Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15]C(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:46])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)([C:50]([F:53])([F:52])[F:51])=O>C(Cl)Cl>[N:40]1([C:36]2[CH:35]=[C:34]([C:30]3[CH:29]=[C:28]([C:27]4[CH2:26][C:25](=[O:46])[NH:24][C:9]5[CH:10]=[C:11]([C:50]([F:53])([F:52])[F:51])[C:12]([O:14][CH2:15][C:50]([F:53])([F:52])[F:51])=[CH:13][C:8]=5[N:7]=4)[CH:33]=[CH:32][CH:31]=3)[CH:39]=[CH:38][N:37]=2)[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(N4CCCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M293) (376 mg, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (111 mg, 33%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>ClCCl>[CH2:1]([C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[N:5]=[C:19]=[S:20])[CH3:2]
Reactant: CCc1cc(OC)ccc1N
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(OC)ccc1N=C=S
Temperature: 0 °C
Yield: 83.3 %

Procedure:
To solution of 2-ethyl-4-methoxyaniline (4.5 g, 30 mmol) and triethylamine (6.0 g, 60 mmol) in dichloromethane (31 mL) was added thiophosgene (3.4 g, 30 mmol) was added drop wise at 0° C. over the period of 1 hour. After completion, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3×200 mL) and washed with ice water (2×100 mL), followed by brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by flash column chromatography using 0-10% ethyl acetate/hexanes as eluent provided 2-ethyl-1-isothiocyanato-4-methoxybenzene as yellow oil (4.9 g, 25 mmol), which was taken onto the next step immediately.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[N:8]([N:12]=[CH:13][CH:14]=2)[C:9](=[O:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:15]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:15][C:14]1[CH:13]=[N:12][N:8]2[C:9](=[O:11])[N:10]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH:6][C:7]=12
Reactant: BrBr
Reactant: CCCCc1nc(=O)n2nccc2[nH]1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(=O)n2ncc(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4.0 g of the product of Example 15 in 25 ml of 3:1 chloroform-acetic acid is added 1.5 ml of bromine. The reaction mixture is stirred at room temperature for 4 hours. The chloroform is removed in vacuo and the residue diluted with ice water. The resulting solid is collected, washed with water and dried to give 3.5 g of the desired product as a brown solid, m.p. 188° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]=[C:6]2[NH:12][CH:13]=[CH:14][C:5]=12.Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]=[C:6]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:14][C:5]=12
Reactant: COc1ncc2[nH]ccc2c1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc2c(ccn2COCC[Si](C)(C)C)c1Br
Temperature: 23 °C

Procedure:
To a suspension of NaH (0.238 g, 5.95 mmol, 1.3 eq, 60%) in THF at 0° C. was added a solution of 4-Bromo-5-methoxy-1H-pyrrolo[2,3-c]pyridine (1.05 g, 4.62 mmol) in THF and the solution stirred until no effervescence was observed (approx. 5 minutes). To the reaction mixture was added (2-Chloromethoxy-ethyl)-trimethyl-silane (1.00 mL, 5.64 mmol, 1.2 eq) and the solution was warmed to 23° C. and stirred for 16 hr. The reaction was quenched using sat'd NaHCO3 (aq) and most of the THF removed under reduced pressure. The aqueous layer was partitioned between EtOAc (100 mL), the organic layer washed with water, brine, dried, and concentrated. The crude reaction was purified using chromatography eluting with 20% EtOAc/Heptane giving 4-Bromo-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridine beige crystalline product (0.950 g, 2.53 mmol, 55%). MS ESI m/z 359.2 (M+2H)+. 1NMR (400 MHz, CDCl3) δ 8.46 (d, J=0.6 Hz 1H), 8.36 (s, 1H), 7.39 (d, J=3.2 Hz, 1H), 6.54 (dd, J=3.2 Hz, 0.6 Hz, 1H), 5.51 (s, 2H), 4.14 (s, 3H), 3.51 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH2:33][C:32]([CH2:34]Br)=[CH:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH2:33][C:32]([CH2:34][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:31][CH2:30]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2=CCC(CO)C2)c(=O)[nH]c1=O
Yield: 21.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound. (52 mg)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Product: COc1ccc(Nc2cc(N3CCCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Temperature: 160 °C
Yield: 15.1 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.3 g, 4.24 mmol) and tert-butyl piperidin-3-ylcarbamate (3.4 g, 16.99 mmol) was heated to 160° C. for 2 h. The residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=120:1) to give the tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamate (300 mg, 15%) as brown solid. LC-MS: 470 [M+1]+, tR=1.44 min
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:14]([O:13][C:9]([NH:10]/[N:11]=[CH:1]/[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCCCC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCCCC/C=N/NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of 46 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was added ground molecular sieves (115 mg, 3A). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred over night. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase washed with brine, saturated NaHCO3, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the water phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene/ethyl acetate 9:1 with 1% triethylamine and toluene/ethyl acetate 6:1 with 1% triethylamine) provided 47 (85 mg, 61%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[N:13]1([C:7]([C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=2)=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
Commercially available 5,6-dichloronicotinic acid (200 mg, 1.04 mmol) was dissolved in dichloromethane (5.0 mL), and azetidine hydrochloride (125 mg, 1.34 mmol), HATU (440 mg, 1.16 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.58 mmol) were added, followed by stirring at room temperature for 5 hours under nitrogen atmosphere. 0.5N hydrochloric acid (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (162 mg, yield 67%) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[CH:33]=[C:32]([Cl:38])[C:31]([Cl:39])=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[C:31]([Cl:39])[C:32]([Cl:38])=[CH:33][C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over-Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.12 g of impure product. Then, crystallization from EtOAc/heptane gave 91 mg (39%) of a white solid: mp 172.5° C.; IR (diffuse reflectance) 3288, 1699, 1661, 1602, 1550, 1498, 1472, 1442, 1421, 1367, 1309, 1298, 1268, 1252, 1162 cm−1; MS (CI) m/z 488 (M+H+), 390, 388, 354, 153, 152, 136, 95, 93, 52, 51; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.49; H, 5.67; N 8.51.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:38]1[CH2:43][CH2:42][CH:41]([C:44](=[S:46])[NH2:45])[CH2:40][CH2:39]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:46][C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[N:45][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: NC(=S)C1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (5.00 g, 11.3 mmol) in DMA (47.2 mL) was added NBS (2.115 g, 11.88 mmol). The reaction stirred 30 min at rt and then tetrahydro-2H-pyran-4-carbothioamide (2.137 g, 14.71 mmol) was added. The reaction stirred 16 h at rt. The reaction mixture was poured into water (500 mL), causing precipitation of a solid. The solid was collected by vacuum filtration, re-dissolved in EtOAc (200 mL), and concentrated onto silica gel. Purification by ISCO chromatography (20 to 100% EtOAc:hexanes) afforded the title compound (3.58 g, 5.87 mmol, 51.9% yield) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.58-7.79 (m, 1H), 7.38-7.52 (m, 2H), 7.33 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.87 (d, J=5.1 Hz, 1H), 3.84-4.00 (m, 2H), 3.41-3.54 (m, 2H), 3.31-3.39 (m, 1H), 1.92-2.13 (m, 2H), 1.66-1.91 (m, 2H); m/z (ESI): 567.03 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCOCC1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCOCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea and methyl thioglycolate
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: BrCCCCBr
Reactant: Oc1cccc2ncccc12
Product: BrCCCCOc1cccc2ncccc12
Yield: 40.4 %

Procedure:
Following the same procedure as in Example 32-(a), reaction and treatment were carried out using 1.0 g of 5-hydroxyquinoline and 2.3 g of 1,4-dibromobutane to obtain 0.78 g of 5-(4-bromobutoxy)quinoline. Furthermore, the same procedure as in Example 32-(b) was repeated with the exception that 0.78 g of N-diphenylmethylpiperazine was used, in order to perform reaction and treatment, so that 0.8 g of the desired compound was obtained.
Reaction SMILES: [CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15](Br)=[CH:14][C:12]=2[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C[O:25][B:26](OC)[O:27]C.Cl>CCCCCC.O1CCCC1>[CH2:1]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([B:26]([OH:27])[OH:25])=[CH:14][C:12]=2[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COB(OC)OC
Reactant: CCCCCCCCc1cc2cc(Br)ccc2o1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc2cc(B(O)O)ccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
In a 500 ml-three-necked flask, 19.0 g (61.5 mM) of 2-octyl-5-bromobenzofuran (II) and 190 ml of anhydrous tetrahydrofuran (THF) were placed. To the mixture, 45 ml (72.0 mM) of 1.6M-n-butyllithium solution in hexane was added dropwise under argon stream at −70° C. or below in 30 min., followed by stirring at that temperature for 4 hours. To the resultant mixture, a solution of 17.8 g (171 mM) of trimethylborate in 70 ml of anhydrous THF was added dropwise at −70° C. or below in 20 min., and stirred at that temperature for 2 hours. The system was heated up to room temperature and stirred for 17 hours. To the reaction mixture, 100 ml of 10%-hydrochloric acid was added dropwise, followed by extraction with ether. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain a white crystal of 2-octylbenzofuran-5-boronic acid (III) (Yield: 10.8 g (64.1%)).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([N:17]([CH:21]([CH:27]2[CH2:29][CH2:28]2)[C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)[CH2:18][CH2:19][CH3:20])[S:14][C:15]=1[CH3:16].[CH3:30]I>CC(C)=O.ClCCl>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([N:17]([CH:21]([CH:27]2[CH2:29][CH2:28]2)[C:22]2[N:23]=[CH:24][N:25]([CH3:30])[CH:26]=2)[CH2:18][CH2:19][CH3:20])[S:14][C:15]=1[CH3:16]
Reactant: CI
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1c[nH]cn1)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1cn(C)cn1)C1CC1
Reaction time: 0.08 h

Procedure:
Add 570 mg of powdered potassium hydroxide to 856 mg of the compound of Example 42 dissolved in 10 ml of acetone. Stir for 5 minutes and then add 0.14 ml of methyl iodide. After 15 minutes at room temperature, dilute the reaction mixture in 100 ml of dichloromethane, and then wash with water and with water saturated with sodium chloride. Dry the organic phase over sodium sulphate, evaporate to dryness and then subject the residue to chromatography on a silica column, using a mixture of cyclohexane and ethyl acetate (1:1 V/V) as eluent.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 134; 120 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, quinoline-3-carboxaldehyde (39.3 mg, 0.25 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated sodium bicarbonate solution (5 mL) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (50% ethyl acetate/hexanes) to give rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (93 mg, 75% yield) as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][CH2:41][C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:40])[CH2:42][OH:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: COC([N:5]1[C:9]2=[N:10][C:11]([Cl:15])=[CH:12][C:13](Cl)=[C:8]2[C:7]([CH3:16])=[CH:6]1)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([F:31])[CH:25]=1.C(OCC)(=O)C>CS(C)=O>[Cl:15][C:11]1[N:10]=[C:9]2[NH:5][CH:6]=[C:7]([CH3:16])[C:8]2=[C:13]([O:30][C:27]2[CH:28]=[CH:29][C:24]([NH2:23])=[CH:25][C:26]=2[F:31])[CH:12]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: COC(=O)n1cc(C)c2c(Cl)cc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c[nH]c2nc(Cl)cc(Oc3ccc(N)cc3F)c12
Temperature: 120 °C

Procedure:
300 mg (1.16 mmol) of methyl-4,6-dichloro-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate and 320 mg (2.32 mmol) of powdered potassium carbonate are suspended in 9 ml of DMSO. The mixture is degassed, and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120° C. for 4 hours. After addition of ethyl acetate, the mixture is filtered off with suction through Celite®, and the celite is washed with ethyl acetate. The filtrate is shaken three times with saturated sodium bicarbonate solution and with saturated sodium chloride solution. The filtrate is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane/methanol=50:1).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[C:19]1([S:25]([O-:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>CC#N>[C:19]1([S:25]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccn1
Reactant: O=S([O-])c1ccccc1
Agent: Br
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.7 %

Procedure:
To a stirred suspension of 2.5 g (0.010 mol) of 2-bromomethyl-pyridine hydrobromide in 10 mL of CH3CN at RT, was added 1.78 mL (0.0105 mol, 1.05 eq.) of Hunig's base. After complete dissolution of the salt, 1.62 g (0.010 mol, 1 eq.) of sodium benzene sulfinat and 0.52 g (0.002 mol, 0.2 eq.) were added. The mixture was stirred at RT for 48 hours, and then the reaction was quenched by addition of water, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and dried under vacuum to afford 1.86 g (80%) of 2-benzenesulfonylmethyl-pyridine.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCCC.CS(C)=O>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]2([O:22][CH2:4]2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCCC
Product: c1ccc(CN2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (55% suspension in mineral oil, 1.57 g, 35 mmol) was washed with heptane, dried in the stream of nitrogen and suspended in dry DMSO (10 ml). A solution of trimethylsulfoxonium iodide (4.8 g, 22 mmol) in DMSO (45 ml) was added dropwise under nitrogen. After stirring for 20 min a solution of 1-benzylpiperidin-4-one (3.78 g, 20 mmol) was added dropwise. The mixture was stirred overnight at room temperature, then poured over ice (200 g), and extracted with dichloromethane (2×200 ml). The combined extracts were washed with water (3×100 ml) and dried over Na2SO4. The solvent was removed i. vacuo. The residue was dissolved in diethyl ether, and the insoluble material was removed by filtration. Evaporation of solven afforded pale-yellow oil (2.95 g, 73%).