Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[C:16]1([NH:15][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), aniline (0.782 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 ml) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and acidified with 1N hydrochloric acid (16 mL). The organic layer was washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL) and then chromatographed on silica gel eluting with methanol/dichloromethane 1:9 to give of 5-phenylaminosulfonyl-2-oxindole.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33]>>[C:32]([NH:31][CH2:30][CH2:29][NH:28][C:22]([C:5]1[C:4](=[O:27])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([C:6]=1[OH:21])=[N:8][CH:9]=[C:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH:11]=2)=[O:23])(=[O:34])[CH3:33]
Reactant: CC(=O)NCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)NCCNC(C)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 60.8 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and N-(2-aminoethyl)acetamide (66 mg, 0.648 mmol) was prepared N-[2-(acetylamino)ethyl]-1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 60% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.31 (br s, 1 H), 8.49 (s, 1 H), 7.38 (s, 1 H), 7.14-7.11 (m, 2 H), 7.01-6.96 (m, 2 H), 6.85 (br s, 1 H), 4.16 (m, 2 H), 4.10 (s, 2 H), 3.54 (m, 2 H), 3.42 (m, 2 H), 1.94 (s, 3 H), 1.20 (m, 3 H); HRMS m/z calcd for C22H24FN4O4: 427.1776 Found: 427.1783.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:7][N:8]=1)[NH2:2].[N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3([CH:32]=O)[CH2:31][CH2:30]3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C.C(O)(=O)C>[N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3([C:32]4[N:4]5[N:5]=[C:6]([C:9]6[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=6)[CH:7]=[N:8][C:3]5=[N:1][N:2]=4)[CH2:31][CH2:30]3)=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=CC1(c2ccc3ncccc3c2)CC1
Reactant: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.6 %

Procedure:
A mixture of methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (115 mg, 0.000469 mol) and 1-quinolin-6-ylcyclopropanecarbaldehyde (92 mg, 0.00047 mol) in ethanol (2 mL) and acetic acid (0.5 mL) was stirred at RT for 6 h. The volatiles were removed under reduced pressure. The residue was dried under high vacuum, and then dissolved in methylene chloride (6 mL). To the solution was added iodobenzene diacetate (180 mg, 0.00056 mol). The reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was flash chromatographed on a silica gel column to afford the desired product (120 mg, 60%). Analytical LCMS: (M+H)+=423.3.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Br[CH2:33][C:34]([C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)=[O:35]>C1COCC1>[C:36]12([C:34](=[O:35])[CH2:33][N:1]3[CH2:8][CH2:7][CH2:6][C@H:2]3[C:3]([N:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 72.9 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (160.7 mg, 0.50 mmol), with triethylamine (3.53 mL, 2.53 mmol, 5.0 eq), and 1-adamantyl bromomethyl ketone (156 mg, 0.61 mmol, 1.2 eq) in THF (20 mL), provided 180 mg (99%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-Prolyl] benzylamide as a white foam.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[Cl:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[Cl:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)c(Cl)c1)c1ccc(NS(C)(=O)=O)c(F)c1
Yield: 29.8 %

Procedure:
(4-tert-Butyl-3-chlorophenoxy)acetic acid (121 mg, 0.50 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (86 mg, 0.53 mmol), triethylamine (0.5 ml) and N{4-[(1R)-1-aminoethyl]-2-fluorophenyl}methanesulfonamide hydrochloride (134 mg, 0.50 mmol, WO 2005003084A1) were mixed in the same procedure described in Example 2(b) to give 68 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([N:18]2[C:26]3[CH2:25][CH2:24][CH2:23]/[C:22](=[CH:27]\[CH2:28][OH:29])/[C:21]=3[CH:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:29])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([N:18]2[C:26]3[CH2:25][CH2:24][CH2:23][C:22](=[CH:27][CH2:28][N+:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:21]=3[CH:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC/C=C1\CCCc2c1cnn2-c1ccccc1
Reactant: c1ccncc1
Product: C(C[n+]1ccccc1)=C1CCCc2c1cnn2-c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
p-toluenesulfonyl chloride (210 mg, 1.10 mmol) is added to a solution of (E)-2-(6,7-dihydro-1-phenyl-1H-indazol-4(5H)-ylidene)etanol (254 mg, 1.05 mmol) in 10 mL de pyridine cooled to a 0° C. The reaction is followed up by TLC. Next, the solvent is evaporated, the crude is diluted with CHCl3, and washed with a diluted solution of NaHCO3. The organic phase is evaporated at reduced pressure, to obtain 1-[2-(1-phenyl-1,5,6,7-tetrahydroindazol-4-ylidene)-ethyl]-pyridinium toluene-4-sulfonate (300 mg, 0.63 mmol, 60%, yellow solid).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[C:8]([C:11]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(C)C(=O)O
Reactant: CNC(=S)NN
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(C(C)(C)C)s1
Yield: 80 %

Procedure:
To a solution of 91.6 g of 4-methylthiosemicarbazide and 102.3 g of pivalic acid in 400 ml of dioxane at 90° is added slowly 160.5 g of phosphorus oxychloride at such a rate that the reaction temperature is maintained at 85°-90° C. without external heating. When the addition is complete, the mixture is heated at 85°-90° C until HCl evolution ceases (several hours), is cooled and the supernatant liquid decanted from the solid mass in the flask. The mass is broken up, slurried with 700 ml of water and made basic (pH 8-9) by the slow addition of sodium hydroxide pellets. The resulting precipitate is filtered, washed with water, air dried and recrystallized from hexane to give 119.4 g (80% yield) of 2-tert.butyl-5-methylamino-1,3,4-thiadiazole, m.p. 79°-81°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:10][C:8]([F:9])([F:11])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1

Procedure:
According to the procedure described in Example 113B, 2-amino-4-trifluoromethylpyridine (462 mg, 2.85 mmoles) was dissolved in 20 ml of tetrahydrofuran. To this solution was added potassium carbonate (511 mgs, 3.7 mmoles) followed by phenyl chloroformate (521 mgs, 3.33 mmoles). The mixture was concentrated and purified according to the procedure in Example 138 to afford phenyl 4-(trifluoromethyl)pyridin-2-ylcarbamate. 1H NMR (300 MHz, CDCl3) δ 9.53 (s, 1H), 8.56 (m, 1H), 8.38 (s, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m, 2H), 6.8 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH:6]([NH2:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.[O:16]=[C:17]1[CH2:21][CH2:20][C:19](=[O:22])[N:18]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[O:34][CH3:35].[CH3:36][CH:37]([CH3:40])[CH:38]=O>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([N:14]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH2:23][N:18]3[C:17](=[O:16])[CH2:21][CH2:20][C:19]3=[O:22])=[C:27]([O:34][CH3:35])[CH:28]=2)[CH2:36][CH:37]([CH3:40])[CH3:38])[CH2:5][C:4]([OH:3])=[O:15])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(N)c1ccc(Cl)cc1
Reactant: COc1cc(C=O)ccc1OCCN1C(=O)CCC1=O
Reactant: CC(C)C=O
Product: COc1cc(CN(CC(C)C)C(CC(=O)O)c2ccc(Cl)cc2)ccc1OCCN1C(=O)CCC1=O

Procedure:
Following procedures outlined in Example 1 step 1 is accomplished with 3-Amino-3-(4-chloro-phenyl)-propionic acid ethyl ester (5.2) and Intermediate 4.1 then using 2-methyl-propionaldehyde (3.1) in step 2 after acidic hydrolysis and purification the title compound is isolated as a white foam. Molecular Formula=C27H33ClN2O6; (M+H)+=517; Rt=2.53 min (A), purity 98.8%.
Reaction SMILES: [CH2:1]([C@H:8]([NH:36][C:37](=[O:47])[O:38][C@@H:39]1[C@H:46]2[C@H:42]([O:43][CH2:44][CH2:45]2)[O:41][CH2:40]1)[C@H:9]([OH:35])[CH2:10][N:11]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:36][C:37](=[O:47])[O:38][C@@H:39]1[C@H:46]2[C@H:42]([O:43][CH2:44][CH2:45]2)[O:41][CH2:40]1)[C@H:9]([OH:35])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(O)cc1
Reaction time: 16 h
Yield: 46.4 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (222 mg, 0.384 mmol) in 3:1 absolute ethanol:ethyl acetate was combined with Palladium on carbon (10 wt %, 44 mg) and reduced under an atmosphere of Hydrogen gas over 16 hours. The reaction was filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate:hexane. Fractions containing the product were combined and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (103 mg, 46%) as a white solid. H1-NMR (chloroform-D3): 0.91 (m, 6H), 1.61 (m, 7H), 2.93 (m, 5H), 3.70 (m, 2H), 3.92 (m, 4H), 4.17 (m, 1H), 4.79 (d, 1H), 5.01 (m, 1H), 5.66 (d, 1H), 6.12 (s, 1H), 6.94 (d, 2H), 7.26 (m, 5H), 7.72 (d, 2H). MS(ESI): 601(M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH3:6].[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1Oc1ccc(SC)cc1
Product: N
Temperature: 65 °C
Reaction time: 10 h
Yield: 83.1 %

Procedure:
2-Chloronicotinic acid methyl ester (12 g, 69.9 mmol), 4-methylsulfanylphenol (9.80 g, 69.9 mmol) and potassium carbonate (14.5 g, 0.105 mol) were suspended in dimethylformamide (300 ml) and the reaction was heated to 65° C. and stirred at this temperature under nitrogen for 10 h. It was then heated to 90° C. and stirred at this temperature for 7 h, and then progressed to 100° C. and stirred for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was diluted with water (300 ml). It was then extracted with diether (3×250 ml) and the combined organic extracts were washed with water (2×100 ml), dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (99.5:0.5:0.05, by volume) to give 2-(4-methylsulfanyl-phenoxy)-nicotinic acid methyl ester (8.0 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.CN(C=O)C.I[CH:19]([CH3:21])[CH3:20]>CCOC(C)=O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: CC(C)I
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)cn1
Temperature: 25 °C

Procedure:
A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt. The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The desired compound (as determined by TLC, I2 stain) was collected as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[S:3][C:4]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:23])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(N)sc1Sc1ccccn1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)sc1S(=O)c1ccccn1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 52.1 %

Procedure:
A mixture of 2-amino-4-methyl-5-(2-pyridylthio)thiazole (1.7 g) and 3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (20 ml) and dichloromethane (50 ml) was stirred at 5° C. for 3.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyridylsulfinyl)thiazole (0.95 g, yield: 52.2 %). mp: 190°-193° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:29]#[N:30])[N:14]2[C:19]([NH:20][CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:18][C:17]([CH3:28])=[N:16][C:15]=12.[ClH:31].C(=O)([O-])O.[Na+].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C>[ClH:31].[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[N:14]3[C:19](=[CH:18][C:17]([CH3:28])=[N:16][C:15]=13)[N:20]([CH:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[C:29]2=[NH:30]
Reactant: CCCC(CCC)Nc1cc(C)nc2c(-c3ccc(C(C)C)cc3Br)cc(C#N)n12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(CCC)n1c(=N)c2cc(-c3ccc(C(C)C)cc3Br)c3nc(C)cc1n32
Temperature: 50 °C

Procedure:
To a suspension of 8-(2-bromo-4-isopropyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (321 mg) in ethanol (1.5 mL) was added conc. HCl (0.75 mL) and heated for 50° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude product. To a solution of the crude product in ethyl acetate (2 mL) and ethanol (0.2 mL) was added 4M HCl/ethyl acetate (0.25 mL) under ice-cooling and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to provide 4-(2-bromo-4-isopropyl-phenyl)-6-methyl-1-(1-propyl-butyl)-1H-1,5,7b-triaza-cyclopenta[cd]inden-2-ylideneamine hydrochloride (350 mg) as a solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[C:17]([I:23])[CH:16]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:3]2([C:1]#[N:2])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[C:17]([I:23])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: BrCc1ccc(Br)cc1I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C#N)(Cc2ccc(Br)cc2I)C1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (2.1774 g, 11.95 mmol) and 4-bromo-1-(bromomethyl)-2-iodobenzene (5.0227 g, 13.36 mmol) in THF (30 mL) was added LiHMDS (1.0 M in THF, 15 mL, 15 mmol) at −78° C. The mixture was allowed to slowly warm to room temperature over 20 h. The reaction mixture was then quenched with saturated NH4Cl, extracted with EtOAc, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 4.2959 g (75%) of tert-butyl 3-(4-bromo-2-iodobenzyl)-3-cyanoazetidine-1-carboxylate as foam. LC-MS tR=2.17 min in 3 min chromatography, m/z 477, 479 (MH+), 462, 464 (MH+-15), 421, 423 (MH+-56).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:24]([O-])(=O)C.[Na+].C=O.[OH-].[Na+]>O.C(O)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:24][N:13]2[CH2:14][CH2:15][N:10]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[CH2:11][CH2:12]2)=[CH:2]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(Cc2c[nH]c3ncccc23)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(1-piperazinyl)benzonitrile (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were combined in water and glacial acetic acid (1:2, 1 mL) and stirred at room temperature for 18 hours. The mixture was treated with a solution of 2M NaOH and concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake was washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H) 3.14 (m, 4H) 4.03 (s, 2H) 5.60 (s, 1H) 7.09 (m, 3H) 7.61 (m, 2H) 8.06 (dd, J=8.31, 1.53 Hz, 1H) 8.20 (dd, J=4.75, 1.70 Hz, 1H). (ESI) m/z 318 (M+H)+.
Reaction SMILES: [O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCC2Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCC2Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of methyl 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylate (400 mg, 1.49 mmol) in tetrahydrofuran, methanol and water (3:1:1, 20 mL) was added lithium hydroxide monohydrate (377 mg, 8.98 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and quenched with hydrochloric acid aqueous (1N, 15 mL). Then the mixture was concentrated to give 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylic acid (350 mg, 92%) as white solid. LRMS (M+H)− m/z: calcd 254.09. found 254.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[N:3]=1>C(O)C(C)C>[ClH:1].[CH2:8]([O:12][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[N:3]=1)[CH:9]([CH3:10])[CH3:4]
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Solvent: CC(C)CO
Product: CC(C)COc1ccc2c(n1)CC(C)(C)CC2=O
Product: Cl
Yield: 35 %

Procedure:
In analogy to the procedure described in Example 9, 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one was treated with iso-butyl alcohol to give the title compound in 35% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-ethyl-benzoic acid (115 mmol) in anhydrous THF (380 mL) at 0° C. was added BH3.THF complex (1.0 N solution in THF, 230 mL) over 30 min. The resulting mixture was slowly warmed up to room temperature and the stirred for 15 hours. The reaction was carefully quenched with slow addition of water. The solvent was removed and the residue was taken up in EtOAc. The organic layer was washed with 1.0 N HCl, H2O, brine and dried over MgSO4. The solvent was removed to afford the desired product. (22 g, 89% yield). 1H NMR (300 MHz, CDCl3): δ 1.23 (t, J=7.5 Hz, 3H), 2.64-3.01 (m, 2H), 4.68 (s, 2H), 7.24-7.26 (m, 1H), 7.32-7.36 (m, 2H).