Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][C:21]([NH2:23])=[O:22].O>CN(C=O)C>[O:13]=[C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[O:7][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: NC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
Potassium carbonate (2.67 g, 19.31 mmol) was added to a solution of N-hydroxyphthalimide (3.0 g, 18.39 mmol) in anhydrous DMF (37 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 1 h. The reaction mixture was cooled to 0° C. and 2-bromoacetamide (2.79 g, 20.23 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature overnight. The reaction mixture was poured into rapidly stirring water and the precipitated solid was collected by filtration and dried to afford 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetamide (2.0 g, 49%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ4.63 (2H, s), 7.85-7.88 (4H, m); ESI MS m/z 221 [C10H8N2O4+H]+.
Reaction SMILES: C(OC1C=C2C(C(CO[Si:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([CH3:28])([CH3:27])[CH3:26])CN2S(C)(=O)=O)=CC=1)C1C=CC=CC=1.[CH2:41]([O:48][C:49]1[C:50]2[CH:70]=[CH:69][CH:68]=[CH:67][C:51]=2[C:52]2[CH:53]([CH2:65][OH:66])[CH2:54][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:56]=2[CH:57]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([O:48][C:49]1[C:50]2[CH:70]=[CH:69][CH:68]=[CH:67][C:51]=2[C:52]2[CH:53]([CH2:65][O:66][Si:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:54][N:55]([C:58]([O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:59])[C:56]=2[CH:57]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)[Si](OCC1CN(S(C)(=O)=O)c2cc(OCc3ccccc3)ccc21)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Product: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2c1cc(OCc1ccccc1)c1ccccc21
Yield: 96 %

Procedure:
This was synthesized essentially as described for the Cl based analog in A (1) above from 5-(Benzyloxy)-3-(tert-butyloxycarbonyl)-(hydroxymethyl)-1,2-dihydro-3H-benz[e) indole (synthesized as described in D. L Boger et al., J. Org. Chem., 1992, 57, 2873-2876). The product was obtained as a pale yellow oil (96% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:37]([CH:34]2[CH2:36][CH2:35]2)=[O:38])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(NC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg, 0.24 mmol) and triethylamine (0.17 mL, 1.22 mmol) in tetrahydrofuran (5.0 mL) was added cyclopropanecarbonyl chloride (0.0664 mL, 0.73 mmol) at 0° C. The mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (55.4 mg, 0.116 mmol, 48%) as colorless crystals.
Reaction SMILES: C(Cl)(=O)C.CO.[NH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][C:21]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:45])[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:20]4)=[CH:13][C:11]=2[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:37][C:34]([CH3:36])([CH3:35])[C:33]([N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:22]=[N:23][C:24]3[C:19]([CH:20]=2)=[N:18][C:17]([C:14]2[CH:15]=[CH:16][C:10]4[O:9][C:8]([NH2:7])=[N:12][C:11]=4[CH:13]=2)=[CH:26][CH:25]=3)[CH2:28][CH2:29]1)=[O:45]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Solvent: O
Product: CC(C)(N)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Acetyl chloride (4.3 mL, 60.5 mmol) was added to MeOH (11 mL) at 0° C., the resulting solution was stirred at 0° C. for 30 min. To this solution, tert-butyl (1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-21) (85 mg, 0.16 mmol, 1.0 eq) was added, and the mixture was stirred at RT for 2 h. The reaction was complete based on TLC analysis. The mixture was diluted with water (20 mL), neutralized with solid Na2CO3 (about 3.5 g) to adjust pH value to 8-9, and extracted with CH2Cl2 (6×30 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (11% MeOH/CH2Cl2) to afford the desired product, 2-amino-1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methylpropan-1-one (43) (43 mg, 62.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.96 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.12-8.09 (m, 2H), 7.92 (d, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.60-7.47 (m, 3H), 4.01 (m, 4H), 3.42 (m, 4H), 1.347 (s, 6H); ESI-MS m/z: 432.21[M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:18]1[CH2:17][CH:16]2[CH2:20][C:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:21])[C:5](=[O:22])[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:12]4=[CH:11][CH:10]=3)=[CH:14][CH:15]2[CH2:19]1)(=[O:36])[CH3:35]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2C=C(c3ccc4c(n3)n(C)c(=O)n4CC(C)(C)C)CC2C1
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4, 100 mg, 0.30 mmol, 1.0 equiv), and DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) were added to anhydrous methylene chloride (3 mL) Stirred for 5 min and acetyl chloride (26.5 mg, 0.33 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 9-1 as a pale yellow oil. MS m/z (M+H): calculated=369.2287; observed=369.2298.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:26][C:27]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=4[N:29]=3)=[CH:23][CH:24]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(I)c([N+](=O)[O-])c4)cc3)sc2c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 4-iodo-3-nitrobenzoic acid (0.286 g, 0.976 mmol) and thionyl chloride (5 ml) was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride, 2-(4-aminophenyl)-6-methoxybenzothiazole (0.25 g, 0.976 mmol) and Hunig's base (0.151 g, 1.17 mmol) in dry THF (10 ml) to give the title compound (0.403 g, 78%) as a yellow solid after work-up.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[C:25]([F:33])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[C:25]([F:33])=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc(Cl)c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(Cl)c4F)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chloro-2-fluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2,2′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 3%): m/z (ES+) 417 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.70 g, 2.6 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.60 g, 2.9 mmol) and potassium carbonate (0.48 g, 3.5 mmol). The product was isolated as a white granular solid. Yield 220 mg (19%). mp 224°-227° C. FDMS m/e=439 (M+ of free base).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1>CN(C)C=O>[N+:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(OCCCl)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCn2ccnc2)c1
Reaction time: 8 h

Procedure:
After dissolving 3.74 g. of imidazole in 60 ml. of dry N,N-dimethylformamide, 1.78 g. of 50% sodium hydride in oil was added. When the effervescence had stopped (circa 1 hr.), 7.35 g. of 1-(2-chloroethoxy)-3-nitrobenzene was added. After stirring overnight, the reaction was concentrated under vacuum. Water was added to the residue and the product was extracted into chloroform. The product was extracted out of the chloroform layer with dilute hydrochloric acid. Next, the aqueous acid layer was neutralized with potassium carbonate and the oily product extracted into chloroform. Upon drying the chloroform extract with sodium sulfate, it was concentrated under vacuum to an oil which crystallized on standing. Recrystallization from isopropyl acetate gave 6.12 g. of product as the monohydrate, m.p. 52.5°-55.5° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCCCC2)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light red solid (77%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][C:56]1[CH:61]=[C:60]([C:62](O)=[O:63])[CH:59]=[CH:58][N:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:55][C:56]1[CH:61]=[C:60]([C:62]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:63])[CH:59]=[CH:58][N:57]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 2-methyl-4-pyridinecarboxylic acid (46.6 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.02 mmol). The reaction mixture was stirred for 2 hours at room temperature. Reaction mixture was transferred to a 100 ml round bottom flask and was reduced to dryness in vacuo. The residue was dissolved in DCM (50 ml) and was transferred to a separating funnel then washed with saturated NaHCO3 solution (5 ml), twice. The organic layer was collected and dried with magnesium sulphate. The solid was removed by filtration and the filtrate collected in a 250 ml round bottom flask and reduced to dryness in vacuo. The residue was then dissolved in 1.8 ml 1:1 MeCN/DMSO and purified by MDAP in 2 batches. The fractions containing desired product were combined in a 250 ml round bottom flask and reduced in vacuo to yield the title compound (81 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:15]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: COc1cc(C#N)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C#N)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in oil,(4.8 g; 0.11 mol) in 40 mL of DMF, a solution of 4-hydroxy-3-methoxy-benzonitrile (14.9 g; 0.1 mol) in DMF (40 mL) was added dropwise over 10 minutes. After addition, the reaction mixture was stirred at ambient temperature for 30 minutes, then bromohexane (16.5 g; 0.1 mol) in DMF (20 mL) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The DMF containing reaction mixture was concentrated to a residue, and H2O (100 mL) was added to the residue. The solid was collected by filtration to obtain 8.2 g (35% yield) of the tide compound as white solid. 1H-NMR (DMSO-d6; 200 MHz) δ7.45 (s, 1H), 7.42 (s, 1H), 7.1 (d, 1H), 4.0 (t, 2H), 3.8 (s, 3H), 1.6-1.8 (m, 2H), 1.2-1.5 (m, 8H), and 0.9 ppm (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44]>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][Br:44]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(-c2c(CO)c(C)nc3sc4c(c23)CCCC4)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2c(CBr)c(C)nc3sc4c(c23)CCCC4)cc1
Reaction time: 21 h
Yield: 80.2 %

Procedure:
To a solution of (2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methanol (0.323 g; 1 mmol) in dry dichloromethane (5 mL) were added triphenylphosphine (0.314 g; 1.2 mmol) and carbon tetrabromide (0.431 g; 1.3 mmol). The resulting solution was stirred for 21 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (1-30%) in heptane to afford 0.310 g (80%) of the title compound as a white solid.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH:10]1([CH2:13][CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH:10]1([CH2:13][CH:14]([O:20][S:22]([CH3:21])(=[O:24])=[O:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C(O)CC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(CC1CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 2 ml (11.5 mmol, 2.4 eq.) of N-ethyl-N-(propan-2-yl)propan-2-amine were added to a solution of 1.9 g (purity 40%, 4.8 mmol) of ethyl 3-cyclopropyl-2-hydroxypropanoate (racemate) in 100 ml of dichloromethane, followed by the quick addition, at 0° C., of 0.45 ml (5.8 mmol, 1.2 eq.) of methanesulphonyl chloride. The reaction mixture was stirred at RT for 2 h and then quenched with ice. After phase separation, the organic phase was washed with three times with water and once with saturated sodium chloride solution. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:23](=[O:22])[CH2:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (150 mg, 0.58 mmol) according to the general procedure M. Obtained as a beige solid (160 mg).
Reaction SMILES: [Cl-].C([P+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Cl:31][SiH:32]([Cl:34])[Cl:33]>>[CH2:23]([Si:32]([Cl:34])([Cl:33])[Cl:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCCCCCCCCl
Agent: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Product: CCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 170 °C
Yield: 87 %

Procedure:
In a 25 ml oven dried stainless steel tube, 0.22 g (0.67 mmol) of benzyltributylphosphonium chloride, 1.00 g (6.73 mmol) of 1-chlorooctane, and 2.71 g (20.0 mmol) of trichlorosilane were added under a dry nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 170° C. for 2 hrs. The resulting mixture was distilled to yield 1.45 g of n-octyltrichlorosilane (yield; 87%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:9]=2[CH:27]=1)[CH3:3].FC(F)(F)C(O)=O>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:9]=2[CH:27]=1)[CH3:1]
Reactant: CC(C)Oc1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 1,1-dimethylethyl 4-{6-[(1-methylethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D49, 351 mg, 0.93 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) and stirred under argon for 1 hr. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate (×3). The combined extract was concentrated under vacuum to leave the title compound as an orange oil (229 mg, 89%). M++H=276.1.
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=2)=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2>C(O)(=O)C>[Br:1][C:6]1[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[S:3][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=1
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nccc(-c2sc3ccccc3c2Br)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
Bromine (0.48 g, 3.02 mmol)was slowly added at rt to a mixture of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (0.73 g, 2.52 mmol) in acetic acid (20 mL). The resulting mixture was stirred at rt for 15 h and then heated at 60° C. for 5 h. After cooling to rt, acetic acid was removed in vacuo. 100 mL of saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane 3×100 mL). ). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the solid treated with 20 mL of methanol, filtered and dried to give the title compound (0.75 g, 80%). MS (M+H)+ 369/371.