Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18]>O>[O:9]=[C:6]1[CH2:7][CH2:8][N:3]([C:17]([O:19][CH3:20])=[O:18])[CH2:4][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (3.07 g, 20.0 mmol) in water (12 mL) cooled to 0° C. was added a cooled solution (also at 0° C.) of potassium carbonate (6.97 g, 50.4 mmol) in water (40 mL). Methyl chloroformate (2.80 g, 29.6 mmol) was added, and the mixture was allowed to stir for 2 h, still at 0° C. Then, the mixture was extracted with dichloromethane (3×40 mL), and the extract was dried over MgSO4, and concentrated. The obtained residue was chromatographed (silica gel, dichloromethane to 95:5 dichloromethane/methanol) to give the title compound (2.96 g, 94%) as a viscous clear liquid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:18]=1B(O)O>C(O)C.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>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)=[CH:22][C:17]=2[F:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: Fc1cc(F)cc(Br)c1
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: [K+]
Solvent: CCO
Product: CCCc1ccc(-c2ccc(-c3cc(F)cc(F)c3)c(F)c2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, a suspension solution containing 3,5-difluorobromobenzene (71 g), potassium carbonate (75 g), tetrakis(triphenylphosphine)palladium (0) (2.2 g), and ethanol (250 mL) was heated to 70° C., and a solution in which 2-fluoro-4-(4-propylphenyl)phenylboronic acid (100 g, prepared by a method disclosed in EP 2123623) had been dissolved in ethanol (200 mL) was dropped thereinto. Then, the resulting solution was stirred at 70° C. for 5 hours. The solution was cooled with ice and filtered to separate precipitated crystals and an inorganic salt, the obtained solid was dissolved in a solution containing hexane and toluene (4:1), and then the solution was purified by silica gel column chromatography. The purified product was recrystallized from ethanol to yield 18.7 g of 3,5-difluoro-[2-fluoro-4-(4-propylphenyl)phenyl]benzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:28][C:29]([C:31]1[CH:35]=[C:34]([OH:36])[N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]=1)=[O:30])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:50][O:51][C:52]([C:54]1[O:55][C:56]([CH2:59]Cl)=[CH:57][CH:58]=1)=[O:53]>CN(C=O)C.C(OCC)(=O)C>[CH3:50][O:51][C:52]([C:54]1[O:55][C:56]([CH2:59][O:36][C:34]2[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=[C:31]([C:29](=[O:30])[NH:28][C@H:9]([C:10]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=4)[CH2:15][CH2:16]3)=[O:27])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:43])[CH:35]=2)=[CH:57][CH:58]=1)=[O:53]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(O)n(-c2ccccc2)n1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1

Procedure:
180 mg of (S)-4-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-5-oxo-5-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]-pentanoic acid tert-butyl ester dissolved in 4 ml DMF was treated with 293 mg of cesium carbonate and 78 mg of Methyl-5-(chlormethyl)furan-2-carboxylate. After 3 h at 70° C. the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic layer over sodium sulfate gave crude 5-(5-{(S)-3-tert-Butoxycarbonyl-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-propylcarbamoyl}-2-phenyl-2H-pyrazol-3-yloxymethyl)-furan-2-carboxylic acid methyl ester which was used for the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:31]=[CH2:32].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:32]=[CH:31]/[CH2:30][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.184 mmol) in MeCN (5 mL) in a pressure vessel is added allylbenzene (22 mg, 0.184 mmol), Pd(OAc)2 (3 mg) and triethylamine (186 mg, 1.84 mmol) and the mixture is heated at 100° C. for 10 h. The solvent is evaporated and the residue is purified by flash chromatography using a gradient of 10% to 40% EtOAc/hexane as eluent to give the title compound as a yellow foam.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]=[C:28]=[O:29])[CH:22]=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:11][CH:12]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine (Example 108) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a white solid: ES-MS: 441.8 [M+H]+; single peak at tR=9.44 min (System 2); Rf=0.38 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.OC1C=CC(NC([C@@H]2CCCN2)=O)=CC=1.Cl>C(O)(C)C>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:32])=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1
Solvent: CC(C)O
Product: O=C(Nc1ccc(O)cc1)[C@H]1CCCN1

Procedure:
This compound was prepared from (R)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester, using the same method used to prepare (S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The free base was dissolved in hot isopropanol (20 mL) and treated with a saturated solution of hydrogen chloride in isopropanol (3 mL). The product crystallized as the hydrochloride salt, 2.43 g (59% for 2 steps). MS m/z 207 (MH+). 1H NMR (DMSO-d6) δ 1.93 (m, 3H), 2.39 (m, 1H), 3.26 (m, 2H), 4.35 (t, 1H), 6.76 (d, 2H), 7.43 (d, 2H), 9.43 (br s, 1H) and 10.70 (s, 1H). Anal. calcd for C11H14N2O2: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.33; H, 6.26; N, 11.57.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1[C:27]2[CH2:26]C3C(=CC=CC=3)[C:19]=2[CH:18]=[N:17][CH:16]=1>>[N:12]1[CH:11]=[CH:10][C:9]([CH2:1][C:2]2([CH2:26][C:27]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccncc1-2
Product: c1ccc2c(c1)-c1cnccc1C2(Cc1ccncc1)Cc1ccncc1

Procedure:
Following the photocyclization conditions described above, 4-styrylpyridine (169) may be converted to 3-azafluorene (170) and alkylated to yield the target 9,9-bis(4-pyridinylmethyl)-3-azafluorene (171) (Scheme 70). ##STR90##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:22](=[O:21])[C:17]2[C:18](=[CH:24][CH:25]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:19]1=[O:20]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCc1ccc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with 4-nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours, the reaction was cooled and checked for completion by LC/MS. The solvent was then removed in vacuo and the resulting product was taken on to the next step without further purification. Rt 3.36 minutes (HP LCMS), LC/MS m/z 365.1 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=O)[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1.[CH2:20]([N:22]1[C:26]([OH:27])=[CH:25][CH:24]=[N:23]1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:25]3[CH:24]=[N:23][N:22]([CH2:20][CH3:21])[C:26]=3[OH:27])=[O:17])[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1
Reactant: CON=C1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Reactant: CCn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
0.9 Gram (3.2 mmol) of the 4-methoxyimino-5-methylthiochroman-6-carboxylic acid-1,1-dioxide and 0.44 g (3.9 mmol) of 1-ethyl-5-hydroxypyrazol were dissolved in 5 ml of t-amyl alcohol, and 0.81 g (3.9 mmol) of DCC(dicyclohexyl-carbodiimide) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then, 0.74 g (5.4 mmol) of potassium carbonate was added, and the mixture was allowed to react at 90° C. for 8 hours. After the reaction, the solvent was distilled off, ethyl acetate was added, and the mixture was extracted with a 5% potassium carbonate aqueous solution. An aqueous layer was neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated sodium hydroxide aqueous solution, dried over sodium sulfate and concentrated to give 0.88 g (yield 72%) of 4-methoxyimino-5-methyl-6 -(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cccc(F)c2[N+](=O)[O-])cc1
Temperature: 75 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
20.0 g (126 mmol) of 2,6-difluoronitrobenzene and 17.0 g (138 mmol) of p-anisidine were dissolved in N,N-dimethylformamide (60 ml), and 20.8 g (150 mmol) of potassium carbonate was added thereto. The mixture was heated with stirring for 12 hours at 75° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with water, 10% hydrochloric acid, water, and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:9), to obtain 21.2 g (yield: 64%) of 3-fluoro-N-(4-methoxyphenyl)-2-nitroaniline as a brown liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:26]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]([CH3:9])[C:11](=[O:34])[CH:12]=[CH:13]3)[CH:29]=1
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCc3cccnc3)ccc21
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(=O)ccc2cc(OCCCCCN(Cc3cccnc3)Cc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine-3-carbaldehyde (0.076 ml) was added to a 1,2-dichloroethane solution (3 ml) of 1-methyl-6-{5-[(pyridin-3-ylmethyl)-amino]-pentyloxy}-1H-quinolin-2-one (237 mg). The mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature for 3 days. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1). The purified product was condensed under reduced pressure to give the title compound (247 mg) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>CCO>[NH:13]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[NH2:14]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])cnc1NN
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloro-3-methyl-5-nitropyridine (35 g, 200 mmol) in EtOH (400 mL) was added hydrazine hydrate (30.0 g, 600 mmol) and the resulting reaction mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled down with an ice bath, the resulting precipitate was filtrated off, washed with cold H2O and Et2O and dried at 50° C. under reduced pressure to afford the title product (25.40 g, 113 mmol, 98%) as a yellow solid. tR: 0.43 min (LC-MS 2); ESI-MS: 169 [M+H]+; ESI-MS: 167 [M−H]− (LC-MS 2).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:17][C:11]2=[CH:12][N+:13]([O-])=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:17][C:11]2=[C:12]([O:22][C:19](=[O:21])[CH3:20])[N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C=NS(=O)(=O)c1cc2cc[n+]([O-])cc2s1
Product: CC(=O)Oc1nccc2cc(S(=O)(=O)N=CN(C)C)sc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of N,N-dimethyl-N'-(6-oxido-thieno[2,3-c]pyridine-2-sulfonyl)formamidine (3.5 g, 12.3 mmol) in acetic anhydride (20 ml), under a nitrogen atmosphere, was heated at 120° C. for 3 hours. The dark solution was poured into ice/water and stirred for 1/2 hour. The product was extracted into methylene chloride, washed with sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to give 4.77 g of crude product. This residue was triturated with methylene chloride/diethyl ether to give 2.0 g (50% yield) of pure product. Recrystallization from ethyl acetate gave product with a broad melting point of 184°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][CH2:30][O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([O:8][CH2:29][CH2:30][O:31][CH3:32])[CH:7]=1
Reactant: COCCBr
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(O)cc(F)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCCOC)c3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
(R)-ethyl 5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 76 Step B, 174 mg, 0.470 mmol), 1-bromo-2-methoxyethane (196 mg, 1.41 mmol), and K2CO3 (325 mg, 2.35 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 15 hours. The crude reaction mixture was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide yield the title compound (183 mg, 91% yield). MS (apci) m/z=429.0 (M+H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[NH:22])[C:19](=[NH:21])[NH2:20])[N:12]=1)[C:5]([NH2:7])=[NH:6].C(Cl)Cl.[S:26](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O.[OH-].[Na+]>C(N(CC)CC)C>[NH2:21][C:19]1[C:18]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[N:12]=[C:8]([NH:4][C:5]([NH2:7])=[NH:6])[S:9][CH:10]=2)=[N:22][S:26][N:20]=1
Reactant: N=C(N)Nc1nc(CSCCNC(=N)C(=N)N)cs1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N=C(N)Nc1nc(CSCCNc2nsnc2N)cs1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of crude N-{2-[(2-guanidinothiazol-4-yl)methylthio]ethyl}ethanediimidamide trihydrochloride (5.65 g, 13.7 mmoles) [prepared in Step A], 50 ml of CH2Cl2 and 5.7 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (5.44 g; 13.7 mmoles) and stirred for one hour to give a thick suspension. The mixture was treated with 40 ml of 2N NaOH and the solvents were decanted from the gum-like material which had separated. The gum was washed with 40 ml of 2N NaOH, water, and then dissolved in methanol and concentrated to give 3.0 g of crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (97:3) as the eluent to give 2.44 g (54%) of the title compound. Treatment of the product in 35 ml of acetone with one equivalent of cyclohexylsulfamic acid gave the salt which was then recrystallized from 95% aqueous ethanol to give the title compound as its cyclohexylsulfamate salt, mp. 171°-173.5° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15](CC2C=CC=CC=2)[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[N:12]=1.Cl.[H][H]>C(O)C.CCOCC.[Pd]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[N:15]=1
Reactant: [H][H]
Reactant: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: BrCCCCCOCCCc1nc2ccccc2[nH]1
Yield: 69.1 %

Procedure:
A solution of 2-[3-[(5-bromopentyl)oxy]propyl]-1-(phenylmethyl) benzimidazole (1.7 g) in absolute ethanol (20 ml) containing 1:9 conc. hydrochloric acid:ethanol (3.27 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal catalyst (300 mg) in ethanol (5 ml) until the uptake of hydrogen (101 ml) ceased. The mixture was filtered through hyflo and evaporated in vacuo to give an oil, which was dissolved in ether (150 ml) and washed with 8% sodium bicarbonate solution (100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (2:3→0:5) gave the title compound as a yellow oil (0.92 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCl>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[Cl:21])=[O:28]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(C(=O)O)ccc1Cl

Procedure:
1 g (5.8 mmol) of 3-amino-4-chlorobenzoic acid were mixed with 0.75 g (5.8 mmol) of diisopropylethylamine and 1.06 g (5.8 mmol) of 2-chlorobenzoyl isocyanate in 5 ml of dichloromethane and reacted at room temperature for 12 hours. The solvent was evaporated, the residue was mixed with 5% strength sodium bicarbonate solution and extracted twice with diethyl ether, and the aqueous phase was adjusted to pH 3 with HCl. The resulting precipitate was filtered off with suction.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)([C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].C(N(C(C)C)CC)(C)C>ClCCCl>[CH:19]1([NH:18][C:17]([C:14]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:41](=[O:43])[CH3:42])=[CH:29][CH:28]=3)[CH2:13][CH2:12][N:11]([C:9](=[O:10])[C@@H:8]([NH2:7])[CH2:34][C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:15]2)=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.352 mmol; 0.2 g) in 1,2-dichloroethane (5 mL) was added acetic anhydride (0.422 mmol; 0.043 g) and N,N-diisopropyl-N-ethylamine (0.703 mmol; 0.123 mL) and the resulting solution was stirred for 3 hours at room temperature. The resulting mixture was then evaporated and the residue was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in tetrahydrofuran (10 mL) and a 4N HCl in 1,4-dioxane solution (15 mL), and the mixture was then stirred for 6 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-acetylaminobenzyl)-1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10](I)(I)[I:11]>O1CCCC1.[Cl-].[Cr+2].[Cl-]>[I:11]/[CH:10]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: IC(I)I
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cr+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/I)cc1
Reaction time: 1 h

Procedure:
To a heterogeneous mixture of chromium (II) chloride (3.98 g, 32.4 mmol) in tetrahydrofuran (40 mL) at 0° C. was added via Syringe pump over 1 hour (in the total absence of light) 4-bromo-benzaldehyde (1.00 g, 5.40 mol) and iodoform (4.25 g, 10.8 mmol) combined as a homogeneous solution in tetrahydrofuran (20 mL). The cold bath was removed, whereupon a quantitative reaction as indicated occurred within 1 hour. The reaction mixture was diluted with 1:1 ether-hexanes (200 mL) then filtered through a short pad of silica gel, concentrated to a solid tainted with residual iodoform.