])[CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Reactant: C[C@@H]1CNCC[C@H]1N1CCCC1
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CC[C@H](N2CCCC2)[C@@H](C)C1

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and (trans)-3-methyl-4-pyrrolidin-1-yl-piperidine dihydrochloride (example 195C) in direct analogy to the general procedure used in example 150. MS: 461.3 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[N:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: Clc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: OC1CCN(c2ccccn2)CC1
Yield: 27.3 %

Procedure:
A solution of piperidin-4-ol (100 mg, 0.99 mmol), desired 2-chlorpyridine (0.99 mmol, 1.0 equiv.), and DIPEA (345 μL, 1.98 mmol) in isopropanol (1.5 mL) was heated by microwave irradiation at 160° C. for 2.5 h. The reaction was purified directly by silica gel chromatography to give the desired 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (using 5-bromo-2-chloropyridine, 5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was isolated in 27% yield, 69.1 mg, 0.27 mmol; using 5-trifluoromethyl-2-chloropyridine, 5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was isolated in 62% yield, 150.1 mg, 0.61 mmol).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:24])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:20][CH2:21][CH2:22][OH:23])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1.Cl.[OH-].[Na+]>C(O)C.CO>[CH3:3][N:4]([CH3:24])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([NH:20][CH2:21][CH2:22][OH:23])[CH:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[OH:13])=[CH:9][CH:10]=1
Reactant: CN(C)c1ccc(C(NCCO)C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CN(C)c1ccc(C(NCCO)C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Sodium borohydride (0.22 g, 0.0057 mole) was added in several portions to a stirred suspension of 2-(4-dimethylaminophenyl)-2-(hydroxyethylamino)acetophenone (0.85 g, 0.00285 mole) in 50 ml of absolute ethanol and the mixture stirred at ambient temperature for 0.5 hr. The mixture was then heated to reflux temperature for 0.5 hr, cooled to ambient temperature, and 6N HCl solution added until the mixture was neutral. The mixture was concentrated to give a yellow solid. This solid was dissolved in a minimum volume of methanol and acidified with 6N hydrochloric acid to give a clear yellow solution. This solution was brought to pH 8 with 6N sodium hydroxide solution, cooled by the addition of ice, and the white solid collected to obtain 0.54 g (63%) of the desired product. Recrystallization from acetoneisopropyl ether gave 0.25 g of title compound, m.p. 147°-148° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([CH3:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1N
Yield: 87.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.4 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (1.0 mL, 12.92 mmol), and 3,4-dimethylaniline (6.2 g, 51 mmol) to afford the product (5.99 g); m.p. 138-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41]4)[CH2:49][CH2:48]3)=[O:23])[CH:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C1CCN(CCN2CCNCC2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CCN4CCCC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (69 mg, 0.20 mmol), CDI (63 mg, 0.39 mmol) and 1-[2-(pyrrolidin-1-yl)ethyl]piperazine (72 mg, 0.39 mmol) in THF (4 mL). The crude product was purified using prep method A.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][CH2:20][O-:21].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:21][CH2:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium ethylate (262 mg, 3.85 mmol) were dissolved in ethanol (20 ml) and then the solution was refluxed on heating under stirring for 20 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (151 mg, yield 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>FC(F)(F)CO>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Solvent: OCC(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(N4CCOCC4)nc3-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)n2)CC1
Yield: 15 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.107 g, 0.188 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.3 g, 1.68 mmol) in 2,2,2-trifluoroethanol (2 mL) the title compound was obtained (0.020 g, 0.028 mmol, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.85 (d, J=5.1 Hz, 2H), 7.70-7.57 (m, 2H), 7.42-7.33 (m, 2H), 7.30-7.03 (m, 4H), 5.47-5.86 (m, 1H) 3.72-3.31 (m, 11H), 2.91-2.73 (m, 5H), 1.92-1.77 (m, 2H), 1.58-1.40 (m, 2H). MS (ESI): 710 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]=O)=O.[NH2:12][C:13]1[N:17]([NH2:18])[CH:16]=[N:15][N:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:10]=[N:18][N:17]2[CH:16]=[N:15][N:14]=[C:13]2[N:12]=1
Reactant: O=CC(=O)c1ccccc1Cl
Reactant: Nc1nncn1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccccc1-c1cnn2cnnc2n1

Procedure:
A solution of 14 g. of o-chlorophenylglyoxal, 10.6 g. of 3,4-diamino-4H-1,2,4-triazole and 6.3 g. of sodium acetate in 180 ml. of 67% acetic acid is heated on a steam bath and then filtered through celite. The filtrate is heated for an additional hour and then allowed to stand at room temperature for several days, producing the desired product as a cream colored solid, m.p. 162°-165° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH:11]([OH:13])[CH3:12])[CH2:6][CH:7](O)[CH3:8])[CH2:2][CH2:3][CH3:4].C1(/C=C/C(=O)C)C=CC=CC=1>>[CH2:1]([N:5]1[CH:6]=[C:7]([CH3:8])[O:13][CH:11]([CH3:12])[CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC(C)O)CC(C)O
Agent: CC(=O)/C=C/c1ccccc1
Product: CCCCN1C=C(C)OC(C)C1
Reaction time: 5 h
Yield: 51 %

Procedure:
N-n-butyl-bis-(2-hydroxypropyl)amine (60g, 0.32 mol) and trans-4-phenyl-3-buten-2-one (85g 10.58 mole) were subjected to a reaction as described in Example 1 above, except that the products stayed in the reaction flask and the reaction was held at 180° C. for 5 hours. A 51% yield of 3,4-dihydro-4-n-butyl-2,6-dimethyl-2H-1,4-oxazine was obtained.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[N:11])C1C1C=CC=CC=1)#[N:2].NCCN1CCN(CCN)C1C1C=CC=CC=1>>[NH2:2][CH2:1][CH2:3][NH:4][CH2:8][CH2:7][NH:6][CH2:9][CH2:10][NH2:11]
Reactant: N#CCN1CCN(CC#N)C1c1ccccc1
Agent: NCCN1CCN(CCN)C1c1ccccc1
Product: NCCNCCNCCN

Procedure:
This Example demonstrates the reduction of (3-cyanomethyl-2-phenyl -imidazolidin-1-yl)-acetonitrile (5) to intermediate 2-[3-(2-Amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine (8). As shown in Scheme 9, intermediate (8) is treated with an acid to form a triethylenetetramine salt. The reduction is effected by LiAlH4, the acid used is hydrochloric acid and the tetrahydrochloride salt of triethylenetetramine is produced.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 57.6 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (70 mg) and (4-formylphenyl)acetic acid (150 mg) according to an analogous synthetic method to Example 212,the title compound (56 mg) was obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:23]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([Cl:23])=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Cl
Reactant: CCCCn1c(=O)c2[nH]c([N+](=O)[O-])nc2n(CCCC)c1=O
Product: CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O

Procedure:
1,3-Di-n-butyl-8-nitro xanthine (0.5 g, 0.0016 mol) was refluxed for 18 hours with concentrated hydrochloric acid (8 ml). The reaction mixture was extracted with dichloromethane (20 ml), the organic layer washed with water to neutrality and then dried over anhydrous sodium sulphate. The solvent was then removed by evaporation in vacuo and the residue was recrystallised from ethanol, to give the title compound, yield 0.38 g (73%), m.pt. 152° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4Br)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccn1
Yield: 46.6 %

Procedure:
A mixture of 1.94 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-bromobenzamide, 2.95 g of 2-pyridyl tri-n-butyl tin and 400 mg of tetrakis(triphenylphosphine)palladium(O) is refluxed for 24 hours in degassed toluene for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 70% ethyl acetate:hexane to give 900 mg of the desired product as a pale yellow solid:M+1=485.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:30][C:26]5[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=5)=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1cccnc1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)Nc4cccnc4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.2 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), pyridin-3-amine (0.05 g, 0.53 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF were stirred at room temperature for 5 hours. Then HATU (0.114 g, 0.3 mmol) was added, the final reaction mixture was stirred for additional. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water, EtOAc and DMSO successively then decanted and dried to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.022 g, 26%) as a white solid. MS: (M+H)+=404; 1H NMR (300 MHz, DMSO): δ 10.20 (s, 1H), 9.09 (s, 1H), 8.90 (s, 1H), 8.63 (s, 1H), 8.54 (d, 1H, J=8.7 Hz), 8.34 (d, 1H, J=4.5 Hz), 8.26 (d, 1H, J=8.7 Hz), 7.98 (s, 1H), 7.47 (dd, 1H, J=8.4, 4.8 Hz), 7.22 (d, 1H, J=8.4 Hz), 4.17 (s, 3H).
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:20]=[C:21]([C:22](/[N:24]=[CH:25]/[N:26](C)C)=O)[C:16]=2[N:15]=[C:14]1[CH3:35].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:20]=[C:21]([C:22]3[N:24]=[CH:25][NH:26][N:2]=3)[C:16]=2[N:15]=[C:14]1[CH3:35]
Reactant: NN
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
Hydrazine monohydrate (2 mL) was added to a solution of 1-[(2,3-dichlorophenyl)methyl]-N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxamide (220 mg, 0.46 mmol) in acetic acid (5 mL) and stirred at 130° C. for 20 min. The reaction mixture was cooled to rt and poured into saturated NaHCO3 solution (15 mL). The mixture was extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM:MeOH=30:1 to give the desired product (110 mg, 53%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 3.12 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 5.62 (s, 2H), 6.36 (d, 1H, J=8.1 Hz), 7.21 (s, 1H), 7.27 (t, 1H, J=8.1 Hz), 7.54 (s, 1H), 7.61 (d, 1H, J=8.1 Hz), 8.08 (s, 1H), 13.80 (s, 1H); LC-MS: m/e=443 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1.[OH-].[Li+]>O.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1
Reactant: COC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2

Procedure:
Methyl 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate 10 was treated with lithium hydroxide in water and tetrahydrofuran (THF) to give 11.
Reaction SMILES: [Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@@H](O)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O1[C@H](C(C)C)C1.[Si]([O:84][C@@H:85]1[C@@:110]2([CH3:111])[C:89](=[CH:90][CH:91]=[C:92]3[C@@H:109]2[CH2:108][CH2:107][C@@:106]2([CH3:112])[C@H:93]3[CH2:94][CH:95]=[C:96]2[C@@H:97]([O:99][CH2:100][C@H:101]([OH:105])[CH:102]([CH3:104])[CH3:103])[CH3:98])[CH2:88][C@@H:87]([O:113][Si](C(C)(C)C)(C)C)[CH2:86]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[OH:84][C@@H:85]1[C@@:110]2([CH3:111])[C:89](=[CH:90][CH:91]=[C:92]3[C@@H:109]2[CH2:108][CH2:107][C@@:106]2([CH3:112])[C@H:93]3[CH2:94][CH:95]=[C:96]2[C@@H:97]([O:99][CH2:100][C@H:101]([OH:105])[CH:102]([CH3:104])[CH3:103])[CH3:98])[CH2:88][C@@H:87]([OH:113])[CH2:86]1
Reactant: CC(C)[C@@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 69.3 %

Procedure:
Using 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (71.5 mg, 0.128 mmol), potassium t-butoxide (170 mg, 1.52 mmol), dibenzo-18-crown-6(32.0 mg, 0.0888 mmol), toluene (4.5 ml) and (R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol), alkylation reacion (108° C., 1 hour) and work up were performed by the same procedure as in Example 119, and then the residue was separated by preparative thin layer chromatography (0.5 mm×3, hexane:dichloromethane:ethyl acetate 45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(R)-hydroxy-3-methyl-butyloxy}pregna-5,7,16-triene (26.8 mg). This was deprotected with tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.4 ml) (reaction temperature 74° C., reaction period 12 hours) and worked up by the same procedure as in Example 119, and then the residue was purified by preparative thin layer chromatography (0.25 mm×1, dichloromethane:ethanol=15:1, developed twice) to give the title compound as a colorless oil (12.0 mg, 23%).