Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[I:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: OCCCI
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: ICCCOC1CCCCO1

Procedure:
A solution of 3-iodopropanol (15 g, 80.65 mole), dihydropyran (14.7 ml, 161.29 mole) and pyridium p-toluenesulfonate (500 g, 2.0 mole) in 100 ml of dry dichloromethane was stirred at room temperature under an atmosphere of nitrogen for 2.5 hours. The resulting mixture was diluted with dichloromethane (150 ml), washed with water and a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed on a silica gel to give 20.43 g of title A compound as an oil, with consistent spectral data.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH2:21]([N:23]([CH2:33][CH3:34])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[CH3:22].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C>[CH2:33]([N:23]([CH2:21][CH3:22])[C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:29])=[CH:26][CH:25]=1)[CH3:34]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Yield: 27.7 %

Procedure:
To a solution of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (625 mg) and 4-diethylamino benzoic acid (386 mg) in DMF (12 ml) was added diethyl phosphorocyanidate (489 mg) and then triethylamine (606 mg), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:10% ammonia containing methanol=20:1) to give colorless amorphous of the title compound (250 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.Br.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Br>C1COCC1>[S:1]1[C:2]([CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)CCBr
Agent: Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCc1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a cooled (−78° C.) solution of benzothiophene (74.5 mmol) in anhydrous THF (100 mL) was added slowly n-BuLi (82 mmol, 1.6 M in hexanes). The mixture was stirred at −78° C. for 1 hr. β-Dimethylaminoethyl bromide hydrobromide (41 mmol) was added at −78° C. and the temperature was allowed to reach 0° C. over 5 hours. The mixture was quenched in sat. NH4Cl, the pH of the aqueous layer was adjusted to 7-8 with sat. NaHCO3, and the mixture was extracted with EtOAc (4×). The combined organic layers were concentrated and extracted with 1N HCl (3×). The combined HCl layers were made basic with sat. NaHCO3, extracted with EtOAc (4×), and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford Compound 1a (2-Benzo[b]thiophen-2-yl-ethyl)-dimethyl-amine (4.96 g, 65%) as a tan solid; MS (MH+)=206.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>NC1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: Nc1ccccc1
Solvent: O
Product: Nc1cccc2c(N)cccc12
Temperature: 20 °C
Yield: 55.2 %

Procedure:
60 g (0.275 mol) of 1,5-dinitro naphthalene were suspended, in a 700 ml stirrer autoclave, in 340 ml of aniline and treated with 8 g of water-moist, 5% strength catalyst of palladium on activated charcoal, corresponding to 2.8 g of dry catalyst. Hydrogenation was performed at a temperature of about 100° C. and an initial hydrogen pressure of about 10 bars. As soon as the hydrogen pressure dropped to 5 bars, the hydrogen supply was stepped up until the original value of 10 bars was reattained. After 104 minutes the hydrogen uptake was finished and the reaction over. The catalyst was separated off at about 70° C. by filtration and the filtrate cooled to 20° C. whereupon 1,5-diamino naphthalene crystallized out. The crystallate was then filtered off and washed twice with 50 ml of methanol; 24 g of 1,5-diamino naphthalene were obtained with a m.p. of 189°-190° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[N:23][CH:22]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cncnc1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cncnc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 14.3 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and Pyrimidine-5-carbaldehyde (17.6 mg, 0.163 mmol) were reacted to produce 9.0 mg (14%) of the title compound. mp: >300° C., 1H NMR (300 MHz, DMSO-d6): 13.7 (s, 1H), 9.42 (s, 2H), 9.28 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.35 (m, 1H), 7.23 (s, 1H), 6.39 (d, J=8 Hz, 1H), 5.22 (t, J=8 Hz, 1H), 3.3 (s, 1H), 2.90 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.40 (d, J=9 Hz, 1H). MS: 426, 428 (M+H), HPLC: 1.91 min (G method).
Reaction SMILES: CN(C)[CH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[S:12](=C)[CH:11]=[N:10]3)[NH:5][C:4]1=[O:16].[CH2:18]([OH:20])[CH3:19]>C(OCC)C>[CH3:4][N:5]([C:6]1[CH:14]=[CH:13][C:9]([NH:10]/[CH:11]=[C:3]2\[C:4](=[O:16])[NH:5][C:6]3[C:14]\2=[C:13]2[S:12][CH:11]=[N:10][C:9]2=[CH:8][CH:7]=3)=[CH:8][CH:7]=1)[C:18](=[O:20])[CH3:19]
Reactant: C=S1C=Nc2ccc3c(c21)C(N(C)C)C(=O)N3
Reactant: CCO
Solvent: CCOCC
Product: CC(=O)N(C)c1ccc(N/C=C2\C(=O)Nc3ccc4ncsc4c32)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A mixture of 8-dimethylamino-methylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure E, 0.040 g, 0.163 mmol), 4-amino-N-methylacetanilide (0.040 g, 0.244 mmol) in absolute ethanol (5 ml) was heated with stirring at 90° C. for 16 h. The reaction was diluted with ethanol and diethyl ether and the product collected by filtration to yield 0.038 g (64%) of the title compound. 1H NMR (DMSO-d6): δ 11.03 (d, 1H, J=12.3 Hz), 10.84 (s, 1H), 9.23 (s, 1H), 8.02 (d, 1H, J=12.3 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.48 (d, 2H, J=8.2 Hz), 7.35 (d, 2H, J=8.2 Hz), 7.09 (d, 1H, J=8.4 Hz), 3.11 (s, 3H), 1.76 (s, 3H); ES-MS m/z 363 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:28]([O:27][C:26]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2cccnc2)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc12

Procedure:
To a solution of 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6, 96 mg, 0.40 mmol) in DMF (2 mL) at room temperature is added triethylamine (30 mg, 0.30 mmol), di-tert-butyl carbonate (65 mg, 0.30 mmol) and 4-(N,N-dimethylamino)pyridine (2 mg, 0.020 mmol). The mixture is stirred under N2. The mixture is purified by Xbridge RP18 with a gradient of acetonitrile in 0.1% aqueous ammonium hydroxide to give 5-cyano-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9H), 2.16 (s, 3H), 7.47-7.55 (m, 1H), 7.65 (dd, J=8.7, 1.6 Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.69 (dd, J=5.1, 1.5 Hz, 1H). HRMS (ESI) m/z 334.1566 [(M+H)+ Calcd for C20H20N3O2: 334.1556].
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:52]([F:53])=[CH:51][C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH2:35][C@@H:34]([CH3:38])[C@H:33]2[CH2:39][N:40]2C(=O)C3C(=CC=CC=3)C2=O)=[O:31])=[C:28]([C:54]2[N:59]=[CH:58][CH:57]=[CH:56][N:55]=2)[CH:27]=1>>[NH2:40][CH2:39][C@@H:33]1[C@H:34]([CH3:38])[CH2:35][CH2:36][CH2:37][N:32]1[C:30]([C:29]1[CH:51]=[C:52]([F:53])[C:26]([F:25])=[CH:27][C:28]=1[C:54]1[N:55]=[CH:56][CH:57]=[CH:58][N:59]=1)=[O:31]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(((2S,3R)-1-(4,5-difluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 347 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:15][N:16]([CH3:21])[S:17](Cl)(=[O:19])=[O:18].O>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:21])[S:17]([N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2])(=[O:19])=[O:18]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCc1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1nccn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a stirred solution of 2-ethylimidazole (100 g) and triethylamine (115 g) in chloroform (800 ml) at 0° C. is added a solution of dimethylsulfamoyl chloride (153 g) in chloroform (200 ml). The mixture is stirred overnight at room temperature. Water (1.5 liter) is added to the reaction mixture after which the organic layer is separated and concentrated. The residue is dissolved in ethyl acetate (1 liter) and washed with water, and then dried over sodium sulfate and concentrated. Distillation gives 1-dimethylsulfamoyl-2-ethylimidazole (182 g) as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]([C:34]([NH2:36])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]([C:34]([NH2:36])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: NC(=O)[C@H](CO)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: NC(=O)[C@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (893 mg) in 2-propanol (20 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-serinamide (1.07 g) and piperidinium acetate (195 mg). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (217 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]([CH3:28])[CH2:13][S:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl.CCOCC>C(O)(C)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]([CH3:28])=[C:13]2[S:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1[nH]c2ccc(Br)cc2c1SC1CCNCC1
Reaction time: 4 h
Yield: 57 %

Procedure:
4-Bromophenylhydrazine hydrochloride (11.5 g) is solubilized in a solution of 1,1-dimethylethyl 4-[(2-oxopropyl)thio]piperidine-1-carboxylate (14 g, prepared in Example 11) in isopropanol (100 ml) under nitrogen. The solution is cooled to 0° C. and saturated with gaseous hydrogen chloride. After 4 hours at room temperature, the precipitate is filtered off, taken up in sodium hydroxide and extracted with ether and then with methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. The solid obtained is taken up in the minimum amount of ether and recrystallized from xylene to give 5-bromo-2-methyl-3-(piperidin-4-ylthio)-1H-indole (9.5 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[NH:7]([C:8]1[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccccc2)n1

Procedure:
A mixture comprising 8.6 g of phenylthiourea, 10 g of ethyl bromopyruvate and 100 ml of ethanol was heated under reflux for 3 hours, and the reaction mixture was then concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crystals which formed were collected by filtration. washed with benzene, and then recrystallized from ethanol, giving the desired compound as pale yellow prismatic crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16]>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1cc2c(cn1)OCCN2
Product: COc1c(Br)cc(C(=O)N2CCOc3cnccc32)cc1Br

Procedure:
By the same method as in the step d) of Example 2, 2,3-dihydro-1H-pyrido[3,4-b][1,4]-oxazine (180 mg, 0.587 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (193 mg, 0.587 mmol) were reacted to obtain the target compound 5, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone, as white solid (85 mg, 34%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[BrH:37].N([O-])=O.[Na+].S(=O)(O)[O-].[Na+]>O.CCOC(C)=O.CCCCCC.CCOC(C)=O.C(#N)C>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a 1 L 3-necked flask equipped with a mechanical stirrer was added 6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (10.0 g, 18.9 mmol) followed by acetonitrile (200 mL) and then 48% aqueous HBr (200 mL). A thick, lumpy suspension resulted which was stirred vigorously for 30 minutes to afford a more uniform suspension. The reaction vessel was cooled in an ice water bath for 30 minutes and the mixture treated with a solution of sodium nitrite (1.96 g, 28.4 mmol) in water (20 mL) via addition funnel over 5 minutes. The resulting yellow suspension was stirred in the ice bath for 1.5 hours and then treated with CuBr (4.1 g, 28.4 mmol) in small portions over 5 minutes. This afforded a dark brown solution that was warmed to 60° C. (internal temperature) with continued stirring. After 40 minutes at elevated temperature the mixture was cooled to RT and poured into a rapidly stirred mixture of 5% aqueous sodium bisulfite (600 mL) and EtOAc (800 mL). The phases were separated and the aqueous solution extracted with two additional 150 mL portions of EtOAc. The combined EtOAc solutions were washed with 5% aqueous sodium bisulfite (2×150 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated brine (1×200 mL), dried over sodium sulfate and concentrated to dryness at reduced pressure to give a yellow foam. This material was subjected to flash chromatography (silica gel, gradient from 9:1 hexane/EtOAc to EtOAc). During concentration of the pure fractions a white solid crystallized out. After concentrating down to a thick suspension the mixture was diluted with 150 mL of hexane and the mixture stirred at RT overnight. The solid was collected by filtration in a medium fritted funnel and dried in vacuo to afford the title compound (8.55 g, 76%) as a white crystalline solid. LCMS (m/z, ES+)=591, 593 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([NH:9]C=O)=[CH:6][S:7][CH:8]=1)[CH3:2].Cl>C(O)C>[NH2:9][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:8][S:7][CH:6]=1
Reactant: CCOc1cscc1NC=O
Agent: Cl
Solvent: CCO
Product: CCOc1cscc1N

Procedure:
A mixture of 15.4 g. of N-(4-ethoxy-3-thienyl)formamide in 50 ml. of 2 N ethanolic hydrogen chloride and 90 ml. of ethanol is refluxed on a steam bath for 2 hours, filtered and evaporated to a residue. Water is added to the residue, which is cooled, made alkaline with 5 N sodium hydroxide and extracted with dichloromethane. The extracts are dried over magnesium dulfate, filtered and evaporated giving 3-amino-4-ethoxythiophene as a dark amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:12]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise 4-(hexyloxy)benzoyl chloride (890 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1073 mg) was obtained as a white solid (91%) in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [ClH:1].[C:2]1([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:14]2=[O:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[ClH:1].[C:2]1([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:14]2=[O:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(Cc3cccc4ccccc34)C2=O)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C1N(Cc2cccc3ccccc23)CCCC12CCNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
HCl (4M in dioxane, 5 ml) was added to a solution of tert-butyl 2-(naphthalen-1-ylmethyl)-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (377 mg, 0.9 mmol) in CH2Cl2 (2 ml) and the mixture was stirred at rt for 18 h. The volatiles were evaporated to afford 270 mg (87%) of crude 2-(naphthalen-1-ylmethyl)-2,9-diazaspiro[5.5]undecan-1-one hydrochloride, which was used without further purification.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:40]([Cl:41])=[CH:39][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23]CC5C=CC=CC=5)=[O:22])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:40]([Cl:41])=[CH:39][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=[O:22])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(OC2CCCC(C(=O)OCc3ccccc3)C2)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)C1
Temperature: 80 °C

Procedure:
To a solution of benzyl 3-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (isomer A from Step A, 0.075 g, 0.112 mmol) in 1.1 mL of THF was added TBAF (0.675 mL, 0.675 mmol) dropwise via syringe. The reaction was heated at 80° C. for 16 h, and then diluted with EtOAc (50 mL) and washed with 2 N HCl (2×20 mL). The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O) afforded the title compound as a white solid. LCMS: calculated for C26H23ClN2O3 446.93, observed m/e 446.92M+ (Rt 2.19/4 min). 1H NMR (500 MHz, CD3OD): δ7.71-7.64 (m, 4H), 7.55 (brs, 1H), 7.50 (d, 2H), 7.48-7.43 (m, 2H), 7.39 (brs, 1H), 7.37-7.32 (m, 1H), 5.00-4.91 (m, 1H), 2.60-2.46 (m, 2H), 2.33-2.24 (m, 1H), 2.06-1.95 (m, 2H), 1.79-1.67 (m, 1H), 1.64-1.49 (m, 2H), 1.49-1.37 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([Li])[CH:6]=[C:5]([CH3:7])[C:4]([CH3:8])=[C:3]1[CH3:9].[CH3:11][Si:12]([CH3:15])(Cl)Cl>>[CH3:11][Si:12]([CH3:15])([CH:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]([CH3:9])=[C:2]1[CH3:1])[CH:6]1[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]([CH3:8])=[C:5]1[CH3:7]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1(C)C=C(C)C(C)=C1C
Product: CC1=C(C)C([Si](C)(C)C2C(C)=C(C)C(C)=C2C)C(C)=C1C
Yield: 65 %

Procedure:
In "Chem. Berichte" 119 1750 (1986) , a solution containing 1,2,3,4-tetramethylcyclopentadienyl lithium and dimethyldichlorosilane is heated for 5 days to obtain dimethylbis(2,3,4,5-tetramethylcyclopentadienyl)silane in a 65% yield.
Reaction SMILES: C1(C=CC=C(O)C=1)O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[O:18])=[CH:12][CH:11]=1.BrC1C=CC(C[C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]=2O)=[O:29])=CC=1.C([O-])=O>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:28](=[O:29])[C:30]3[C:31](=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=3)[O:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: O=C(Cc1ccc(Br)cc1)c1ccc(O)cc1O
Agent: O=C[O-]
Agent: Oc1cccc(O)c1
Product: O=c1c(-c2ccc(Br)cc2)coc2cc(O)ccc12

Procedure:
Resorcinol is reacted with 2-(4-bromophenyl)acetyl chloride forming the product 2-(4-bromophenyl)-1-(2,4-dihydroxyphenyl)ethanone. Such reactions are described in Chemistry of Heterocyclic Compounds (NY, N.Y., USA) 1977 Vol., 13, p. 948-953. The product is reacted with triethylorth formate to form 3-(4-bromophenyl)-7-hydroxy-chromen-4-one which can be reacted with methane sulfonyl chloride and a base to form [3-(4-bromophenyl)-4-oxo-chromen-7-yl] methanesulfonate.