Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([OH:22])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[N:27]1([CH2:26][CH2:25][CH2:24][NH:23][C:20]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:22])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: NCCCn1ccnc1
Product: O=C(NCCCn1ccnc1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of the 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 1-(3-aminopropyl)imidazole under the conditions of Example 37 gave the title compound, mp 216°-217.5° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.S([CH2:28][N+:29]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>C(COC)OC.C(O)(C)(C)C>[C:28]([CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1)#[N:29]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)C1CCC(C#N)CC1
Reaction time: 3 h

Procedure:
To a −15° C. solution of 1 eq. of N-[2-[4-oxocyclohexyl]propyl] 2-propanesulfonamide (see Preparation 2) and 1 eq. of tosylmethyl isocyanide in dimethoxyethane is added a solution of 2.8 eq. of potassium t-butoxide in t-butanol. The cooling bath is removed and the mixture is stirred for three hours. The mixture is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to provide the crude material. Chromatography (silica gel) of the crude material affords the purified title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 91.9 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (5.3 g, 0.029 mol), ethanol (15 mL, 0.26 mol), toluene (40 mL, 0.4 mol) and sulfuric acid (1.75 mL, 0.0328 mol) were added to a 100 mL round-bottomed flask fitted with a Dean Stark trap and reflux condenser. The reaction mixture was heated with stirring under nitrogen to reflux and maintained at reflux for 5 hours. The reaction mixture was concentrated to about half volume diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and dried over sodium sulfate. Concentration yielded a straw colored oil (5.68 g, 93%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25][CH2:26][O:27][CH3:28])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:38][CH2:39][O:40][CH3:41].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:38][CH2:39][O:40][CH3:41])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25][CH2:26][O:27][CH3:28])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCCOC)c2)cc1OCOC
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 4-[4-(2-hydroxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxymethoxy benzoic acid ethyl ester (0.12 g) and potassium carbonate (0.10 g) in N,N-dimethylformamide (1 mL) was added 1-bromo-3-methoxy-propane (0.092 g), and this mixture was stirred at 70° C. for 18 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.12 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:22][C:15]1([CH3:23])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([B:29]([OH:32])[OH:30])[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[CH:12][CH:13]=2
Reactant: COB(OC)OC
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Temperature: 25 °C

Procedure:
93.9 g (259 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)[CH:35]=O>>[CH2:1]([N:3]([CH2:35][C:34]1[CH:37]=[CH:38][C:39]([O:40][CH:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[C:32]([F:31])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN1CCC(Oc2ccc(C=O)cc2F)CC1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 34.5 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 3-fluoro-4-(1-methylpiperidin-4-yloxy)benzaldehyde (55 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (9.2 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Oc2ccccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc2c(c1)CC(=O)c1ccccc1O2

Procedure:
52.5 G. of 10,11-dihydro-2-nitro-dibenz[b,f]oxepin-10-one are suspended in 900 ml. of ethyl acetate and 450 ml. of ethanol and hydrogenated in the presence of 300 mg. of platinum oxide at room temperature and normal pressure. The catalyst is removed by filtration, the filtrate evaporated in vacuo. The residue is crystallized from benzene/hexane, and there is obtained 2-amino-10,11-dihydro-dibenz-[b,f]oxepin-10-one having a melting point of 116°-117° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2].C(=O)([O-])[OH:33].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])(O)=O.[Na+]>ClCCl>[C:1]([C:4]1[C:12]2[S:11](=[O:33])[CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a mixture of N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (960 mg, 2.19 mmol) obtained in Example 166 and sodium hydrogen carbonate (276 mg, 3.29 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (530 mg, 3.07 mmol) at 0° C. and the resulting mixture was stirred at room temperature for two hours. To reaction solution was added an aqueous sodium hydrogensulfite solution, the organic layer separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 123 mg (yield: 12%) of the title compound as a low polarity isomer. Melting point: 214-216° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([N:3]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].[ClH:27]>C(Cl)Cl>[ClH:27].[CH2:1]([N:3]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][O:18][C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCN1CC2(CCNCC2)OCC1c1ccccc1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of tert-butyl 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (295 mg, 0.82 mmol) in DCM (3 mL) was added hydrogen chloride (2 mL of 4 M dioxane, 8.18 mmol). The reaction mixture was stirred for 1 hour. The solvent was decanted and the residue was triturated with methanol and hexanes. The solvent was concentrated in vacuo to obtain 8-ethyl-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride salt (230 mg, 95%) as a fluffy solid. ESI-MS m/z calc. 260.2. found 261.1 (M+1)+; Retention time: 0.2 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:23]1([C:29]#[C:30][C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)c2cc(C#Cc3ccccc3)nc(N3CCCC3)c2)cc1
Yield: 64.4 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 112 mg (1.1 mmole) phenylacetylene, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride in 5 ml dimethylformamide and 5 ml diethylamine is refluxed for 2 hours. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Recrystallisation of the residue from chloroform/ethanol yields 260 mg (64%) pure 4-(2-phenylethynyl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine als a pale yellow solid mp.: 202-204° C.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>ClCCCl>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([C:11]2([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:19]=1
Reactant: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(Cc4ccccc4)CC32)c1
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(c3cccc(C)c3)(c3cccc(C)c3)C2C1

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis(3-tolyl)perhydro-4-isoindolone (13.7 g) in 1,2-dichloroethane (150 cc) is treated with vinyl chloroformate (3.7 cc) and heated to reflux for 3 hours, then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on silica gel (particle size 0.04-0.063 mm, column 5.4 cm in diameter and 39 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80:20). Fractions 23 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(3-tolyl)-2-vinyloxycarbonylperhydro-4-isoindolone (7.4 g) in the form of a white meringue-like product.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH:14]=[O:15].O>CS(C)=O>[F:1][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH:14]=[O:15]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(C(F)(F)F)c(C=O)c1F
Temperature: 130 °C
Reaction time: 5 h
Yield: 66.4 %

Procedure:
42.0 g (711.9 mmoles) of potassium fluoride was added to a solution of 60.4 g (282.7 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 700 ml of dimethyl sulfoxide. The mixture was stirred at 120 to 140° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 36.8 g (yield: 66.0%) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>>[CH3:14][O:15][CH2:16][C:17]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:18]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCCc2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure outlined in Description 4, the title compound was prepared from 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (178 mg, 1 mmol) and methoxyacetyl chloride (101 ul, 1.1 mmol) as a yellow gum (212 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.54 (br, 1H), 7.96 (dd, 1H), 7.30 (d, 1H), 4.25 (s, 2H), 3.81 (m, 2H), 3.48 (s, 3H), 2.88 (t, 2H), 2.04 (qn, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:19][C:20]1[C:21]([CH2:32]Cl)=[N:22][CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29].[OH-].[Na+]>C(O)C>[CH3:19][C:20]1[C:21]([CH2:32][S:10][C:8]2[NH:7][C:6]3[CH:11]=[C:2]([F:1])[C:3]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:4][C:5]=3[N:9]=2)=[N:22][CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]([F:31])([F:29])[F:30]
Reactant: Fc1cc2[nH]c(S)nc2cc1N1CCCCC1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Yield: 49.5 %

Procedure:
The title compound (0.45 g, 50%) was prepared by the general procedure using 6-fluoro-5-(piperidin-1-yl)-2-mercapto-1H-benzimidazole (0.5 g, 2.0 mmol) (obtained in preparation 3), 3-methyl-4-(2,2,2,-trifluoroethoxy)-2-chloromethylpyridine hydrochloride (0.47 g, 2.0 mmol), sodium hydroxide (0.16 g, 4.0 mmol) and ethanol (10 mL). mp 160-161° C.; 1R (KBr) 3122, 1585, 1432 cm-1 ; 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.80 (m, 4H, (CH2)2), 2.38 (s, 3H, CH3), 3.00 (m, 4H, N(CH2)2), 4.40 (s, 2H, SCH2), 4.46 (q, J=7.8 Hz, 2H, OCH2CF3), 6.74 (d, J=5.5 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.26 (d, J=10.0 Hz, 1H), 8.42 (d, J=5.5 Hz, 1H), 12.50 (s, 1H, NH); Mass (m/z) 454 (M+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[NH:21]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:22]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:23][CH2:24][C:25](=O)[OH:26].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:21]([C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C@H:22]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:23][CH2:24][C:25]([NH:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:26]
Reactant: CC(C)[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Then, H-Val-Gly-OBzl•HCl and Z-Glu-OBzl (5.57 g, 15.0 mmol) were dissolved in methylene chloride (50 ml), and the solution was kept at 0° C. Triethylamine (2.30 ml, 16.5 mmol), HOBt (1-hydroxybenzotriazole, 2.53 g, 16.5 mmol), and WSC•HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 3.16 g, 16.5 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in heated ethyl acetate (1500 ml). The solution was washed with water (200 ml), 5% citric acid aqueous solution (200 ml× twice), saturated brine (150 ml), 5% sodium hydrogencarbonate aqueous solution (200 ml× twice), and saturated brine (150 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The deposited crystals were collected by filtration, and dried under reduced pressure to obtain white crystals of Z-Glu(Val-Gly-OBzl)-OBzl (6.51 g, 10.5 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1>>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Yield: 43 %

Procedure:
This compound was prepared according to the procedure of Example B19 step E, using tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate and 2,4,5-trichloropyrimidine as the starting materials in 43% yield. LCMS calculated for C27H33Cl2N6O4(M+H)+: m/z=575.1, 577.1.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O>[CH:2]1([CH2:1][CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)C(CC1CCCCC1)CC1CCCCC1
Yield: 98.3 %

Procedure:
A solution of 3.0 g (12.5 mmol) of dibenzyl acetic acid in 100 mL of HOAc was treated with 0.5 g PrO2 and reduced with H2 at 25° C., 50 psi. When the required amount of H2 had been taken up, the mixture was filtered and the solvent removed under reduced pressure. Hexane was added and the solvent removed again leaving 3.1 g (98.4% yield) of the product as an oil which crystallized on standing, mp 67°-69° C. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH2:21]([NH2:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:23][CH2:21][CH3:22])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 1-(3,4-dichloro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea (Intermediate 6, 0.3 mmol) was taken up in a 2.0 M solution of ethylamine in tetrahydrofuran (5 ml). Reaction was stirred at room temperature for 1 hour. The volatiles were removed in vacuo and the crude title compound was taken on as is, ˜75% pure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][CH:36]([F:55])[C:37]1[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][N:38]=1.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:39][N:38]=[C:37]([CH:36]([F:55])[F:35])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)F)ns1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C(F)F)ns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (50 mg, 0.100 mmol), 3-(difluoromethyl)-5-(tributylstannyl)isothiazole (296 mg, 0.699 mmol) and tetrakis (triphenylphosphine)palladium(0) (57.7 mg, 0.050 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to yield the title compound as a mixture with byproduct. The crude product was used without further purification.