Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH3:13][NH2:14]>>[CH3:13][NH:14][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CN
Agent: Cl
Product: CNc1cc(O)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
To a pressure vessel was added 3-fluoro-4-nitro-phenol (5.0 g, 31.82 mmol) and a 40% aqueous solution of methylamine (10 mL). The reaction mixture was stirred at 85° C. for 5 h, then it was cooled to room temperature, poured on water, and acidified to pH 1 with 1 N aqueous HCl. The resulting precipitate was filtered, washed with water, and dried in vacuo to give 5.23 g of 3-methylamino-4-nitro-phenol as an orange solid (98% yield): 1H NMR (DMSO-d6) δ 2.88 (d, 3H), 6.14 (dd, 1H), 6.17 (d, 1H), 7.96 (d, 1H), 8.25 (q, 1H), 10.8 (broad s, 1H); MS (m/z) 167 [M−H]−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3]1.Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1.[F-].[K+].O>CS(C)=O>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[N:16]3[N:17]=[C:12]([NH:1][C@H:2]4[CH2:6][CH2:5][C@H:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3]4)[CH:13]=[CH:14][C:15]3=[N:20][CH:19]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)[C@H]1CC[C@H](N)C1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(O)[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)C1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(trans-3-aminocyclopentyl)propan-2-ol (82 mg, 0.57 mmol), 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol) and KF (66.2 mg, 1.14 mmol) in DMSO (1 mL) was stirred at 130° C. overnight. LCMS showed the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-82 (45 mg, 32%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)=[C:4]([NH2:18])[CH:3]=1.[CH2:19](OC=C(C#N)C#N)C.C(OCC)(=O)C>C(O)CC.C(Cl)Cl>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([N:8]3[C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=4[N:18]=[CH:19]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccc(Nc2ccc3[nH]ccc3c2)c(N)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCO
Product: Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Yield: 81 %

Procedure:
5-(4-Methyl-2-nitrophenylamino)-1H-indole (0.47 g, 2.0 mmoles) was reduced by catalytic hydrogenation to form 5-(4-methyl-2-aminophenylamino)-1H-indole (0.41 g, 2.0 mmoles). The 5-(4-methyl-2-aminophenylamino)-1H-indole was cyclized with ethoxymethylenemalononitrile (0.49 g, 2.0 mmole) in propanol, while being heated for 14 hours. Column chromatography using 10% ethyl acetate in methylene chloride afforded the title compound (81%) as a yellow solid. Mp, 215.0°-216.0° C.; Rf =0.3 in 10% ethyl acetate in methylene chloride; 1H NMR (DMSO-d6) δ11.43 (br s, NH), 8.42 (s, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.56 (d, J=0.5 Hz, 1H), 7.52 (t, J=2.6 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.30 (dd, J=8.5 and 1.7 Hz, 1H), 7.12 (br d, J=8.3 Hz, 1H), 6.56 (dd, J=2.7 and 0.9 Hz, 1H), 2.44 (s, 3H); 13C NMR (DMSO-d6) δ156.5, 144.3, 143.8, 137.2, 134.0, 130.0, 129.1, 128.0, 126.4, 119.7, 119.0, 117.3, 113.4, 111.7, 103.0, 21.6; FAB LRMS (m/z, relative intensity) 249 (23), 248 ([MH]+, 100); HRMS calculated for C16H13N3 247.1107, found 247.1092.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.O=C1C(C2C=CC=CC=2)(C2C=CC=CC=2)CCN1CC(O)=O.[NH2:47][C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=1.FC(F)(F)C1C=CC(N)=NC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:47][C:48]3[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=3)=[O:16])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: Nc1ccc(C(F)(F)F)cn1
Agent: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Product: N#Cc1ccc(NC(=O)CN2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2=O)nc1

Procedure:
The title compound was prepared using the procedure described in Example 246 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid and 6-aminonicotinonitrile for 5-(trifluoromethyl)pyridin-2-amine. 1H NMR (300 MHz, CDCl3) δ ppm 8.55 (s, 2H), 8.25 (d, J=8.7, 1H), 7.93 (dd, J=2.1, 8.7, 1H), 7.43-7.22 (m, 4H), 7.07-6.98 (m, 4H), 4.21 (s, 2H), 3.55 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (DCI) m/z 433.0 (M+H)+.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:22])[C:14]([O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15].[P:23](Cl)(Cl)(=[O:35])[O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C(Cl)[Cl:39]>>[Cl:39][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[O:24][P:23](=[N:12][C@@H:13]([CH3:22])[C:14]([O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15])=[O:35]
Reactant: C[C@H](N)C(=O)OC1CCCC1
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OC1CCCC1
Yield: 65 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates the tosylate salt of (S)-cyclopentyl 2-aminopropanoate (4.00 g, 12.14 mmol), naphthalen-1-yl phosphorodichloridate (3.17 g, 12.14 mmol) and TEA (1.60 mL, 24.28 mmol) in 30 mL of dry DCM, were combined to give (2S)-cyclopentyl 2-(chloro(naphthalen-1-yloxy)-phosphorylamino)propanoate in 65% yield (3.01 g), as a clear, yellow, thick oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A solution of the compound of Example 67, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.47 g, 5.14 mmol) in 40 mL 1-methyl-2-pyrrolidinone was treated with triethylamine (1.43 mL, 10.3 mmol). With vigorous stirring, the solution was treated dropwise with benzoyl chloride (0.597 mL, 5.14 mmol). After 18 h, the reaction was concentrated. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave a clear, colorless oil. The oil was triturated in ether and filtered to yield 531 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}benzamide as a white solid.
Reaction SMILES: C([C:6]1[N:7]([CH2:15][CH2:16][CH2:17][NH:18]C(C2C3C(=CC=CC=3)C(=O)O2)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(OCC)=O.[BH4-].[Na+].[C:33]([OH:36])(=[O:35])C.[CH:37](O)(C)[CH3:38]>O>[C:33]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:6]=[CH:14]2)([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)c1cc2ccccc2n1CCCNC(=O)C1OC(=O)c2ccccc21
Reactant: CC(C)O
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccc2ccn(CCCN)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.93 g (2.5 mmol) of carboethoxy-N-(3-phthalidamidopropyl)indole in 21 mL of isopropanol and 3.5 mL of water was added 0.47 g (12 mmol) of NaBH4 and the reaction mixture was stirred overnight at rt. To the reaction mixture was carefully added 2.4 mL of glacial acetic acid and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc and 2N HCl. The aqueous layer was made basic with solid K2CO3 and extracted with EtOAc. The combined organic fractions were washed with sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated to give 0.57 g of 7-carboethoxy-N-(3-aminopropyl)indole that was used without further purification.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17].F[C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH:17][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)c(Cl)c1
Yield: 84.2 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 3-chloro-4-fluoro-aniline (2.48 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.32 g of the crude title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][CH:14]([OH:15])[CH3:16])=[CH:6][CH:5]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)Cn1ccc2ccc(F)cc21
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.97 g of 6-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with 7 ml of water. The mixture was diluted with 180 ml of ether, washed twice with 90 ml of water and with 50 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 28 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 1.1 g (79.3%) of (RS)-1-(6-fluoro-indol-1-yl)-propan-2-ol as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15](SC)[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.O[O:35][S:36]([O-:38])=O.[K+].[CH2:40]1COCC1>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([S:36]([CH3:40])(=[O:38])=[O:35])[CH:18]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=S([O-])OO
Reactant: CSc1cccc(Nc2nccc3c(Nc4ncccc4-c4ccncn4)c(C)ccc23)c1
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(Nc3cccc(S(C)(=O)=O)c3)nccc2c1Nc1ncccc1-c1ccncn1
Temperature: 0 °C

Procedure:
A solution of 6-methyl-N1-(3-(methylthio)phenyl)-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine (0.250 g, 0.555 mmol) in THF (30 mL) and MeOH (20 mL) was stirred in an ice bath and treated with a solution of oxone® (0.750 g, 1.22 mmol) in water (10 mL). The resulting cloudy reaction mixture was stirred at 0° C. (warming slowly to ˜10° C.) for 3 h. The reaction mixture was quenched at 0° C. by the addition of satd aq Na2SO3 (100 mL) and stirred at that temperature for 15 min. The mixture was concentrated in vacuo to remove THF and the remaining aqueous mixture was extracted with 3:1 CHCl3:IPA (3×100 mL). The organic extract was washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 8% MeOH in CH2Cl2, to provide 6-methyl-N1-(3-(methylsulfonyl)phenyl)-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine. MS (M+H)+ 483.5.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].O1CCCC1>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1[nH]c2c(NS(=O)(=O)c3cccs3)cccc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 3-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.33 g), 8N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (5 mL) and ethanol (10 mL) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (1.15 g, yield 94%) as colorless crystals. melting point>263° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 91.7 %

Procedure:
1.50 g (6.9 mmol) of ethyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in N,N-dimethylformamide (30 mL), and 1.43 g (10.4 mmol) of potassium carbonate and 1.36 g (7.9 mmol) of benzyl bromide were added thereto. The resulting mixture was stirred for one whole day and night at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic phase was dried, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=3:7 to 1:1), and thus 1.95 g (yield: 92%) of the title compound was obtained as colorless crystals.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[C:9]2[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][C:10]=2[N:11]([CH2:21][C:22](OC)=[O:23])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O.C[NH:34][CH2:35][CH2:36][NH:37][CH3:38].[BH3-][C:40]#N.[Na+].CCOC(C)=O>CO>[CH3:40][N:37]([CH3:38])[CH2:36][CH2:35][N:34]1[CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2=[C:8]([C@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[F:1])[C:9]3[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][C:10]=3[N:11]2[CH2:21][C:22]1=[O:23]
Reactant: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2F)c2sc(C(=O)OC)cc21
Reactant: CNCCNC
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2c(s1)c([C@H]1CCCC[C@@H]1F)c1n2CC(=O)N(CCN(C)C)Cc2ccccc2-1
Reaction time: 72 h
Yield: 60 %

Procedure:
A solution (0.1 M) of methyl 6-(2-fluorocyclohexyl)-5-(2-formylphenyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate and dimethylethylenediamine (1.5 eq.) in MeOH was stirred at RT for 3 h, then NaCNBH3 (excess) was added and the mixture was stirred for 3 days; evaporation to dryness gave a residue that was taken into EtOAc and washed with sat. NaHCO3-solution and brine, dried and concentrated i. vac. to obtain methyl 6-[2-(dimethylamino)ethyl]-13-[(1R,2S)-2-fluorocyclohexyl]-7-oxo-5,6,7,8-tetrahydrothieno[2′,3′:4,5]pyrrolo[2,1-a][2,5]benzodiazocine-11-carboxylate that was used without further purification. The latter was dissolved in dry THF (0.1M) and treated with 2M borane dimethylsulfide complex in THF (excess), and the mixture was stirred overnight at RT. 1.25M HCl in MeOH was added dropwise, the flask was opened and the mixture was stirred for 3 h at 85° C. Evaporation to dryness gave a residue that was hydrolised with 1M aq. KOH (3 eq.) in dioxane (85° C., 2 h); after quenching with 6M aq. HCl and removal of all volatiles the title compound was isolated by RP-HPLC. Yield: 60%. 1H-NMR (400 MHz, DMSO-d6, 300K, δ) 8.04 (d, 1H, J 2.2) 7.85-7.46 (m, 4H), 4.74-4.69 (m, 1H), 4.86-4.45 (m, 1H), 4.40 (bt, 1H, J 12.5), 3.74-3.42 (m, 8H), 2.88 (s, 3H), 2.87 (s, 3H), 2.74-2.61 (m, 1H), 2.26-1.03 (m, 8H); MS (ES+) m/z 470 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]#[C:14][C:16]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:24]=[CH:25][N:26]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccnc(C#Cc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
3,4,5-Trimethoxyphenylacetylene (1.80 g), ethyl 2-chloroisonicotinate (2.08 g) and copper iodide (71 mg) were dissolved in a mixed solvent of DMF (4 mL) and triethylamine (8 mL), and to the solution bis-(triphenylphosphine)palladium dichloride (0) (131 mg) was added, and the mixture was stirred at 45° C. for 4 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1) to obtain the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:25]Br.C(Cl)(Cl)Cl>CO.C(Cl)(=O)C>[Br:25][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)Cl
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
3α-Hydroxy-5α-pregnane-11,20-dione (1 g.) in stirred methanol (7 ml.) at 30° was treated with acetyl chloride (1 drop). After two minutes bromine (0.19 ml.) in methanol (4.5 ml.) was added dropwise. The solution being allowed to decolourise between the addition of each drop. The resulting clear solution was poured into chloroform (100 ml.), washed with water (3 × 50 ml.) dried (Na2SO4) and evaporated to a white froth (1.40 g.). Preparative t.l.c. afforded title compound (715 mg.) which crystallised from chloroform/ether as clusters of colourless needles, m.p. 160°-163°; [α]D + 109° (c 0.82).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[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][CH3:16].[OH:32][CH2:33][CH2:34][C:35]1[S:39][CH:38]=[N:37][C:36]=1[CH3:40]>>[CH3:30][S:27]([O-:29])(=[O:28])=[O:26].[CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][N+:37]1[C:36]([CH3:40])=[C:35]([CH2:34][CH2:33][OH:32])[S:39][CH:38]=1)[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][CH3:16]
Reactant: Cc1ncsc1CCO
Reactant: C=C(COCCCCCCCCCCCCCCCC)COCCCCOS(C)(=O)=O
Product: C=C(COCCCCCCCCCCCCCCCC)COCCCC[n+]1csc(CCO)c1C
Product: CS(=O)(=O)[O-]

Procedure:
1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (from Preparation 7) (0.30 g) was heated with 5-(2-hydroxyethyl)-4-methylthiazole at 56° C. for 5 days. Excess 5-(2-hydroxyethyl)-4-methylthiazole was removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([OH:19])=O)[CH:9]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH:49]1[C:54]#[N:55]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([N:51]3[CH2:52][CH2:53][NH:48][CH:49]([C:54]#[N:55])[CH2:50]3)=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(Cl)c(-c2ccc(Cl)cc2)cc1C(=O)O
Reactant: N#CC1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2ccc(Cl)cc2)cc1C(=O)N1CCNC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 4′,6-dichloro-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid (309 mg, 1.04 mmol), EDCI (272 mg, 1.43 mmol), HOBt (195 mg, 1.43 mmol), Et3N (288 mg, 2.85 mmol) in dichloromethane (10 mL) at 0° C., piperazine-2-carbonitrile was added at 0° C. and the resulting mixture was stirred at RT for 8 h. The mixture was partitioned between dichloromethane and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (225 mg, 61% yield). ESI-MS m/z: 444.3[M+H]+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>C1COCC1>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5ccc(NC(=O)c6cccs6)cc5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (53.9 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 59% (86 mg, 0.153 mmol) of the title compound.