Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[I-:10].[K+].C(=O)([O-])O.[Na+].II>C(Cl)Cl.O>[I:10][CH:4]1[CH:5]2[CH2:6][CH:1]([C:7](=[O:9])[O:8]2)[CH2:2][CH2:3]1
Reactant: [I-]
Reactant: O=C(O)C1CC=CCC1
Agent: II
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C1OC2CC1CCC2I
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a mixture of cyclohex-3-enecarboxylic acid (racemate, 42.0 g, 333 mmol), potassium iodide (72.0 g, 433 mmol) and sodium hydrogencarbonate (36.4 g, 433 mmol) in methylene chloride (750 mL) and water (750 mL) was added iodine (110.0 g, 433 mmol) at an internal temperature of 5° C., and the reaction mixture was stirred at room temperature for 3 hours. After quenched with 1 N aqueous sodium thiosulfate (1500 mL), the resulting mixture was extracted with methylene chloride (1000 mL×2). The combined organic layers were washed with aqueous sodium hydrogencarbonate (1000 mL), water (2000 mL) and brine (1000 mL), dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with hexane, followed by drying, to thereby give the title compound (80.2 g, 95%) as a white solid.
Reaction SMILES: I[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][O:27][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:10][N:6]1[C:5]2[CH:29]=[CH:30][C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:3][C:4]=2[N:8]=[C:7]1[NH2:9]
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cn1
Reactant: CN1CCNCC1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(N5CCN(C)CC5)ccc43)cc2OC)cn1

Procedure:
1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-amine was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine and 1-methylpiperazine according to the procedure described for the synthesis of Example 3-13: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.5, 3.0 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.79-6.75 (m, 2H), 6.72 (s, 1H), 6.67 (d, J=8.5 Hz, 1H), 5.03 (s, 2H), 5.02 (s, 2H), 3.94 (s, 3H), 3.77 (s, 3H), 3.22-3.17 (m, 4H), 2.65-2.59 (m, 4H), 2.37 (s, 3H) ppm; (M+1)=489.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]#[CH:23].C(N(CC)CC)C>CC(N(C)C)=O.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.[Cu]I>[C:27]([O:26][C:25]([NH:24][CH2:21][C:22]#[C:23][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1)=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)nc(C#CCNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 90 °C
Yield: 33.8 %

Procedure:
Methyl 2-chloro-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (0.4 g, 1.371 mmol), tert-butyl prop-2-ynylcarbamate (0.426 g, 2.74 mmol), tetrakis(triphenylphosphine)palladium (0.032 g, 0.027 mmol), and copper (I) iodide (0.026 g, 0.137 mmol) was dispersed in DMA (5 mL). Triethylamine (0.382 mL, 2.74 mmol) was added and the mixture was degassed with nitrogen for 5 min. The reaction mixture was placed in a sealed tube and heated at 90° C. for 4 h, after which it was filtered through a pad of Celite, which was rinsed with MeOH. The filtrate was purified via reverse phase preparative HPLC and the fractions were concentrated in vacuo to give the title compound as a brown oil (0.190 g, 34%). [M+H] calc'd for C22H26N4O4, 411. found, 411.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7](C(C)(C)C)=[C:8]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1)[C:9]([O-:11])=[O:10]>O.C(#N)C.CN(C)C=O.S([O-])([O-])(=O)=O.[Fe+2]>[O:31]=[C:22]1[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:21]1[CH:18]1[CH2:17][CH2:16][N:15]([C:14]2[CH:6]=[CH:7][C:8]([C:9]([O:11][C:8]([CH3:12])([CH3:9])[CH3:7])=[O:10])=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)c1c(C(=O)[O-])ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c1N
Agent: [Fe+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.11 g) in water (1 ml) was added to a stirred solution of the product from example 159 step (ii) (0.456 g) in acetonitrile (10 ml) at room temperature. After 1 h a solution of iron sulphate (0.3 g) in N,N-dimethylformamide (20 ml) was added and the mixture stirred for a further 30 min. The mixture was partitioned between ethyl acetate and water, the organics dried and evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate/isohexane. Yield 0.29 g as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][O:22][CH:23]([CH3:27])[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:24](=[O:25])[CH:23]([O:22][CH3:21])[CH3:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: COC(C)C(=O)O
Product: COC(C)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; MS (EI) 389.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH3:17][N:18]([CH:20]=[O:21])C>>[CH2:5]([C:17]1[N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[C:20](=[O:21])[CH:2]=[CH:3][CH:4]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1cccc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.17 h

Procedure:
1.12 g of potassium tert-butylate are added to a solution of 1.5 g of 6-butyl-1,2-dihydro-2-oxopyridine ["IIIa"; m.p. 69°; obtainable by condensation of hexan-2-one with ethyl formate in toluene, in the presence of NaOCH3, to give 1-hydroxyhept-1-en-3-one, condensation with cyanoacetamide in water, in the presence of piperidine and acetic acid, at 90°, to give 6-butyl-3-cyano-1,2-dihydro-2-oxopyridine ("IIIb"; m.p. 110°), hydrolysis with 37% hydrochloric acid (boiling for 5 hours) to give 6-butyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid (m.p. 149°) and decarboxylation at 180°-200°] in 25 ml of DMF. The mixture is stirred for 10 minutes, a solution of 2.72 g of 4'-bromomethyl-2-cyanobiphenyl ("IIa") in 15 ml of DMF is added dropwise over 30 minutes and the resulting mixture is stirred for 16 hours at 20°. It is evaporated, worked up in a conventional manner (pH 7; ethyl acetate) and purified by chromatography (silica gel; methylene chloride/methanol 98:2) to give 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine; Rf 0.4; (M+H)+ 343. 6-Butyl-2-(2'-cyanobiphenyl-4-yl-methoxy)pyridine is obtained as a by-product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]([NH:19][CH2:18][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:28])(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccccc1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 125 %

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (50 mg, 0.21 mmol) in CH2Cl2 (1 mL) was treated with hippuric acid (38 mg, 0.21 mmol), EDCI (48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (38 μL, 0.27 mmol). The reaction mixture was stirred for 16 h at 25° C., diluted with 1 mL of CH2Cl2, washed with 2 N aqueous NaOH solution (2×0.75 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 6 to 8% CH3OH/CH2Cl2 gradient elution) afforded 4-{(N-benzoylglycyl)amino)methyl-1-(compound No. 458) which was treated with TFA to give a TFA salt(105 mg, 97%): The purity was determined by RPLC/MS (85%); ESI/MS m/e 400 (M++H, C22H26ClN3O2)
Reaction SMILES: [C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)(OC)=[O:2].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:35][CH3:36])[C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)=[O:2])[CH3:33]
Reactant: CCNCC
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Yield: 50 %

Procedure:
The crude 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-1,4-dien-3-one (1.50 g, 3.50 mmol), prepared in part A, is hydrolyzed as in Example 3, part F and then coupled with diethylamine as described in Example 1, part A to give after chromatography (50% ethyl acetate/hexanes) 17β-N,N-diethylcarbamoyl-6-t-butylcarboxy-6-azaandrost-1,4-dien-3-one as a white foam; yield: 1.07 g (65%). Anal. Calcd. for C28H42N2O4 ; C, 71.45; H, 9.00; N, 5.95. Found C, 71.38; H, 9.07; N, 5.90.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:20][CH2:21][C@@:22]2([CH3:25])[CH2:24][O:23]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:25][C@:22]([OH:23])([CH3:24])[CH2:21][O:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Yield: 41.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (18.4 g, 125 mmol) and (R)-2-methyloxiran-2-ylmethyl 4-methylbenzene sulfonate (36.2 g, 149 mmol) were suspended in acetonitrile (150 ml). Benzyl(triethyl)ammonium chloride (5.7 g, 25 mmol) was added to the suspension, and the resulting mixture was stirred under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford (R)-2-chloro-1-[2-hydroxy-2-methyl-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole (20.1 g, 43%) as a white amorphous form.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:34]([CH3:35])=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:34]([CH3:35])=[C:22]4[N:21]=3)=[CH:18][CH:19]=2)[CH2:9][C:10]([CH3:12])([OH:13])[CH2:11]1
Reactant: Cc1c(-c2ccccc2)nn2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CC(C)(O)C4)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccccc2)nn2cc(-c3ccccc3)c(-c3ccc(C4(N)CC(C)(O)C4)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 10-5 (23 mg, 0.04 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 10-6.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36]C3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(O)(=O)C1C=C[N:47]=CC=1>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](=[O:33])[C:34]2[CH:35]=[CH:36][N:47]=[CH:38][CH:42]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccncc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 44.2 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using isonicotinic acid. After preparative HPLC purification, the TFA salt was free-based using an SCX-ion exchange column to obtain (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)isonicotinamide as a tan solid (44.2% yield). MS m/z=534.2 [M+H], calc 533.67 for C29H39N7O3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: BrCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(SCCc2ccccc2)cc1
Yield: 95 %

Procedure:
A solution of 4-methoxy-benzene thiol (5.7 g), triethylamine (4.1 g) and 2-bromoethylbenzene (5.6 ml) in DMF (50 ml) at 0° C. was stirred for 2 h, then added to water and extracted with ether. The solvent was washed with water, 1M NaOH and brine, then dried and evaporated to give the title compound as colourless oil (8.9 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[CH:29]=[CH:30][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
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: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester and 4-carbamoylphenyl boronic acid (2 eq.) were coupled in 7:2 toluene-H2O with Na2CO3 (3 eq.) and Pd(PPh3)4 (0.1 eq.). After heating for 4 hours at 80° C., the reaction mixture was purified by flash chromatography to provide (S)-2-tert-butoxycarbonylamino-3-(4′-carbamoyl-biphenyl-4-yl)-propionic acid methyl ester. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was treated with excess NEt3 in DCM to produce a free amine. The free amine was coupled with 2,5-dimethyloxazole-4-carboxylic acid (2 eq.) in dry DCM with HBTU (2.2 eq.) and NEt3 (3 eq.). After reacting for 2 hours at room temperature, the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed according to general procedure B to give the title compound (11 mg). LCMS (m/z) 876.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9]CCC1(CCC)OCCO1.ClC1C=C[N+]([O-])=C(C)C=1C.[CH2:42]([C:44]1([CH2:49]O)[O:48][CH2:47][CH2:46][O:45]1)[CH3:43]>>[Na:1].[CH2:42]([C:44]1([CH2:49][O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)=[O:22])[C:3]=2[CH3:2])[O:48][CH2:47][CH2:46][O:45]1)[CH3:43]
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Reactant: CCC1(CO)OCCO1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: CCC1(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Yield: 9.6 %

Procedure:
The same procedure as in the steps (3c) to (3h) of Example 3 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and (2-ethyl-1,3-dioxolan-2-yl)methanol to obtain the title compound (355 mg, 6 steps: 9.6%) as a white solid.
Reaction SMILES: P([O-])([O-])(O)=O.[K+].[K+].[CH3:8][O:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13].S(Cl)(O[CH2:21][Cl:22])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C.O>[Cl:22][CH2:21][O:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][O:9][CH3:8]
Reactant: COCC(C)(C)C(=O)O
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: COC(C)(C)C
Product: COCC(C)(C)C(=O)OCCl
Temperature: -5 °C
Reaction time: 8 h

Procedure:
To a mixture of water (25 mL) and TBME (40 mL), dipotassium hydrogen phosphate (45.2 g), tetrabutylammonium hydrogen sulfate (1.76 g), and 3-methoxy-2,2-dimethylpropionic acid [CAS No. 64241-78-7] (6.86 g) were sequentially added. After cooling the resulting mixture to −5° C., a mixture of chloromethyl chlorosulfate (12.8 g) and TBME (10 mL) was added dropwise thereto, and the resulting mixture was stirred overnight at room temperature. Water (50 mL) and TBME (30 mL) were added to the resulting mixture. After shaking the resulting mixture, the organic layer was collected, and TBME (50 mL) was added to the remaining aqueous layer. The resulting mixture was shaken again and the organic layer was collected. The combined organic layers were washed twice with water (30 mL) and with saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was distilled (boiling point: 85-86° C./20 mmHg) under reduced pressure to obtain the captioned compound (5.68 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][S:30][CH2:31][CH2:32][CH2:33][NH2:34].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>>[CH3:29][S:30][CH2:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CSCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSCCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 69.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-methylsulfanyl-propyl)-amide (69 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (82 mg), 3-methylthio-propylamine (38 mg), HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 497.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([OH:30])(=[O:1])=[O:29].[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Agent: CCOc1ccc(C(=O)NCCCCO)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 6 °C
Reaction time: 0.17 h

Procedure:
A 22-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 2.00 kg (8.43 mole) of N-(4-hydroxybutyl)-4-ethoxybenzamide (V-5), 2.94 L (2.18 kg, 16.85 mole, 2.00 eq) of diisopropylethylamine, and 11 L of DCM. The white slurry was cooled to 6° C., and 718 mL (1.062 kg, 9.27 mole, 1.10 eq) of methanesulfonyl chloride was added over a period of 1.5 h while maintaining a pot temperature of 5-12° C. with cooling. After stirring for 10 min at 5-10° C. the pale-brown solution was quenched into an extractor that contained 14 L of 1 N HCl. The phases were separated. The organic extract was washed with 14 L of 1 N HCl, washed with 9 L of saturated aq. NaHCO3, dried (MgSO4), filtered and concentrated (30° C., 50 mbar), to give, after air drying, 2.65 kg (99.7%) of N-(4-hydroxybutyl)-4-ethoxybenzamide methanesulfonate (V-6) as a pale-beige solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:25][C:23]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:22]=1[CH2:21][C:20]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccccc1Cl)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1Cl)CCCC3
Yield: 78.3 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-chlorophenyl)methanone (0.291 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.302 g (78%) of the title compound as a yellow solid.