Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:26][CH2:25][CH2:24][O:23]3)[C@H:13](Br)[CH2:12]4)[C@H:9]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33]C(=O)C)[CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH-].[K+]>CS(C)=O.CO>[CH2:25]1[CH2:24][O:23][C:14]2([CH:13]=[CH:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C:20]2[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=2[CH2:8][C@H:9]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[O:26]1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](C[C@@H](Br)C34OCCO4)[C@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Yield: 68.9 %

Procedure:
A solution of 74.1 g of 3-acetoxy-7α-(5-acetoxypentyl)-16α-bromo-17,17-ethylenedioxy-estra-1,3,5(10)-triene in 740 ml of dimethyl sulfoxide and 74 ml of methanol is stirred with 74 g of potassium hydroxide for 7.5 hours at a bath temperature of 85° C. Then, it is precipitated with ice/water/common salt, taken up with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 36.12 g of pure 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol is obtained as foam.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].C#C.[C-]#[C-].[Li+].[Li+].[CH2:30](N)[CH2:31]N>CC(N(C)C)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:30]#[CH:31])[OH:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CCC2=O
Reactant: NCCN
Agent: C#C
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(C)C4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CC
Reaction time: 4 h
Yield: 89.8 %

Procedure:
Dissolve dl-13-ethyl-6-methyl-3-methoxygona-2,5(10)-dien-17-one (3.6 g) in dimethylacetamide (35 ml) and stir in a stream of acetylene for 0.5 hour. Add solid lithium acetylide-ethylenediamine (2.7 g) and stir the solution for 4 hours. Pour the reaction mixture onto ice, extract with ether, wash the ether layer with water, dry, and evaporate to obtain dl-13-ethyl-3-methoxy-6-methyl-17α-ethynyl-17-hydroxygona-2,5(10)-diene (3.5 g) as a gum; infrared absorption peaks (sodium chloride) at 2.90 μ, 3.05 μ, 5.90 μ, 6.03 μ.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)=[C:8]([CH:11]=1)[C:9]#[N:10].CS[C:25]1[NH:26][CH:27]=[C:28]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[N:37][CH:38]=2)[C:29](=[O:31])[N:30]=1>C(O)C>[O:31]=[C:29]1[C:28]([CH2:32][C:33]2[CH:38]=[N:37][CH:36]=[N:35][CH:34]=2)=[CH:27][NH:26][C:25]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=3)=[C:8]([CH:11]=2)[C:9]#[N:10])=[N:30]1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Solvent: CCO
Product: N#Cc1cc(CCNc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 125 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
5-(2-amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)benzonitrile (0.163 mmol, 1 eq) and 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.065 mmol, 0.4 eq) were dissolved in dry ethanol (200 μL) and stirred at 125° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-15% in 20CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-[2-(4-oxo-5-pyrimidin-5-ylmethyl-1.4-dihydro-pyrimidin-2-ylamino)-ethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)benzonitrile (0.028 mmol, yield: 17%, HPLC-MS/UV: [M+H]+=494.17; rt: 9.91 mins; purity: 91%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.98 (t, J=6.57, 2H), 3.52-3.75 (m, 4H), 5.31 (br.s., 1H), 7.12-7.30 (m, 3H), 7.48-7.56 (m, 1H), 7.57-7.62 (m, 1H), 7.71 (s, 1H), 7.98 (dd, J=8.40, J=2.55, 1H), 8.57-5.69 (m, 2H), 9.04 (s, 1H), 11.80 (br.s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:23]2[C:14](=[CH:15][C:16]3[O:21][CH2:20][CH2:19][O:18][C:17]=3[CH:22]=2)[O:13][CH2:12]1.[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2([C:36]3=[CH:37]C4OCOC=4C=C3OC2)C1=O.Br.BrCC1C=CC=CN=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:31][C:32]1[CH:27]=[CH:26][CH:36]=[CH:37][N:24]=1)[C:8](=[O:11])[C:7]12[C:23]2=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=[C:14]2[O:13][CH2:12]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(Cc2ccccn2)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (38%) as a colorless solid: mp 205-207° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ8.55 (d, J=4.8 Hz, 1H), 7.69-7.63 (m, 1H), 7.23-7.16 (m, 2H), 6.99-6.89 (m, 3H), 6.50 (s, 2H), 5.35 (d, J=16.4 Hz, 1H), 5.17 (d, J=16.4 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.22-4.19 (m, 2H), 4.15-4.13 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 155.7, 155.1, 149.6, 144.7, 138.4, 136.7, 124.0, 124.0, 122.4, 121.0, 120.7, 119.7, 119.6, 116.7, 116.5, 112.1, 99.3, 80.3, 64.5, 63.9, 58.4, 47.0; MS (ES+) m/z 405.0 (M+1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([CH3:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[CH3:48][C:49]([O:52][C:53]([NH:55][C@H:56]([C:65]([O:67]CC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=1)=[O:54])([CH3:51])[CH3:50]>>[NH:55]([C:53]([O:52][C:49]([CH3:48])([CH3:50])[CH3:51])=[O:54])[C@H:56]([C:65]([NH:1][C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([CH3:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9])=[O:67])[CH2:57][C:58]1[CH:59]=[CH:60][C:61]([OH:64])=[CH:62][CH:63]=1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 81.7 %

Procedure:
Using BOC-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 (0.70 g) and BOC-Tyr-ONB (0.50 g), the desired compound (0.71 g) is obtained in a similar manner to(V) of Example 26. m.p. 196°-198° C., [α]D23 -2.0°(c=0.47, DMF), Rf1 =0.46
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([OH:45])[CH:41]=[C:42]([OH:44])[CH:43]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C1COCC1.CN(C=O)C>[CH2:62]([O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:45][C:40]1[CH:39]=[C:38]([O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:43]=[C:42]([O:44][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:41]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: BrCCOCCOCCOCCOCCOCc1ccccc1
Reactant: Oc1cc(O)cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(COCCOCCOCCOCCOCCOc2cc(OCCOCCOCCOCCOCCOCc3ccccc3)cc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.7 %

Procedure:
To an ice-cooled mixed suspension of sodium hydride (350 mg, 8.8 mmol; 60% in mineral oil) in THF (4.5 ml) and DMF (1.5 ml), a mixed solution of Compound 45 (1.0 g, 1.7 mmol) in THF (4.5 ml) and DMF (1.5 ml) was gradually added, and this was followed by stirring for 30 minutes. A solution of Compound 20 (2.7 g, 6.8 mmol) in THF (4 ml) was added thereto, and this was followed by stirring for 20 minutes. After the ice bath was removed, stirring was further conducted at room temperature for 4 hours. After the product was again immersed in the ice bath, water was carefully added to stop the reaction, and this was followed by concentration under reduced pressure. Extraction from ethyl acetate was conducted, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate:methanol 19:1)) to yield Compound 46 (light-yellow oil 1.22 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(C)=O)cc1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 175.3 %

Procedure:
To 100 g of 2-(4-methoxyphenyl)ethylamine in 500 mL of chloroform was slowly added 100 mL of triethylamine acetic anhydride (72 g), and this was stirred at 20° C. for 40 minutes. The mixture was then extracted twice with a dilute aqueous solution of HCl (0.4 N, 400 mL) followed by a saturated aqueous solution of NaHCO3 (2×400 mL). The solvent was removed by rotary evaporation, and the residue was dried in a vacuum oven (45° C.), resulting in an off-white powder, N-[2-(4-methoxyphenyl)ethyl]acetamide (120 g, 93.9% yield). 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1.C([Li])CCC.[B:18]([O:27]C(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][B:18]([OH:27])[OH:23])=[CH:3][CH:4]=1
Reactant: COCOCc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOCc1ccc(OB(O)O)cc1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis(triphenylphosphine)palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[CH:30]=[CH:31][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (240 mg, 0.50 mmol), 4-formylphenylboronic acid (150 mg, 1.0 mmol) and 4 mg of tetrakis(triphenylphosphine)palladium(0) in 20 mL of ethylene glycol dimethyl ether and 16 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with chloroform to provide 160 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 261-262° C.; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.90-8.03 (m, 4H), 8.15 (s, 1H), 8.65 (s, 1H), 9.83 (s, 1H), 10.05 (s, 1H); MS 454.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:42])[C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:13]=2[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([N:8]([CH3:42])[C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]([OH:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:13]=2[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nc2ccc(N(C)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-(N-benzyl-methylamino)-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:10][C:4]=2[O:3]1.C([O:23][C:24]([N:26]1CC[N:29]([CH2:32][C:33]2[CH:43]=CC3OC(F)(F)OC=3C=2)[CH2:28][CH2:27]1)=O)(C)(C)C>>[N:29]1[CH:32]=[CH:33][CH:43]=[C:27]([NH:26][C:24]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:1])([F:18])[O:3][C:4]=4[CH:10]=3)[CH2:17][CH2:16]2)=[O:23])[CH:28]=1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
1-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine. The title compound was prepared from 4-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester in analogy with Example 6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Br)=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[S:6](=[O:21])(=[O:20])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:24][Si](C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:24])=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[S:6](=[O:21])(=[O:20])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)(=O)C(C(=O)OCc2ccccc2)=C1Br
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)C(C(=O)OCc2ccccc2)=C1N
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a suspension of 3-ethoxy-4-bromo-5-benzyloxycarbonylisothiazole-1,1-dioxide (1.50 g, 0.0040 mol) in acetonitrile (6 ml) there was added hexamethyldisilazane (0.91 ml, 0.0043 mol). The mixture was heated at 70° for 3.5 hours. Additional hexamethyldisilazane (0.21 ml, 0.0010 mol) was added and the solution stirred at 70° for 1.5 hours. The mixture was then concentrated to dryness in vacuo and the residue dissolved in ethanol (50 ml) and stirred for 15 minutes. The solution was concentrated to dryness in vacuo and the residue recrystallized from ethanol to give the title product (0.95 g, 77%, mp 149°-151°).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].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.Cl[Pd]Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3ccc(Cl)cc3)nc(N3CCCC3)c2)cc1
Yield: 71 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 86 mg (0.55 mmole) 4-chlorphenylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1.5 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 147 mg (71%) pure 4-[2-(4-chloro-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a white solid mp.: 236-237° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20]([O:22]C)=[O:21])(=[O:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20]([OH:22])=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)OC)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)O)[nH]c2cc(Cl)ccc12
Yield: 86 %

Procedure:
Methyl 3-acetylamino-6-chloro-1-(ethoxycarbonyl)indole-2-carboxylate (step 2; 1.48 g, 4.37 mmol) dissolved in ethanol (20 ml) and 1N aqueous KOH (10 ml) were heated together at reflux for 1 h. The mixture was cooled and concentrated, and the residue diluted with 1N aqueous HCl (20 ml) and extracted with ethyl acetate (30 ml×2). The organic extract was dried (MgSO4) and evaporated to afford 0.95 g (86%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][C:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:40]([C:34]2([CH3:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.21 g (1.31 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt of the title compound with ethanolic HCl to yield 0.41 g (86%) of white solid; mp=208-210° C.; MS (+) ESI m/z=470 (M+H)+.
Reaction SMILES: CN(C)C=O.I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC>[Cu]=O.O>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3nccs3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), tri-n-butyl-(thiazol-2-yl)-tin (132 mg), and copper(II) oxide (1.9 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (5.2 mg, yield 12%).