Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: C#CCN(C)C
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33](O)=[O:34])([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:39])=[N:3]1.[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH2:45])[CH3:41].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:40]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][NH:45][C:33]([C:32]1[CH:31]=[C:30]([S:27]([CH3:29])(=[O:28])=[N:26][C:24](=[O:25])[C:20]2[CH:19]=[C:18]([C:17]#[C:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:39])[CH:5]=4)=[O:8])[CH:11]=3)[CH:23]=[N:22][CH:21]=2)[CH:38]=[CH:37][CH:36]=1)=[O:34])[CH3:41]
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(C(=O)O)c4)c3)c2)n(C)n1
Reactant: CCN(CC)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoic acid (52 mg, 0.096 mmol), 2-diethylaminoethylamine (0.016 ml, 0.115 mmol), and N,N-diisopropylethylamine (0.034 ml, 0.192 mmol) in 3.0 ml DMF at room temperature was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (47 mg, 0.106 mmol). The reaction was stirred at room temperature for 1.5 hours, and then partitioned between EtOAc and dilute brine. The EtOAc layer was washed with saturated NaHCO3 solution, dilute brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow oil (combined 7 mg impure product from another lot) was chromatographed eluting with EtOAc/MeOH, then rechromatographed using a preparative TLC plate (eluted with (1:1:2.5) CHCl3:EtOAc:MeOH plus NH4OH) to give the title compound as a white solid foam (28 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O-:39])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[Cs+]>>[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(CCCCCCCCCCBr)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Yield: 51.1 %

Procedure:
This compound was prepared from the product of 13a (0.96 g; 2.7 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The crude product was purified on a 70×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. The fraction containing the product (3) was evaporated and 0.69 g (47%) product was obtained (pinkish solid, mp 70-72° C.).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>O>[Cl:12][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cn1cnc2c(Cl)nc(Cl)cc21
Solvent: O
Product: COc1ccc(CNc2nc(Cl)cc3c2ncn3C)c(OC)c1
Temperature: 110 °C
Yield: 95 %

Procedure:
In a 200 mL round bottom flask, 4,6-dichloro-1-methyl-1H-imidazo[4,5-c]pyridine (15 g, 74.2 mmol) (prepared as per WO2006122137 example A1.5) was dissolved in 2,4-dimethoxybenzylamine (25 mL, 166 mmol). The reaction mixture was heated to 110° C. for 3 h and cooled to room temperature. Water was added and a tan colored solid precipitated out. Vacuum filtration yielded a tan solid. The solid was washed with ethyl acetate and hexane to yield 6-chloro-N-(2,4-dimethoxybenzyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-amine (23.459 g, 95% yield) as a cream colored solid.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.IC.[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:36])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([O:34][CH3:35])[CH:24]=2)[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:36])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33][CH3:1])=[O:32])=[C:25]([O:34][CH3:35])[CH:24]=2)[CH2:17][CH2:18]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: COC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Reaction time: 16 h

Procedure:
30 ml of diisopropylethylamine and 1.0 ml of iodomethane were added to a solution of 1.84 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172) in 50 ml methylene chloride. The solution was stirred for 16 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.38 g of N-(trans-4-methylcyclohexyl)4-(methoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](=O)[CH3:9])=[C:5]([CH3:7])[N:6]=1.C[O:12][CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][C:4]=1/[CH:8]=[CH:9]/[C:13]([N:14]([CH3:16])[CH3:15])=[O:12]
Reactant: CC(=O)c1sc(C)nc1C
Reactant: COC(OC)N(C)C
Product: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of 1-(2,4-dimethyl-thiazol-5-yl)-ethanone (10 g, 0.06 mol) in of N,N-dimethylformamide dimethylacetal (10 mL) was refluxed under N2. After 18 h, the reaction mixture was evaporated to dryness in vacuo. The resulting solid material was crystallised from a minimum amount of isopropyl ether/CH2Cl2 to afford 9.94 g 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone as a brown powder (79%). 1H-NMR (CDCl3) δ: 2.66 (s, 6H, CH3), 2.70 (s, 6H, CH3), 5.37 (d, 1H, J=12.2 Hz, CH), 7.66 (d, 1H, J=12.2 Hz, CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[OH:11].I[CH3:24]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][N:8]([CH2:9][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[OH:11])[CH3:24]
Reactant: CI
Reactant: COc1ccc(CCNCC(O)c2ccc(C)s2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(CCN(C)CC(O)c2ccc(C)s2)cc1OC

Procedure:
A solution of α-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanol (2.29 g, 0.007 mole), described in Example 16, and the lower alkyl halide, iodomethane (9.94 g, 0.07 mole), in 70 ml benzene is stirred at 25° C for 3 days. The mixture is concentrated under reduced pressure. The residual oil is taken up in methanol and made alkaline with 10% NaOH. The mixture is extracted with chloroform. The extract is washed with water, dried (K2CO3) and concentrated to give a yellow oil, which is purified by chromatography to give the title compound; nmr (CDCl3) δ 2.41 (s, 3H), 2.46 (s, 3H), 2.6 - 2.8 (m, 6H), 3.68 (s, 1H), 3.83 (s, 3H), 3.88 (s, 3H), 4.88 (t, 1H), 6.6 - 6.9 (m, 5H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)phenylcarbamate (0.50 g, 2.24 mmol) in dichloromethane was added pyridine (3 drops), followed by the dropwise addition of thionyl chloride (0.35 mL, 4.98 mmol). The resulting reaction mixture was stirred for 30 minutes, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(chloromethyl)phenylcarbamate as an orange solid in 50% yield (0.27 g, 50%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 6.51 (br s, 1H), 4.55 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[OH:11][CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH3:10]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCC(O)c1ccc(Br)cn1
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: CCO
Solvent: Cc1ccccc1
Product: CCC(O)c1ccc(-c2ccc(C#N)cc2)cn1
Temperature: 80 °C
Yield: 45.6 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)propan-1-ol (0.3 g, 1.38 mmol) in toluene (8 mL) and ethanol (4 mL) was added 4-cyano phenyl boronic acid (0.244 g, 1.6 mmol) and a 2 M solution of aq. Na2CO3. The reaction mixture degassed with argon, Pd(PPh3)4 (0.08 g, 0.069 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 80° C. for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (100 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 15% ethyl acetate and hexane) to give 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.15 g, 45.45% yield). 1H NMR (400 MHz DMSO-d6): δ 8.78 (s, 1H), 7.89 (dd, 1H), 7.78 (d, 2H); 7.69 (d, 2H), 7.39 (d, 1H), 4.77 (t, 1H), 3.90 (s, 1H), 1.91-1.81 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:16]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C

Procedure:
A mixture of 2.6 g of methyl 3-methoxy-4-[3-(2-quinolinylmethyloxy)benzyloxy]benzoate and 0.6 g of NaOH in 15 ml of THF and 2 ml of H2O are heated at 60° C. overnight. The reaction mixture is diluted with 20 ml of HO and acidified to pH 4. The product is collected on a filter and dried to give 3-methoxy-4-(3-(2-quinolinylmethyloxy)benzyloxy)benzoic acid. (M.P. 188°-190° C.)
Reaction SMILES: [NH2:1][CH2:2]CNC1N=CC(C#N)=CC=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+]([O-])=O)=[CH:33][N:32]=2)[CH:24]=[CH:23][C:22]=1[C:40]1[NH:41][CH:42]=[CH:43][N:44]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[N:32]=[CH:33][C:34]([C:2]#[N:1])=[CH:35][CH:36]=2)[CH:24]=[CH:23][C:22]=1[C:40]1[NH:44][CH:43]=[CH:42][N:41]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(NCCN)nc1
Product: N#Cc1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[6-(2,4-dichlorophenyl)-5-imidazol-2-yl-2-pyridyl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH2:35][O:36][CH3:37])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:40](O)C>O1CCCC1.ClCCl>[CH2:37]([O:36][CH2:35][CH2:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]([CH3:23])[CH3:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH3:40]
Reactant: COCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 34 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-{1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-1H-pyrrolo[2,3-b]pyridine (0.6 g, 1.1 mmol) in ethanol (8 mL), tetrahydrofuran (15 mL) and an aqueous sodium hydroxide solution (10%, 10 mL) was heated at 45° C. for 16 h. The mixture was diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 2-{1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (160 mg, 34%): LC/MS m/e calcd for C22H25FN2O3S [M+H]+ 417.52, observed 416.8.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:47])[F:45])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 3-(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)-benzylamino)pyridin-2-yl)phenylcarbamoyl)benzylthio)propanoate (300 mg, 0.35 mmol, 1.00 equiv, 78%) in tetrahydrofuran/H2O (20/5 mL), and LiOH (150 mg, 10.00 equiv, 40%). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The solution was adjusted to pH 6-7 with hydrochloric acid (1 N). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of ethoxyethane. The resulting mixture was concentrated under vacuum. The crude product (250 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford the product (27 mg, 10%) as a yellow oil. 1H-NMR (300 MHz, DMSO-d6, ppm) δ 13.49 (s, 1H), 10.05 (m, 1H), 8.89 (m, 1H), 8.02 (m, 1H), 7.68 (m, 4H), 7.37 (m, 5H), 7.08 (m, 1H), 6.91 (m, 2H), 6.28 (m, 1H), 3.80 (s, 2H), 3.23 (s, 4H), 2.27 (m, 2H), 1.63 (s, 6H). MS (ES, m/z): 649 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][OH:12])[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]=2[CH2:3][CH2:2]1
Reactant: OCCc1cccc2c1CCO2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc2c1CCO2

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-4-yl)-ethanol (1.13 g) in dichloromethane (11 ml) was treated with triethylamine (1.25 ml), followed by methanesulfonyl chloride (0.64 ml). After 5 min the reaction mixture was poured into 2M hydrochloric acid (10 ml) and extracted with dichloromethane (2×10 ml). The combined extracts were washed with water (10 ml), dried (Na2SO4) and the solvent evaporated to give the title compound (1.76 g) as a yellow oil.
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:20]>CO>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([O-:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na+:20]
Reactant: O=C(c1cccs1)c1ccc2n1CCC2C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1cccs1)c1ccc2n1CCC2C(=O)[O-]

Procedure:
To a solution of 300 mg. of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0.1N solution. The solvent is then evaporated under reduced pressure and the residue taken up in 2 ml. of methanol, followed by precipitation with ether, to yield crude sodium 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate which can be crystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-chlorobenzylamine (45 mg, 0.32 mmol). The title compound was obtained as a yellow solid (18 mg, 14% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.40 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 7.43 (2H, dd), 7.31 (2H, dd), 4.39 (2H, m). MS m/z: 471.97, 473.95 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1CCCCC1.C(O)C>[CH2:17]([NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:29][CH:28]=1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)NCc2ccccc2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)NCc2ccccc2)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (54 mg, 0.25 mmol), 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid benzylamide (63.5 mg, 0.2625 mmol) and piperidine (2 drops) in ethanol (0.5 mL) was stirred at room temperature for 7 days. The precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:38])[C:11](=[O:37])[NH:12][C@@H:13]([CH2:34][C:35]#[CH:36])[C:14](=[O:33])[N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:32])[NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:45]>O1CCOCC1>[ClH:45].[CH3:1][NH:2][C@@H:10]([CH3:38])[C:11]([NH:12][C@@H:13]([CH2:34][C:35]#[CH:36])[C:14]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:32])=[O:33])=[O:37]
Reactant: C#CC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C#CC[C@H](NC(=O)[C@H](C)NC)C(=O)N1CCC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reaction time: 0.25 h

Procedure:
The title compound of Example 3 (33 mg) was dissolved in 4N HCl in dioxane (2 mL). This was stirred for approximately 15 mins. By TLC (100% ethyl acetate), UV spot was baseline. Excess 4N HCl in dioxane was removed via vacuum. For final compounds, material was left on vacuum pump overnight. For batch 2, material was dissolved in HPLC grade water, filtered through a 0.45 micron filter, and lyophilized overnight to give the title compound as a white semi-fluffy solid. 1H NMR (CD3OH): consistent with proposed structure. MS (m/z): 424.3.