Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C.O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][NH:22][C:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][CH2:30][O:40][C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:41])[F:42])[CH:35]=5)=[CH:6][CH:7]=4)[CH:12]=[N:13][C:14]=3[CH:19]=2)=[O:21])[CH:25]=1
Reactant: CC(Cl)COc1ccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)cc1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCCCOc2cccc(OC(F)(F)F)c2)cc1

Procedure:
1-[4-(2-Chloropropoxy)phenyl]-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (prepared as described above using 1-(4-hydroxyphenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as phenol and 1-bromo-3-chloropropane as alkylating agent) (100 mg, 0.24 mmol), 3-trifluoromethoxyphenol (42 mg, 31 μL 0.24 mmol) and potassium carbonate (36 mg, 0.26 mmol) were suspended in acetonitrile (2 mL), DMF (1 mL), and water (0.5 mL) and the mixture stirred at 60° C. for 18 h. The reaction mixture was then concentrated in vacuo and purified by reverse-phase preparative HPLC to give N-pyridin-3-ylmethyl-1-(4-{3-[3-(trifluoromethoxy) phenoxy]propoxy}phenyl)-1H-benzimidazole-5-carboxamide. 1H NMR (CDCl3, 400 MHz): δ 8.66 (d, J=2.0 Hz, 1H), 8.56 (dd, J=4.8, 1.2 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.05 (s, 1H), 7.90 (dd, J=8.4, 1.6 Hz, 1H), 7.78 (ddd, J=8.0, 2.0, 2.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.43-7.37 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.08 (m, 3H), 6.90-6.78 (m, 3H), 4.75 (d, J=5.6 Hz, 2H), 4.27 (t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.35 (quin, J=6.0 Hz, 2H); MS (ES+): m/z 563 [MH+]
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[CH3:22][C:23]1[CH:24]=[C:25]([SH:30])[CH:26]=[CH:27][C:28]=1[CH3:29]>>[CH3:22][C:23]1[CH:24]=[C:25]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1ccc(S)cc1C
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(C)c(C)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[F:18][C:19]1[CH:31]=[C:30]([O:32][C:33]([F:34])([F:36])[F:35])[CH:29]=[CH:28][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:26][CH2:27]1
Reactant: Fc1cc(OC(F)(F)F)ccc1OC1CCNCC1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)cc2F)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 50.9 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(2-fluoro-4-(trifluoromethoxy)phenoxy)piperidine (279 mg, 1.0 mmol) as crude materials, 128 mg title compound was generated and yield was 51%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][CH2:22][CH2:23]2)[C@H:19]1[CH2:26][OH:27])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][CH2:22][CH2:23]2)[C@H:19]1[CH:26]=[O:27])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C=O
Reaction time: 0.17 h

Procedure:
To a cold (−60° C.) solution of oxalyl chloride (0.14 mL, 1.2 eq) in dry DCM (3.7 mL) was added dropwise a solution of DMSO (0.215 mL, 2.2 eq) in dry DCM (2.9 mL) within 4 min. After 10 min, was added dropwise (1S,2S,5R)-2-hydroxymethyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (330 mg) in dry DCM (1.7 mL) during 5 min. After 2 min a white suspension was formed. Stirring was continued 30 min at −55° C., then DIPEA (1.17 mL, 5 eq) (which was dried over 3A M.S.) was added during 3-4 min. The reaction mixture was allowed to come to RT, diluted with water and extracted with DCM. The combined org. extracts were washed with citric acid (5%), brine, dried over anh. MgSO4, filtered and evaporated to yield the title compound as an oil which was used for the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:46]([C:48]1[N:49]=[C:50]([C:61]([O-])=[O:62])[N:51]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:52]=1)#[N:47].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=2[NH:14][C:61]([C:50]2[N:51]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:52]=[C:48]([C:46]#[N:47])[N:49]=2)=[O:62])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CNS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 123 mg (0.418 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 292 mg (0.627 mmol) of PyBroP, 140 mg (0.460 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 218 μL (1.25 mmol) of DIEA. The mixture was stirred at RT for 2 h, diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 177 (71%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C26H37N5O4SSi, 544.2 (M+H). found 543.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:19]=[C:12]2[CH:13]=[CH:14][C:15]([CH2:17]O)=[CH:16][N:11]2[N:10]=1.O=S(Cl)[Cl:22]>>[Cl:22][CH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])[N:19]=2)[CH:16]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(CO)cn2n1
Reactant: O=S(Cl)Cl
Product: Cc1cccc(C)c1-c1nc2ccc(CCl)cn2n1
Yield: 100 %

Procedure:
A solution of [2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol (0.17 g, 0.67 mmol) in SOCl2(2.0 mL) is stirred for 2 hours at room temperature. The reaction mixture is evaporated to dryness and co-distilled with toluene to give the title compound as a yellow solid (0.198 g, 100% crude) which is used without further purification. LCMS m/z 272 (M+H)+.
Reaction SMILES: [CH3:1][O-].[Na+].[I-].C[S+](C)(C)=O.[CH3:10][C:11]([C:14]([CH2:16][N:17]1[N:21]=[CH:20][N:19]=[CH:18]1)=[O:15])([CH3:13])[CH3:12]>CS(C)=O.O1CCCC1>[C:11]([C:14]1([CH2:16][N:17]2[CH:18]=[N:19][CH:20]=[N:21]2)[CH2:1][O:15]1)([CH3:10])([CH3:12])[CH3:13]
Reactant: C[O-]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(Cn2cncn2)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
6 g (0.11 mol) of sodium methylate were introduced in portions into a suspension of 24 g (0.11 mol) of trimethylsulphoxonium iodide in 24 g of dimethylsulphoxide. 10 ml of tetrahydrofuran were also added, and the reaction mixture was then stirred for 5 hours at room temperature. Thereafter, a solution of 16.8 g (0.1 mol) of 1,2,4-triazol-1-yl-pinacolin in 100 ml of tetrahydrofuran was added dropwise, and the mixture was heated at 70° C. for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform, and the solution was washed with water, dried over sodium sulphate, filtered and concentrated. 13.8 g of a 69.4% pure 2-tert.-butyl-2-(1,2,4-triazol-1-yl-methyl)-oxirane of refractive index nD20 =1.4872 were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:38][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 2-methyl-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester, Example 24 (1.0 g, 3.48 mmol) in dry carbon tetrachloride (50 mL) was added 126 mg (0.52 mmol) of benzoyl peroxide and 712 mg (4.0 mmol) of recrystallized N-bromosuccinimide. A reflux condensor was attached and the mixture was heated to reflux and stirred overnight. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (250 mL) and washed with water, followed by saturated sodium bicarbonate, and then brine. The organic layer was dried (MgSO4) and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography using 10% ethyl acetate in hexanes gave 560 mg (44%) of the title compound as a white solid: 1HNMR (CDCl3): d 8.83 (d, J=2 Hz, 1H), 8.48 (dd, J=2 Hz, 9 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 4.96 (s, 2H), 3.85 (s, 2H), 1.0 (s, 9H); MS (ES-NEG): [M−H] 364/366; Anal. Calc. for C12H16BrNO5S: C, 39.35; H, 4.40; N, 3.82. Found: C, 39.88; H, 4.16; N, 3.85.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[CH2:17](S)[CH2:18][CH2:19]C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([S:8][CH2:10][CH2:17][CH2:18][CH3:19])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCCCS
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCSc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, butanethiol and DBU in dioxane. EI-MS m/e (%): 329 (M{81Br}+, 29), 327 (M{79Br}+, 28), 287 ([M{81Br}-C3H6]+, 46), 285 ([M{79Br}—C3H6]+, 45), ), 273 ([M{81Br}—C4H8]+, 98), 271 ([M{79Br}—C4H8]+, 99), 248 ([M—Br]+, 54), 206 (100), 192 (34), 117 (34).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH2:36])=[CH:34][C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=4[F:22])[C:3]=3[CH3:23])=[CH:34][C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinoline (150.0 mg, 0.45 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.58 (1H, dd, J=6.2, 2.8 Hz), 8.39 (1H, ddd, J=9.0, 4.3, 2.9 Hz), 7.89 (1H, dd, J=9.0, 5.9 Hz), 7.79 (1H, dd, J=9.8, 2.5 Hz), 7.64 (1H, d, J=2.7 Hz), 7.32-7.44 (2H, m), 6.90 (1H, br. s.), 6.26 (1H, d, J=1.2 Hz), 3.94 (4H, t, J=4.6 Hz), 3.69-3.85 (4H, m), 3.13-3.32 (4H, m), 2.90-3.03 (4H, m), 2.19 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=563.3 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)(O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (S)--N--(benzyloxycarbonyl)leucine methyl ester (8.22 g, 29.4 mmol) in dry toluene (80 ml) was treated dropwise at -78° C. with a solution of di-iso-butylaluminium hydride (1.0 M, 74 ml, 74 mmol) in toluene. The solution was stirred at -78° C. for 30 min. before methanol (3.5 ml) was added to quench the reaction. The cold mixture was then added to a stirred aqueous solution of potassium hydrogen tartrate (200 ml). After further stirring for 1 hour the mixture was extracted with ether (3×200 ml), the combined extracts washed with brine (400 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound as a colourless oil. This material was used without purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:23])[CH2:19][CH2:20][C:21]#[CH:22].Cl>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][OH:23])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Agent: [Cu]I
Agent: [Pd]
Agent: Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)n1ccc2cc(C#CCCCO)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
To 3.73 g (12.5 mmol) 5-Bromo-indole-1-carboxylic acid tert-butyl ester in 25 ml piperidine were added 722 mg (0.63 mmol) tetrakis-(triphenylphosphine)-palladium and 120 mg (0.625 mmol) CuI. The solution was purged with argon, and was heated to 80° C. over a period of 45 min, during which 0.9 ml (9.4 mmol) 4-pentynol were added. Additional 0.9 ml (9.4 mmol) 4-pentynol were added and the mixture was stirred at 80° C. for 2 h, poured on ice water and 2M HCl was added. The inorganic phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Purification on silica gel yielded 2.9 g (77%) 5-(5-Hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butyl ester as brown oil, MS: 299 (M).
Reaction SMILES: CO[CH:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[N:5][CH2:4]1.Br>>[S:7]1[CH:3]=[CH:4][N:5]=[C:6]1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COC1CN=C(N2CCN(c3ccc(O)cc3)CC2)S1
Agent: Br
Product: Oc1ccc(N2CCN(c3nccs3)CC2)cc1
Yield: 68 %

Procedure:
A mixture of 4 parts of 4-[4-(4,5-dihydro-5-methoxy-2-thiazolyl)-1-piperazinyl]phenol and 150 parts of a hydrobromic acid solution 48% is stirred and refluxed for 12 hours. The reaction mixture is evaporated and the residue is dissolved in water. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2.5 parts (68%) of 4-[4-(2-thiazolyl)-1-piperazinyl]phenol; mp. 169.9° C.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]3[CH2:40][O:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]3[CH2:40][O:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc3c(c2)CCC3)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc2c(c1)CCC2)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 65 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2,3-dihydro-1H-inden-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (62.6 mg, 0.110 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 30.7 mg (65%) of the title compound. LC-MS: RT=4.79 min, [M+H]+=353.2.
Reaction SMILES: CO.[Cl:3][C:4]1[N:12]=[C:11](Cl)[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].C(O)(=O)C.Cl>[Zn].O>[Cl:3][C:4]1[N:12]=[CH:11][C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(F)cnc1Cl
Temperature: 35 °C
Yield: 70.4 %

Procedure:
Into a 2 L round bottomed flask, zinc powder (847 g) and methanol (4,080 mL) were charged and dispersed with stirring. A methanol (2,720 mL) solution of 2,6-dichloro-5-fluoronicotinic acid (1,700 g) was slowly added dropwise thereto, and then, acetic acid (535 g) was further added dropwise thereto. The internal temperature was raised to 35° C., followed by stirring at that temperature for 5 hours. After confirming that the starting material became at most 3% by the HPLC analysis, the residue of zinc powder was removed by filtration. Methanol was distilled off under reduced pressure, and then, water (3,000 mL) was added, whereby crystals precipitated. Then, the crude reaction product containing the crystals was transferred to a 20 L reactor by means of water (3,750 mL). The internal temperature was heated to at least 50° C., and then, 6 mol/L hydrochloric acid (1,960 g) was dropwise added thereto. After stirring for 3 hours as it was, the mixture was gradually cooled to room temperature, and a precipitated solid was collected by filtration and washed with water. The obtained crystals were dried under reduced pressure (60° C., 30.7 Pa, 12 hours) to obtain a salt of 2-chloro-5-fluoronicotinic acid (1,000 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.O>CN(C)C=O>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1csc(Cn2cnc3ccccc32)c1
Reaction time: 0.5 h

Procedure:
To 11.81 g of benzimidazole in 50 ml of dimethylformamide was added 4.8 g of 50% sodium hydride in oil over 30 minutes. After stirring 30 minutes, 13.25 g of 2-chloromethylthiophene was added over a period of 30 minutes, and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the pH adjusted to 1.5. After extracting with ether, the pH was raised to 11 and precipitated product was filtered and dried, 19.9 g.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C1(NC2CCCCC2)CCCCC1.[C:48]([O:52][C:53]([NH:55][C@@H:56]([CH:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1)[C:57](O)=[O:58])=[O:54])([CH3:51])([CH3:50])[CH3:49]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:48]([O:52][C:53]([NH:55][C@@H:56]([CH:60]1[CH2:61][CH2:62][CH2:63][CH2:64]1)[C:57]([N:11]1[C@@H:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][CH3:15])=[O:13])=[O:58])=[O:54])([CH3:51])([CH3:49])[CH3:50]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (1.2 g, 5.32 mmol) in dichloromethane (30 mL) at ambient temperature under nitrogen was added 4-dimethylamino pyridine (0.65 g, 5.32 mmol), 4-methylmorpholine (0.9 mL, 7.98 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (1.22 g, 6.39 mmol), and (2S)-((tert-butoxycarbonyl)amino)(cyclopentyl)acetic acid dicyclohexylamine salt (1.55 g, 6.39 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with ethyl acetate and washed with 1 M HCl. The aqueous layer was further extracted with ethyl acetate (2×) and the combined ethyl acetate layers were dried (Na2SO4) and evaporated. The residue was purified by flash chromatography 30% ethyl acetate/hexane to provide the titled compound. MS (CI) m/e 451 (M+H)+.
Reaction SMILES: Cl[C:2]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[C:5]1([CH3:16])[CH3:15])=[O:3].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>ClCCl>[CH3:15][C:5]1([CH3:16])[N:4]([C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14]
Reactant: C1COCCN1
Reactant: CC1(C)C(=O)Nc2ccccc2N1C(=O)Cl
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccccc2N1C(=O)N1CCOCC1
Reaction time: 0.5 h

Procedure:
To 2.70 g of 4-(chlorocarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one (prepared from 3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 2) and phosgene) in 30 ml of dichloromethane are added 1.97 g of morpholine. After stirring for 30 min, the reaction mixture is partitioned between dichloromethane and saline. The organic layers are dried over sodium sulfate, concentrated, and crystallized from dichloromethane/hexane to give the title compound, mp 190.5°-193°; MS (m/z) at 289; IR (mineral oil) 1683, 1661, 1409, 1238, 1121, 1506 cm-1 ; NMR (CDCl3) δ 1.3-1.9, 3.0-4.1, 6.70, 6.84, 6.95-7.03, 8.31.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:26])([F:25])[C:9]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14]C=1C(O)=O.CN(C=O)C>CCOCC>[F:7][C:8]([F:25])([F:26])[C:9]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:15]=[CH:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(=O)Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 115.3 %

Procedure:
Oxalyl chloride (0.64 g) in dry ether (7 ml) was added dropwise with stirring to 2-trifluoromethyl-4-(2',2'-dimethylpropionamido)-benzoic acid (0.926 g) in dry ether (40 ml) at room temperature. A drop of DMF was added during the addition. After two hours further oxalyl chloride (0.257 g) was added and the reaction stirred for a further two hours. The organic solution was then decanted from a precipitate, and evaporated to yield 2-trifluoromethyl-4-(2',2'-dimethylpropionamido)-benzoyl chloride as a liquid (1.136 g), which was used without purification.