Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:4]2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[C:3]=2[CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 109.4 %

Procedure:
In a 1 L 3-neck RBF equipped with magnetic stir bar, condenser, thermocouple, and N2 inlet, crude D1 (30 g, 0.124 mol) was dissolved into 300 mL of ethylene glycol dimethyl ether (DME). To this was added a solution of Na2CO3 (21 g, 0.2 mol in 200 mL of H2O) followed by addition of 4-methoxyphenyl boronic acid (22 g, 0.145 mol) and Pd(PPh3)4 (1.2 g, 8.3 mmol). The reaction mixture was heated in a 85° C. oil bath, under N2, for 2 h and then cool to room temp. To this was added 200 mL of EtOAc and the mixture stirred for 5 min. The organic layer was separated and washed with H2O (200 mL) and brine (200 mL). The organic layer was dried over MgSO4 and then concentrated to dryness to give 53 g of crude product. This material was subjected to silica gel chromatography using 210 g of silica gel and EtOAc/hepatene (12:88 to 30:70 to 50:50 to 70:30; total of 8 L mobile phase). Fractions containing pure product were combined and concentrated to dryness to give 42.7 g of pure product in approximately quantitative yield. 1H NMR (300 MHz, CDCl3) δ 3.38 (s, 3H), 3.73 (d, 1H), 3.85 (s, 3H), 4.75 (d, 1H), 6.9 (m, 2H), 7.31 (m, 2H), 7.48-7.58 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([N:18]=[CH:19][N:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[Br-].[CH2:24]([Zn+])[CH2:25][CH3:26].O.Cl>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][N:20]([CH3:22])[CH:19]=[N:18][S:15]([C:8]1[N:6]2[N:7]=[C:2]([CH2:24][CH2:25][CH3:26])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([F:14])([F:13])[F:12])(=[O:17])=[O:16]
Reactant: CN(C)C=NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Reactant: CCC[Zn+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc2nc(C(F)(F)F)c(S(=O)(=O)N=CN(C)C)n2n1
Temperature: 25 °C

Procedure:
To a suspension of N′-(6-chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-dimethylformamidine (1.00 g, 2.81 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.076 g, 0.14 mmol) in tetrahydrofuran (8.0 ml) was added dropwise a solution of n-propylzinc bromide in tetrahydrofuran (0.5 M, 8.43 ml, 4.22 mmol) with stirring under ice-cooling and nitrogen stream. The reaction mixture was stirred for 30 minutes under ice-cooling and 4.5 hours at room temperature, then poured into cold water and made acid with dilute hydrochloric acid. The precipitated solid was collected by filtration, washed with dilute hydrochloric acid, then water, and purified by silica gel column chromatography (ethyl acetate:chloroform=2:5) to give the title compound as white crystals. The yield was 0.62 g (60.7%).
Reaction SMILES: C(O)C.OCC[N+](C)(C)C.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][C:26]#[N:27])=[CH:22][CH:21]=1>CO>[NH2:27][C:26]1[CH2:25][CH:24]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:29][CH:28]=2)[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Agent: C[N+](C)(C)CCO
Solvent: CO
Solvent: CCO
Product: NC1=NN(c2ccccc2)C(c2ccc(Cl)cc2)C1
Reaction time: 16 h

Procedure:
A mixture of 500 ml. of absolute ethanol, 5.0 ml. of 50% choline in methanol, 32.4 g. of phenylhydrazine and 49.08 g. of p-chlorocinnamonitrile is refluxed for 7 hours then is allowed to stand at room temperature for 16 hours, then is evaporated to dryness in vacuo. The procedure of Example 16 is followed to give 12.0 g. of the product of the Example as colorless needles, m.p. 183.5°-185.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.I[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N:18]1[CH:19]=[CH:20][C:15]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=3)[CH:7]=[CH:8]2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: Ic1ccncc1
Product: FC(F)(F)c1ccc2ccn(-c3ccncc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-(trifluoromethyl)-1H-indole and 4-iodopyridine: ESMS m/e: 262.9 (M+H)+.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:40])[C:24]=1[NH:25][C:26]1[C:35]2[C:30](=[C:31](O)[C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[O:29][C:28](=[O:39])[CH:27]=1>>[CH:13]1([CH2:12][O:11][C:31]2[C:32]([O:36][CH3:37])=[CH:33][CH:34]=[C:35]3[C:30]=2[O:29][C:28](=[O:39])[CH:27]=[C:26]3[NH:25][C:24]2[C:23]([Cl:40])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:18])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC1CCCC1

Procedure:
The title compound was prepared from cyclopentylmethyl 4-methylbenzenesulfonate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 3.91 (s, 3H), 3.84 (d, 2H), 2.28 (m, 1H), 1.80-1.35 (m, 8H); MS (ESI): 434.9.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([O:25]CC4C=CC=CC=4)=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:3]1.[H][H].C1COCC1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 12 h

Procedure:
A solution of 2.50 g (4.38 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 50 mL DCM was combined with 250 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure for 4.5 h. To complete the reaction a further 250 mg of catalyst were added, the mixture was hydrogenated for 12 h at 40° C., combined with 25 mL THF and 250 mg catalyst and hydrogenated for a further 12 h at 40° C. The catalyst was removed by suction filtering and the filtrate was concentrated by evaporation i.vac. The residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12]C(O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:16])[CH:8]=2)[N:3]=1.[S:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]1>C(O)CCC.ClCCl>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:16])[CH:8]=2)[N:3]=[C:2]([N:20]2[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:17][CH2:18][CH2:19]2)[CH:11]=1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1ccc2nc(Cl)cc(CC(=O)O)c2c1
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(C)c2c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A solution of (2-chloro-6-methylquinolin-4-yl)acetic acid (118 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (247 mg, 1.5 mmol) in n-butanol (0.2 mL) was heated with stirring in a sealed 0.5 mL of microwave process vial for 2 hours at 160° C. After being cooled to room temperature, the reaction mixture was diluted with dichloromethane (50 mL), washed with a saturated aqueous solution of sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to afford 100 mg of the desired product (yield was 62%). MS (ESI+) [(M+H)+] 321.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[NH3:14]>>[CH3:1][O:2][C:3]1[C:4]([C:10]([NH2:14])=[O:12])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: N
Reactant: COC(=O)c1ncc(C)nc1OC
Product: COc1nc(C)cnc1C(N)=O
Temperature: 50 °C
Yield: 87 %

Procedure:
1 g (5.5 mmol) of methyl 3-methoxy-5-methylpyrazine-carboxylate was initially charged in 15 ml (198 mmol) of NH3 (25%) and the mixture was stirred at 50° C. After concentration, 0.8 g of 3-methoxy-5-methylpyrazine-2-carboxamide was obtained. The yield was 86 percent. Other data concerning the title product was:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][N:8]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[N:7]=1)=[O:5])C.[OH-].[K+]>C(O)C.O.O>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[N:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:9]1
Reactant: CCOC(=O)c1nn(-c2c(Cl)cccc2Cl)nc1COc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn(-c2c(Cl)cccc2Cl)nc1COc1ccccc1
Yield: 87.3 %

Procedure:
A solution of the product from step b (1.43 g, 3.65 mmol) and potassium hydroxide (632 mg, 11.3 mmol) in ethanol/water (14 mL/2 mL) was heated at reflux for 2 h. The reaction mixture was allowed to cool and diluted with water (30 mL). The reaction mixture was washed with ether (30 mL) and the organic phase was discarded. The pH of the aqueous phase was adjusted to 1 with aqueous 2M hydrochloric acid and extracted twice with chloroform (40 mL). The combined chloroform extracts were dried (MgSO4) and the filtrate evaporated at reduced pressure to afford the title compound (1.16 g, 87%). 1H NMR (CDCl3) 7.52 (3H, m), 7.33-7.27 (2H, m), 7.08-6.99 (3H, m), 5.54 (2H, s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH2:10][O:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:10]([O:11][CH2:12][CH2:13][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:9]
Reactant: O=Cc1ncc[nH]1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCn1ccnc1C=O
Temperature: 110 °C
Yield: 17 %

Procedure:
To a solution of imidazole-2-carboxaldehyde (2.00 g, 21 mmol) in DMF (1 mL) was added 1.1 eq. of 1-bromo-2-ethoxyethane (3.51 g, 22 mmol), potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (580 mg, 3.56 mmol, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, H), 7.6 (s, H), 7.21 (s, H), 4.45 (dd, 2H), 3.62 (dd, 2H), 3.38 (m, 2H), 1.05 (t, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.[Br:19][C:20]1[N:25]=[C:24](Br)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(O)C>[Br:19][C:20]1[N:25]=[C:24]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH2:7][CH2:8]2)[CH:23]=[CH:22][N:21]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Brc1ccnc(Br)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2ncccc2n1C1CCN(c2ccnc(Br)n2)CC1

Procedure:
1.4 g (4.8 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one-dihydrochloride, 1.1 g (4.8 mmol) 2,4-dibromo-pyrimidine, a spatula tip of DMAP and 3.3 mL (19.1 mmol) DIPEA in 35 mL ethanol were stirred at RT. After the reaction had ended the precipitate was suction filtered, washed with a little ethanol and dried.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].Cl.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:40][O:39][C:37]([CH:34]1[CH2:33][CH2:32][CH:31]([NH:30][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([C@H:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:14][CH:15]=2)[CH2:36][CH2:35]1)=[O:38]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)C1CCC(NC(=O)c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)CC1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with trans-methyl 4-amino-cyclohexanecarboxylate hydrochloride using benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light yellow viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[CH:28]3)[C:22]([OH:35])=[C:21]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:47]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[CH:28]3)[C:22]([O:35][CH3:47])=[C:21]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cn1ccc2cc(-c3nc(OCc4ccccc4)c(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3c(ccn3C)c2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Into a solution of benzyl 2,4-bis(benzyloxy)-5-hydroxy-6-(1-methyl-1H-indol-5-yl)nicotinate (80 mg, 0.14 mmol) in DMF (0.3 mL) was added 60% NaH (7.3 mg, 0.18 mmol). After 15 min, iodomethane (13 μL, 0.20 mmol) was added. The mixture was stirred at room temperature for another 30 min and then loaded directly onto a silica column and chromatographed to give benzyl 2,4-bis(benzyloxy)-5-methoxy-6-(1-methyl-1H-indol-5-yl)nicotinate (73 mg, 89%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C([BH3-])#N.[Na+].C=O>C(O)C.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: O=C(O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.7 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (120 mg), 3-azetidinecarboxylic acid (64.8 mg) and acetic acid (0.1 mL) in ethanol (10 mL) was stirred at room temperature for 15 min, then sodium cyanoborohydride (60.4 mg) was added. The mixture was stirred at room temperature for 6 h, then formaldehyde (0.11 mL) was added. The mixture was stirred at room temperature overnight. After concentration, the residue was acidified with 2M HCl to pH 5-6, ethyl acetate was added, the organic phase was washed with saturated brine, then dried and evaporated. The residue was purified by Mass Directed AutoPrep to afford 1-[(3-{2-[3-cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid (E43) (32 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.92 (6H, d), 1.05 (3H, t), 1.98 (1H, m), 2.76 (4H, m), 3.65 (1H, m), 4.27 (4H, m), 4.54 (2H, br. s.), 7.40 (1H, m), 7.48 (2H, m), 7.62 (1H, d), 7.94 (1H, s), 8.22 (1H, dd), 8.35 (1H, d), 10.21 (1H, br s), 13.19 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H29N3O2S requires 459. found 460.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cccc(C)c4)CC3)nc2c1
Yield: 95 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 3.26 (s, 4H), 3.72-3.89 (m, 6H), 4.09-4.18 (m, 4H), 6.72-6.78 (m, 4H), 7.03-7.37 (m, 3H), 7.57-7.65 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:9]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OC)cc2)c(Nc2ccc(OC)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.0 g (24 mmol) of 4-anisidine in 24 ml ofglacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel withethyl acetate/hexane 1:1 and the product fractions are concentrated by evaporation, yielding the title compound in the form of a yellow foam, FAB-MS: 437 [M+ +H].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: COC(C)(C)CN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 43 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (78.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (50.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 493; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, br. s), 8.20-8.17 (1H, m), 8.11 (1H, br. s), 7.81 (1H, m), 7.70 (1H, m), 7.57 (1H, m), 4.25 (2H, m), 3.37-3.35 (2H, d), 3.32 (2H, s), 3.18 (3H, s), 1.35-1.32 (3H, t), 1.14 (6H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[H-].[Na+].[CH3:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:27][C:15]1[CH:14]=[C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:3]([CH3:28])[CH:4]=2)([CH2:9][CH3:10])[CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(=O)C(C)(C)C
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of the compound of example 7 (100 mg, 0.26 mmol) in DMF (2.5 mL) was added NaH (7.0 mg, 0.29 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then pinacolone (39 mg, 0.29 mmol) was added. The reaction was stirred at ambient temperature for I h or until judged complete by TLC (20% ethyl acetate in hexanes). The reaction mixture was quenched with water, and diluted with ethyl acetate. The organic fraction was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 10% ethyl acetate in hexanes) afforded 117 mg (0.24 mmol, 92%) of 11. 1HNMR (CDCl3) δ: 6.91 (m, 4 H, Ar—H), 6.69 (d, J=8.3 Hz, 1 H, Ar—H), 6.49 (d, J=8.3 Hz, 1 H, Ar—H), 4.83 (s, 2 H, CH2), 4.09 (dd, J=11.3 Hz, J=3.3 Hz, 1 H, CH2), 3.85 (t, J=11.3 Hz, 1 H, CH2), 3.69 (d, J=11.3 Hz, 1 H, CH2), 2.23 (s, 3 H), Ar—CH3), 2.18 (s, 3 H, Ar—CH3), 2.00 (q, J=7.3 Hz, 4 H, CH2CH3), 1.24 (s, 9 H, t-Bu), 1.00 (s, 9 H, t-Bu), 0.58 (t, J=7.3 Hz, 6 H, CH2CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The product from Example 1 (10.0 g; 38 mmol) is dissolved in anhydrous pyridine (185 ml), and methanesulphonyl chloride (3.7 ml; 46 mmol) is slowly added dropwise at 0° C. The solution is stirred at room temperature for 6.5 h. Subsequently, the solution is diluted with dichloromethane (740 ml) and extracted twice with a 10% solution of sodium hydrogen carbonate (250 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated, and the residue is subsequently distilled repeatedly with toluene. Yield: 10.79 g (85%), brown oil.