Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][C:17]=2[O:30]CC2C=CC=CC=2)=[C:14]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:13]2[S:44][C:45]([C:47]([O:49][CH3:50])=[O:48])=[CH:46][C:12]1=2)[C:2]1C=CC=CC=1.Br.C(O)(=[O:54])C>C(O)(=O)C>[C:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:30])=[C:14]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[C:13]2[S:44][C:45]([C:47]([O:49][CH3:50])=[O:48])=[CH:46][C:12]1=2)(=[O:54])[CH3:2]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(OCc3ccccc3)cc1OCc1ccccc1)n2CCOCc1ccccc1
Agent: Br
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(O)cc1O)n2CCOC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a solution of methyl 4-(2-benzyloxyethyl)-5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.21 g, 1.77 mmol) in acetic acid (3 ml) was added 25% hydrogen bromide-acetic acid solution (3 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure and the residue was subjected to azeotropic evaporation with toluene (5 ml×2). The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-0:1) to give methyl 4-(2-acetoxyethyl)-6-cyclohexyl-5-(2,4-dihydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (762 mg, yield 94%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[I:20]I>C1COCC1>[I:20][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCCCCCC#CC#CCCCCCCCC
Reactant: II
Solvent: C1CCOC1
Product: CCCCCCCCC#CC#CCCCCCC#CI
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Nonadeca-1,8,10-triyne (0.802 g, 3.133 mmol) and anhydrous THF (96 mL) was cooled to −78° C. in a dry flask under nitrogen. LiN[Si(CH3)]2 (LHMDS) in THF (3.76 mmol) was added to the reaction mix slowly via dry syringe. In a separate flask I2(9.55 g, 3.76 mmol) was dissolved in dry THF (20 mL). The iodine solution was added dropwise to the nonadeca-1,8,10-triyne solution until reaction completion (notably becoming orange-red). The reaction was stirred for 30 min, and slowly warmed to room temperature. The reaction was extracted with diethyl ether and 1M K2S2O3. The organic phase was dried over anhydrous MgSO4, and concentrated by evaporation to yield 1-iodo-nonadeca-1,8,10-triyne (0.93 g, 2.45 mmol). GC/MS showed no starting material remaining. 79% yield; 1H NMR (CDCl3) δ 2.15-2.33 (m, 6H, CH2—C≡C), 1.48 (m, 6H, CH2—C—C≡C), 1.33-1.39 (m, 2H, CH2—CH2—CH3), 1.28 (m, 10H, C—CH2—C), 0.85 (t, 3H, CH3).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([OH:23])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl>C(O)(C)C>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=1[Cl:30])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O)cc3c12
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4Cl)cc3c12
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
A solution is prepared from 500 mg (1.6 mmol) of 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester in 50 ml of isopropanol, combined with 500 mg (3.6 mmol) of anhydrous, pulverized potassium carbonate, and stirred under argon for 10 minutes. Then 0.25 ml (1.99 mmol) of 2-chlorobenzyl chloride is added and the mixture refluxed for 2 hours. After suctioning off from the potassium carbonate, the filtrate is concentrated and separated over silica gel with methylene chloride:acetone=3:1 as the eluent, thus producing 172 mg of 6-(2-chlorobenzyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 135°-141° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH:15]1([NH:14][C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([F:20])[CH:22]=4)[CH:7]=3)[CH:13]=[CH:12][N:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1cccc(F)c1
Reactant: Clc1cc(-c2ccnc(NC3CCCC3)n2)ccn1
Product: Fc1cccc(Nc2cc(-c3ccnc(NC4CCCC4)n3)ccn2)c1

Procedure:
The title compound was prepared in the same fashion as described in Example 7, Step D using 4-(2-chloro-4-pyridinyl)-N-cyclopentyl-2-pyrimidinamine (i.e., the product of Step A) and 3-fluoroaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](OC)[C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: COC(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cccc(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1

Procedure:
To 3-[(3-nitro-phenyl)-methoxy-methyl]-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (535, 431 mg, 1.20 mmol, per Example 26, Scheme 49 Step 1) in acetonitrile (130 mL), were added trifluoroacetic acid (18 mL, 230 mmol) and triethylsilane (36 mL, 230 mmol). The reaction was refluxed for three hours. The reaction mixture was poured into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 80% ethyl acetate in hexane to give the compound (P-1402, 323 mg, 82%). MS (ESI) [M+H+]+=331.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[N:39][CH:38]=[CH:37]3)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][N:39]([CH3:44])[CH2:38][CH2:37]3)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cnccc3c2)C1
Reactant: CI
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4)cc3)ccc2C1

Procedure:
In an analogous manner to that previously described, by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate with methyl iodide in chloroform and subsequently reducing with sodium borohydride in methanol there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate, which was used in the next step as the crude product without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2(O)[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[Na+].[Na+].S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:19])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)=CC1=O
Reaction time: 0.67 h
Yield: 189.6 %

Procedure:
A solution of the 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol (368 g, 1.47 mol) obtained in (a) in 40/60 petroleum (40 ml) was added in a steady stream to a solution of sodium dichromate (217 g, 0.74 mol) in dilute sulphuric acid (250 g, 2.6 mol 98% sulphuric acid in 1.5 liters of water). The reaction mixture was then held at a temperature between 10° and 30° C. and stirred for 40 minutes. Water (500 ml) and diethyl ether (700 ml) were added and the aqueous layer extracted twice with diethyl ether (2×700 ml). The organic phases were then combined and backwashed with saturated sodium bicarbonate solution (1×500 ml) and water (1×500 ml). The solvent was then flashed off to give 349 g crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one as a beige coloured granular solid. Trituration in petrol gave a pure sample of the desired product, m.pt. 87°-90° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[CH:3]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[C:4]2[CH:3]=1
Reactant: O=C(Cl)c1cnn2cnc(Cl)cc12
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1cnn2cnc(Cl)cc12
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred solution of crude 5-chloropyrazolo[1,5-c]pyrimidine-3-carbonyl chloride (200 mg, 0.9 mM, 1.0 equiv) in 15 mL of dichloromethane was added cyclohexylamine (400 ul, 4.0 mM, 4 equiv). The reaction mixture was stirred for 15 minutes then quenched with 0.4 mL of acetic acid. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and dichloromethane. The dichloromethane phase was concentrated, and the crude product purified by flash chromatography on silica gel (97:3 dichloromethane:methanol) to yield 310 mg (100%) of 5-chloro-N-cyclohexylpyrazolo[1,5-c]pyrimidine-3-carboxamide. LCMS (ESI) m+H=279.1; 1H NMR (400 MHz, CDCl3) δ: 8.66 (s, 1H), 8.65 (d, 1H), 7.47 (d (broad exchangeable) 1H), 6.93 (d, 1H), 4.08 (m, 1H), 2.02 (m, 2H), 1.80 (m, 2H), 1.62 (m, 1H), 1.40 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[NH4+].[Cl-]>ClCCl.CN(C)C1C=CN=CC=1>[Si:20]([O:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=O)C1CCC(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(CO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 391A (43.6 g) and triethylamine (42.3 mL) in dichloromethane (633 mL) was added tert-butyldimethylsilyl chloride (38.1 g) and 4-dimethylaminopyridine (3.09 g) and the reaction was stirred overnight at room temperature. A saturated solution of aqueous NH4Cl was added and the layers were separated. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 0-40% hexanes/ethyl acetate.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([NH2:8])[N:4]=1.[Cl:9][C:10]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15]>>[NH2:17][C:16]1[N:6]2[N:7]=[C:3]([S:2][CH3:1])[N:4]=[C:5]2[N:8]=[C:12]([C:11]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:10]=2[Cl:9])[C:13]=1[C:14]#[N:15]
Reactant: CSc1nc(N)n[nH]1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: CSc1nc2nc(-c3ccc(Cl)cc3Cl)c(C#N)c(N)n2n1

Procedure:
According to the procedure of Example 1, Step A, commercial 5-(methylthio)-1H-1,2,4-triazol-3-amine and (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted to give the title compound as a dark brown solid. LC-MS 351 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CN(C)c1nc(NC2CCN(Cc3ccccc3)C2)nc2ccccc12
Yield: 33.6 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (5.1 g, 28.9 mmol) and 1-Benzyl-pyrrolidin-3-ylamine (5.1 g, 28.9 mmol) in BuOH (8 mL) was stirred at reflux for 26 hr, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 10% to 16% EtOAc in hexane) to give N2-(1-benzyl-pyrrolidin-3-yl)-N4,N4-dimethyl-quinazoline-2,4-diamine (3.37 g, 50%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][S:43][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (1.6 g, 3.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 6.0 mmol), Xantphos (0.087 g, 0.15 mmol), and Dioxane (25 mL). Nitrogen was bubbled through the solution for 10 minutes. Methyl 3-mercaptopropanoate (0.40 mL, 3.6 mmol) and Pd2dba3 (0.068 g, 0.075 mmol) were added and the reaction was plunged into a 95° C. oil bath for 6 hours. The reaction was cooled to room temperature and the solids filtered through celite and concentrated. The residue was purified on silica (30% EtOAc in hexanes) to afford tert-butyl 4-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (1.4 g, 81.48% yield) as a white foam.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[CH2:9][CH2:8][C:7]([CH2:15][OH:16])([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C1COCC1.CO>[F:3][C:4]1([F:17])[CH2:5][CH2:6][C:7]([CH2:15][OH:16])([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(CO)CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(CO)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1 N NaOH (0.994 mL, 0.994 mmol) was added to a solution of ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (73.6 mg, 0.331 mmol) in THF (1 mL) and MeOH (1 mL) and the mixture was stirred at rt for 3-4 h. The reaction mixture was acidified and extracted with EtOAC, washed with brine and dried (MgSO4). Evaporation of the solvent afforded Cap-6 as a beige solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.74 (s, 2H), 2.30-2.20 (m, J=13.3 Hz, 2H), 2.13-1.85 (m, 4H), 1.71-1.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][S:8][C:9]([CH3:43])([CH3:42])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.[C:46](Cl)(Cl)=[S:47]>ClCCl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][S:22][C:20]([CH3:32])([CH3:21])[C:19]([NH:18][CH2:17][CH2:16][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]=[C:46]=[S:47])=[CH:37][CH:36]=2)[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]([CH3:43])([S:8][CH2:7][C:6]2[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:42])=[O:33])=[CH:25][CH:26]=1
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)Cc2ccc(N)cc2)cc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)Cc2ccc(N=C=S)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.3 %

Procedure:
To a round bottom flask with the aniline 20 (55.7 mg, 0.0853 mmol) and dichloromethane (5 mL) was added 0.2011M solution of thiophosgene (0.42 mL, 0.0845 mmol) in dichloromethane. The heterogeneous reaction mixture was stirred at room temperature for 1 hour and the solvent was removed in vacuo to give the isothiocyanate 21 as a brown solid (68.9 mg, 116%).
Reaction SMILES: I.CS[C:4](=[NH:18])[CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:19]([NH:27][NH2:28])(=O)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CC(O)C>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[NH:18][C:4]([CH2:5][CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])=[N:28][N:27]=2)=[CH:21][CH:22]=1
Reactant: CSC(=N)CCN1C(=O)c2ccccc2C1=O
Reactant: NNC(=O)c1ccncc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1nnc(-c2ccncc2)[nH]1
Temperature: 85 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a suspension of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiopropionimidic acid methyl ester hydroiodide (880 mg, 2.34 mmol) in 2-propanol (16 mL) were added isonicotinohydrazide (337 mg, 2.46 mmol) and sodium carbonate (248 mg, 2.34 mmol). The reaction mixture was stirred at 85° C. for 1 h. Acetic acid (32 mL) was added and the reaction mixture was stirred at 130° C. for 3 h. After cooling down to ambient temperature, all volatiles were evaporated. The residue was dissolved in acetic acid (30 mL) and the reaction mixture was stirred at 130° C. for 16 h. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was poured into saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was washed water (40 mL) and brine (40 mL), dried over MgSO4 and concentrated in vacuo. The residue was suspended in dichloromethane, filtered, washed with dichloromethane and dried in vacuo to give the product as brown solid (480 mg (purity 80%), 0.96 mmol, 41%). The filtrate was evaporated and pure product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (180 mg, 562 μmol, 24.0%). MS: M=321.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11]I>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.97 mmol) in acetone (40 mL) was treated with solid CsCO3 (1.17 g, 4.97 mmol) and methyl iodide (0.310 mL, 4.97 mmol) and heated to 40° C. for 3 h. Additional methyl iodide (0.310 mL, 4.97 mmol) was added over the course of the reaction to replace that lost to evaporation. The acetone was removed in vacuo. The resulting white solid residue was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with water (1×25 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the product 2-bromo-5-methoxy-1,3-dimethyl-benzene (1.01 g, 94%) as a colorless oil, which slowly solidified upon standing. 1H NMR (CDCl3): δ 6.644 (s, 2H), 3.762 (s, 3H), 2.382 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10](=[O:12])[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][C:22]1([CH3:33])[O:26][C:25]2=[N:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][N:24]2[CH2:23]1)(=O)=O.[I-].[Na+]>O.CN(C=O)C>[CH3:33][C:22]1([CH2:21][CH2:20][N:9]2[N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[O:11][C:10]2=[O:12])[O:26][C:25]2=[N:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][N:24]2[CH2:23]1
Reactant: O=c1[nH]nc(-c2ccncc2)o1
Reactant: CC1(CCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CCn2nc(-c3ccncc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A mixture of 5-(pyridin-4-yl)-3H-[1,3,4]-oxadiazol-2-one (150 mg, 0.92 mmol), sodium hydride (41 mg, 1.03 mmol) and DMF (1.5 ml) was stirred at room temperature for 1 hour. To the reaction mixture, 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl methanesulfonate prepared in Example 42 (200 mg, 0.69 mmol) and sodium iodide (140 mg, 0.93 mmol) were added in this order followed by stirring at 50-60° C. for 6 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=25/1) to afford 3-[2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl]-5-(pyridin-4-yl)-3H-[1,3,4]oxadiazol-2-one (137 mg, yield 56%) as a white powder.