Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](I)(C)C.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:13]2[C:18]([CH:19]=1)=[C:17]([Cl:20])[C:16]([O:21]C)=[CH:15][CH:14]=2)=[O:10])[CH3:7].CO>C(Cl)(Cl)Cl>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][N:12]1[C:13]2[C:18](=[C:17]([Cl:20])[C:16]([OH:21])=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:9]([O:8][CH2:6][CH3:7])=[O:10]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(Cl)c(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 54.5 %

Procedure:
Trimethylsilyliodide (0.6 ml) was added to a solution of ethyl-N-(3,4-dichlorobenzyl)-4-chloro-5-methoxyindole-2-carboxylate (190 mg) in chloroform (20 ml). The mixture was heated to 50 C. for 18 hours then poured into methanol (50 ml) and concentrated under vacuo. The residue was purified by column chromatography using isohexane-20% ethyl acetate/isohexane as eluent to yield the product as a yellow solid (100 mg,71%) NMR: δ (CDCl3) 1.39 (t, 3H), 4.35 (q, 2H), 5.72 (s, 2H), 6.84 (dd, 1H), 7.05-7.13 (m, 3H) 7.3 (d, 1H) 7.35 (s, 1H);m/z396.2/398.2 (M−H+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:13][NH:14][C:15]([CH2:17][N:18]([C:36](=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42]C(OC(C)(C)C)=O)[CH2:19][C:20]([NH:22][CH2:23][C:24]2[CH:33]=[C:32]([OH:34])[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([OH:35])[CH:25]=2)=[O:21])=[O:16])[CH:5]=[C:6]([OH:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O>ClC(Cl)C>[NH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([N:18]([CH2:19][C:20]([NH:22][CH2:23][C:24]1[CH:33]=[C:32]([OH:34])[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([OH:35])[CH:25]=1)=[O:21])[CH2:17][C:15](=[O:16])[NH:14][CH2:13][C:4]1[CH:5]=[C:6]([OH:12])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([OH:1])[CH:3]=1)=[O:50]
Reactant: COC(=O)c1c(O)cc(CNC(=O)CN(CC(=O)NCc2cc(O)c(C(=O)OC)c(O)c2)C(=O)CCCCCNC(=O)OC(C)(C)C)cc1O
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)c1c(O)cc(CNC(=O)CN(CC(=O)NCc2cc(O)c(C(=O)OC)c(O)c2)C(=O)CCCCCN)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 113 %

Procedure:
The methyl 4-[(2-{N-[(N-{(3,5-dihydroxy-4-(methoxycarbonyl)phenyl]methyl}-carbamoyl)methyl]-6-[(tert-butoxy)carbonylamino]hexanoylamino}acetylamino)methyl]-2,6-dihydroxybenzoate (2.31 g, 3.28 mmole) was suspended in 10 mL of dichloroethane and 2 mL of trifluoroacetic acid (26.0 mmole) was added. The deprotection reaction was stirred for 3 hours at room temperature. Dichloroethane and trifluoroacetic acid were removed in vacuo, and the resulting residue was dissolved in 20 mL of methanol, and the product precipitated by addition of ethyl ether. The product was collected by filtration, waashed with ethyl acetate and dried in vacuo under a high vacuum. Obtained 2.24 grams (97% yield) of product as the trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1ccccc1
Yield: 60 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-chloro-2-(1H-tetrazol-5-yl)aniline (3.6 mmol) and benzoyl chloride to yield the desired product (647 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.75 (d, 1H), 8.08-8.05 (m, 3H), 7.69-7.62 (m, 3H), 7.49 (dd, 1H); MS (EI) for C14H10ClN5O: m/z 300 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH2:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH3:15].[Br-].Br[C:18]1[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([CH:24]2[O:28][CH2:27][CH2:26][O:25]2)[CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:14][C:18]2[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([CH:24]3[O:25][CH2:26][CH2:27][O:28]3)[CH:23]=2)[C:10]([F:12])([F:13])[F:11])=[CH:5][C:4]=1[CH3:15]
Reactant: Cc1cc([C@H](N)C(F)(F)F)ccc1Cl
Reactant: Cc1ccc(Br)cc1C1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc([C@H](Nc2ccc(C)c(C3OCCO3)c2)C(F)(F)F)ccc1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
(S)-1-(4-Chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethylamine hydrochloride (5.00 g, 19.22 mmol) was taken up in EtOAc and washed with saturated aqueous NaHCO3, water (3×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. To a solution of the residue and bromide INT 31 (6.08 g, 24.99 mmol) in toluene (83 mL) and tert-butanol (33 mL) was added XPhos (1.83 g, 3.84 mmol) followed by Cs2CO3 (18.79 g, 57.67 mmol). The mixture was degassed for 10 minutes and Pd(OAc)2 (0.43 g, 1.92 mmol) was added. The reaction mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc and washed with H2O (3×). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (2×), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 32.
Reaction SMILES: [C:1]([C:3]1([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1(C#N)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide (140 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 4 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc to afford 92 mg (86%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide as a light yellow powder. MS (M+Na)+=454; mp=300-315° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.96 (br. s., 1H), 9.11 (s, 1H), 8.51-8.56 (m, 1H), 8.50 (s, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.67 (dd, J=9.8, 1.9 Hz, 1H), 7.15 (td, J=9.1, 2.3 Hz, 1H), 4.34-4.50 (m, 1H), 4.14 (s, 3H), 1.92-2.14 (m, 3H), 1.63-1.90 (m, 5H), 1.46 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:23][NH:24][CH3:25]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:24]([CH3:25])[CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Yield: 97.6 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (250 mg, 0.716 mmol) and dimethylamine (0.716 mL, 1.432 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-N,N-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (250 mg, 0.699 mmol, 98% yield). LC-MS (M+H)+=358.0.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:22][C:20]1[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[C:9]([NH:8][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1N
Reactant: Fc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 15 mL solution of tert-butyl 2-amino-4-bromobenzoate 1.0 g were added 1-fluoro-4-iodobenzene 0.85 mL, cesium carbonate 3.6 g, palladium acetate 8 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 23 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 8 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 23 mg were added to it, it was heated and refluxed under nitrogen atmosphere for 8 hours. After the reaction mixture was cooled to room temperature, water was added to it, insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.55 g of pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20]([CH3:24])([OH:23])[C:21]#[CH:22])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20]([O:23][C:32]([C:33]1[C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:42])([C:21]#[CH:22])[CH3:24])(=[O:3])[CH3:2]
Reactant: C#CC(C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C#CC(C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
A mixture of 21.25 g (0.064 mol) of (rac.-5-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-3-methyl-1-pentyn-3-ol), 12.12 g (0.12 mol) of triethylamine, 2.44 g (0.02 mol) of 4-dimethylaminopyridine, and 11.84 g (0.08 mol) of phthalic anhydride in 100 mL of dichloromethane was stirred at 25° C. for 3.0 h, then heated under reflux for 10 h. The reaction mixture was cooled to 25° C. and diluted with 200 mL of diethylether. The solution was washed with 3×150 mL of 1.0N HCl. The aqueous phase was further extracted with 2×200 mL of diethylether. The organic phases were combined and extracted with 3×100 mL of 1.0N ammonium hydroxide. The basic aqueous extracts were combined, cooled in an ice-bath, and acidified carefully to pH 5.0 with approximately 60 mL of cold 6.0N HCl. It was then extracted with 4×200 mL of dichloromethane. The combined extracts were dried over MgSO4. Filtration and solvent removal on a rotary evaporator (35° C., 40 mm) gave a light yellow oily residue. This material was transferred to a flask with about 100 mL of diethylether, and the solvent was evaporated as described above to give a foam, which was further dried at 25° C./0.5 mm for 18 h to yield 31 g of rac.-benzenedicarboxylic acid [3-[2,5-bis (acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl] ester as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH2:21][CH3:22])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:24])([CH3:25])[C:17](=[O:23])[N:18]2[CH2:21][CH3:22])=[CH:14][CH:13]=1)=[O:6]
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: O=C(O)c1ccncc1Cl
Product: CCN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3Cl)cc21

Procedure:
Prepared in analogy to example 26 from 3-chloroisonicotinic acid and 6-amino-1-ethyl-3,3-dimethylindolin-2-one (G. Georges et al., US2006/142247 A1). The title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([N:8]([S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=1)(=[O:52])=[O:51])[NH:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:14][N:13]1[S:37]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1)(=[O:39])=[O:38])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([N:8]([S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=1)(=[O:52])=[O:51])[NH:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([SH:17])[CH2:14][N:13]1[S:37]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1)(=[O:39])=[O:38])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)NC(=O)[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)NC(=O)[C@@H]2C[C@@H](S)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
(step 13) To 148 mg (0.17 mmol) ) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid N′-benzyl-N′-(4-methoxy-benzenesulfonyl)-hydrazide in 3.0 ml TFA were added 276 μl (1.73 mmol, 10 eq) triethylsilane at 0° C. The mixture was stirred at RT for 30 min, the solvent was evaporated and the residue was redissolved in ethyl acetate, sat. aq. NaHCO3 solution, the layers were separated and the inorganic one extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography with a gradient of ethyl acetate:hexane (1:1.5 to 1:1) yielding 76 mg (72%) (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-benzyl-N′-(4-methoxy-benzenesulfonyl)-hydrazide as white foam, MS: 612 (MH+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:10][C:6]([CH3:11])([CH2:5][S:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: C[S-]
Reactant: CC(C)(CCl)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC(C)(C)C(=O)O
Temperature: 23 °C
Reaction time: 24 h
Yield: 112.4 %

Procedure:
Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro-2,2-dimethylpropanoic acid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at 0° C. The resulting brown suspension was allowed to warm to 23° C. and stirred for 24 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (300 mL) and washed with diethyl ether (3×75 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with diethyl ether (3×75 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a colorless oil (1.2 g, 99%): 1H NMR (300 MHz, CDCl3) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37].[CH3:38][NH2:39]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:39][CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:37]
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide, (0.054 g, 0.1 mmol) was dissolved in THF (20 mL) and a 2M solution of methylamine in THF (1 mL) was added. The mixture was stirred at room temperature for 4 days. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with 0-10% MeOH/CH2Cl2 to give the title compound as an off-white amorphous solid. mp (dec) 203-207° C.; LC-MS m/z 507 (M+H)+, 1.76 min (ret. time).
Reaction SMILES: [CH2:1]([N:6]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:1]([N:6]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:22])([CH3:23])[C:12]=2[CH:11]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCN(C(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A solution of methyl 4-[1-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (190 mg) in 20 mL THF, 5 mL methanol 5 mL water was treated with lithium hydroxide hydrate (0.3 g) and stirred at room temperature for two hours. The mixture was diluted with 20 mL water, the pH adjusted to 2 with concentrated HCl and extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to give a pale yellow solid. The product was purified by flash chromatography (SiO2, 10% methanol/dichloromethane), to yield 75 mg of 4-[1-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (42) as a white solid. M.P.: 201-202° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(/C=C/C(=O)O)cn1
Yield: 71.7 %

Procedure:
A solution of benzyl (E)-3-(6-aminopyridin-3-yl)acrylate (1.3 g, 5.1 mmole) and 1.0 N NaOH (10 mL, 10 mmole) in MeOH was heated at reflux overnight. The solution was concentrated in vacuo, and the residue was dissolved in H2O. The pH was adjusted to 6 with dilute HCl, and the solid precipitate was collected by suction filtration and dried to give the title compound (0.6 g, 72%) as a white solid: MS (ES) m/e 165 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]5[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=5)[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].O>C(Cl)Cl>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]5[N:28]=[CH:27][C:26]([NH:29][C:39](=[O:41])[CH3:40])=[CH:25][N:24]=5)[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(=O)Cl
Reactant: Nc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-{4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidin-5-ylamine (Example 107) (0.321 mmol) was dissolved in DCM and triethylamine (2 eq.) was added. The reaction was cooled to 0° C., acetylchloride (1 eq.) was added dropwise and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography of the resulting oil (DCM/MeOH) provided the expected product. 1H NMR (CDCl3): δ 8.84 (1H, s), 8.36 (2H, s), 7.55 (2H, m), 7.19 (1H, s), 7.11 (2H, m), 6.94 (1H, s), 5.16 (2H, s), 4.77 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.16 (2H, m), 2.15 (3H, s), 1.75 (2H, m).
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.[C:12]([O:16][C:17](=[O:35])[NH:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:15])([CH3:14])[CH3:13]>C(COC)OC>[C:12]([O:16][C:17](=[O:35])[NH:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH2:24])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)NC2CCCC2NC(=O)OC(C)(C)C)cc1
Agent: [Li]
Solvent: c1ccc2ccccc2c1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1CCCC1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of lithium granules (1.52 g, 226.6 mmol) and naphthalene (10.9 g, 85.0 mmol) in dry dimethoxyethane (350 mL) were stirred at room temperature for 2 h. The deep blue solution was then cooled to 0° C., a solution of 4 (10.0 g, 28.33 mmol) in dry dimethoxyethane (40 mL) was added dropwise over 20 min. The mixture was stirred at 0° C. for 5 h. The undissolved lithium was filtered off, and 1 N HCl solution (60 mL) was added to the filtrate. The organic layer was separated and extracted with 1 N HCl (50 mL×2). The aqueous layers were combined, extracted with diethyl ether (50 mL×3), and then basified with 2 N NaOH solution to pH 12-14. The aqueous solution was extracted with ethyl acetate (50 mL×5). Organic layers were combined, dried over Na2SO4, solvent was removed under vacuum to afford rac-1 as a colorless oil, which solidified under vacuum to a white solid (4.08 g, 72%). Rf=0.31 (hexanes/EtOAc 2:1). Mp 60-62° C. IR (film) 3301, 2967, 1689, 1526, 1453, 1390, 1365, 1250, 1170, 1045, 1020, 870, 781 cm−1. 1H NMR (300 MHz, CDCl3) δ 4.48 (s, hr, 1H), 3.48 (m, 1H), 2.99 (m, 1H), 2.14 (m, 1H), 1.98 (m, 1H), 1.70 (m, 2H), 1.45 (s, 9H), 1.38 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 156.1, 78.9, 60.5, 59.4, 33.0, 30.9, 28.4, 20.7. HRMS (EI) m/z calcd for C10H21N2O2 [M+1]+ 201.1603, found 201.1632.
Reaction SMILES: C([NH:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:21])[C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:22]>C(O)C.[Pd]>[ClH:22].[NH2:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:21])[C:16](=[O:20])[C:17]([CH3:18])([CH3:19])[C:12]2=[CH:11][CH:10]=1
Reactant: CN1C(=O)C(C)(C)c2ccc(NCc3ccccc3)nc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1C(=O)C(C)(C)c2ccc(N)nc21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 6-(benzylamino)-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (610 mg, 2.17 mmol) and 25% aqueous HCl solution (1.2 g, 1 ml, 8.23 mmol) in ethanol (20 ml) was evacuated three times and flushed with argon. Pd (10% on activated charcoal, 231 mg, 217 μmol) was added. Degassing was repeated, then evacuated three times and flushed with hydrogen. The reaction mixture was heated to 40° C. and stirred 4 hours at this temperature under the hydrogen atmosphere. The reaction mixture was filtered through a glass fiber filter, washed with EtOH and the solvent was evaporated. The title compound was obtained as grey solid (388 mg) and was used without further purification.