Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:20][CH2:21]OS(C)(=O)=O)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:20][CH2:21][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1
Reactant: COc1cc(CN2CC(CCOS(C)(=O)=O)(Cc3ccccc3)CC2=O)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccccc4)CC(=O)N(Cc4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-(phenylmethyl)-5-oxopyrrolidine (0.05 g, 0.10 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.03 g, 0.10 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.20 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:22][CH:23]=3)[N:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17]=2[O:40][C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=2[CH3:48])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:47][C:45]1[CH:44]=[CH:43][C:42]([CH3:48])=[C:41]([CH:46]=1)[O:40][C:17]1[N:18]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(OCC(=O)OC(C)(C)C)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccc(OCC(=O)O)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
The compound of step 1 (88 mg, 133 μmol) was dissolved in DCM (20 ml), TFA (5 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the obtained solid was purified by preparative HPLC. The eluate was lyophilized overnight. The residue was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 45 mg of the title compound were obtained in the form of the [2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indol-6-yloxy]-acetic acid hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[C:33]3[C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][CH:32]=[C:33]4[C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Yield: 75 %

Procedure:
A solution of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (0.11 g, 0.36 mmol), methyl 7-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.083 g, 0.30 mmol), and cesium carbonate (137 mg, 0.42 mmol) in dimethylformamide (0.73 mL) was heated to 65° C. for 3 hours. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes) to provide the title compound (0.123 g, 75%). 1H NMR (DMSO-d6): δ 8.93 (s, 1H), 8.19-8.14 (m, 2H), 8.07 (d, J=9 Hz, 1H), 7.84 (dd, J=2, 9 Hz; 1H), 7.63 (d, J=8 Hz, 4H), 7.59-7.52 (m, 2H), 6.93 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.93 (s, 3H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI LCMS m/z 546 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8]C[C@H:6]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=[O:3])[CH3:2].BrC1C=CC(O[C@@H]2CCC[C@H]2O)=CC=1[F:33]>>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:6]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[C:16]([F:33])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1
Product: CC(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1

Procedure:
The title compound in Step 2 was prepared according to the general procedure for the synthesis of (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate in Example 7, except that trans-2-(4-bromo-3-fluorophenoxy)cyclopentanol was used instead of trans-2-(4-bromophenoxy)cyclohexanol. The less polar material from the chromatographic purification on silica gel provided (1R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate as an oil. Yield: 6.42 g, 20.2 mmol, 48% over 2 steps. 1H NMR (400 MHz, CDCl3) δ 1.67-1.75 (m, 1H), 1.79-1.92 (m, 3H), 2.05-2.20 (m, 2H), 2.08 (s, 3H), 4.60 (m, 1H), 5.14 (m, 1H), 6.66 (ddd, J=8.9, 2.8, 1.1 Hz, 1H), 6.78 (dd, J=10.5, 2.8 Hz, 1H), 7.40 (dd, J=8.8, 8.1 Hz, 1H).
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]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc(OC)c1OC

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3,4,5-trimethoxyaniline (93.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (71.0 mg, 32% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.45 (1H, m), 9.01 (2H, m), 8.68 (1H, m), 7.06 (2H, m), 3.32 (9H, s). MS m/z: 514.19, 516.12 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1.[ClH:36]>CCOCC>[ClH:36].[ClH:36].[CH3:1][O:2][CH2:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6]1
Reactant: COCC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: COCC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
tert-Butyl [(1R,3S)-3-(2-methoxyethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (252 mg, 0.503 mmol) was dissolved in a 2 M solution of hydrogen chloride in ether (8 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated to give the desired product as a yellow powder (0.36 g, 96%). MS calculated for C19H27F3N4O2 (M+H) 401.3; found 401.3.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(F)cc2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (50 mg, 0.24 mmol) in THF (2 mL) at −78° C. was added 1.0 M 4-fluorophenylmagnesium bromide in THF (0.5 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH:14][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
Triethylamine (7 mL, 50 mmol) was added to a solution of β-alanine methyl ester hydrochloride (5.25 g, 37.5 mmol) in methylene chloride (100 mL). The solution was cooled to 0° C. and t-butyl bromoacetate (4.88 g, 25 mmol) in methylene chloride (100 mL) was then added. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo; 0.80 g (14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=2)[N:10]=1
Reactant: COc1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Yield: 65.1 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (2.0 g, 4.23 mmol), TFA (30 mL) and DCM (5 mL) to afford 1.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 4.47 (d, J=5.4 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.67-7.74 (m, 3H), 7.93 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 10.11 (m, 1H), 12.86 (br s, 1H); MS (m/z): 471.88 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)[CH:12]=[CH2:11]
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1ncc2cc(Br)ccc21
Yield: 35.9 %

Procedure:
5-Bromoindazole (Bioorg. Med. Chem. Lett., 11:1153-1156 (2001)) (3.94 g, 20.0 mmol), allyl bromide (2.6 mL, 30 mmol) and potassium carbonate (4.15 g, 30.0 mmol) were heated in DMF (25 mL) at 100° C. for 18 hours. The reaction was cooled, filtered through celite, and the solids were washed with EtOAc. The solution was concentrated to near dryness and then partitioned between EtOAc and water. The organic phase was washed with NaHCO3, dried (MgSO4), concentrated, and purified by column chromatography (silica gel, 7% EtOAc/hexanes) to provide the N1 isomer (faster eluting) 1-allyl-5-bromo-1H-indazole (1s) (1.7 g, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.06-5.97 (m, 1H), 5.24 (dd, J=10.2, 1.6 Hz, 1H), 5.12 (d, J=16.4 Hz, 1H), 5.01-5.00 (m, 2H); MS (ESI+) m/z 237, 239 (M+H, Br pattern) detected; HPLC (5 to 95%) 2.98 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:17][C@@H:18]1[C@@H:22]([CH2:23][O:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1)c1cccnc1
Reaction time: 3 h
Yield: 69 %

Procedure:
A 0.21 g quantity of nicotinoyl chloride (hydrochloride) was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at 80° C. for 3 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed twice with 20 ml of water. The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.18 g of the title compound in a yield of 69%.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:11]>CO.O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:11]
Reactant: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1ccccc1

Procedure:
50 mmol benzoic acid is dissolved in 50 mL methanol. 50 mmol NaOH dissolved in 50 mL water is added slowly to the benzoic acid solution prepared while stirring to obtain sodium benzoate. 50 mmol silver nitrate dissolved in 50 mL water is added to the sodium benzoate solution, and then white precipitate forms fast. The precipitate is silver benzoate formed by exchange of Na+ and Ag+ by ionization tendency, washed to remove unreacted silver nitrate and NaOH with water, filtered and further washed several times to remove unreacted benzoic acid with methanol, and dried at 50° C. to obtain final silver benzoate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].FC(F)(F)S(O[CH2:21][CH:22]([F:24])[F:23])(=O)=O.[H-].[Na+]>CN(C)C=O>[F:23][CH:22]([F:24])[CH2:21][N:4]1[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]1=[O:14]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC(F)F)CC1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 75.8 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) in N,N-dimethylformamide (4 ml) at −35° C. under argon was added sodium hydride (80 mg, 1.998 mmol). The reaction mixture was warmed to 0° C. over 2 hours, quenched with water (10 ml) and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg). LC/MS [M+H]+=265. (ii) 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.757 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene (×2) to give 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (0.757 mmol) which was used in the next step. LC/MS [M+H]+=209.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][Si:10]([CH3:15])([CH3:14])[CH2:11]CO>>[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:15])([CH3:14])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: C[Si](C)(C)CCO
Reactant: COC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCC[Si](C)(C)C
Yield: 98 %

Procedure:
10.66 gm (91.8 mMol) methyl acetoacetate and excess 2-(trimethylsilyl)ethanol were heated together at reflux. Methanol was distilled (68° C.) from the reaction mixture and heating was continued until the head temperature dropped below 65° C. The reaction mixture was then concentrated under reduced pressure at 40° C. to provide 18.24 gm (98%) of the desired compound as a pale yellow oil.
Reaction SMILES: F[C:2]1[C:30]([CH3:31])=[C:29]([F:32])[C:28]([F:33])=[CH:27][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([NH:22][C:16]1[N:15]=[C:14]([N:13]2[C:2]3[C:3](=[CH:27][C:28]([F:33])=[C:29]([F:32])[C:30]=3[CH3:31])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[C:19]([F:20])=[CH:18][C:17]=1[F:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)C(=CNc1nc(NC(C)(C)C)c(F)cc1F)C(=O)c1cc(F)c(F)c(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
To the solution of 4.6 g of the thus obtained ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)-3-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]aminoacrylate in 10 ml dimethylformamide was added 1.35 g of potassium carbonate, and the mixture was stirred at 100° C. for 50 minutes. The reaction solution was extracted by adding water and acetic acid, and the organic layer was collected and dried over magnesium sulfate. The solvent was distilled off, and the residue was collected by filtration with ethanol and washed with diethylether to obtain 2.6 g of the title compound as a pale yellow powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12](=[O:17])[C:11]=1[C:18]#[N:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([O:17][C:12]1[C:11]([C:18]#[N:19])=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]=[C:14]([CH3:16])[N:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Reactant: ClCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(OCc2ccccc2)n1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd H, 6.6 g, 24 mmol), Ag2O (6.3 g, 27 mmol), and benzylchloride (4.1 g, 33 mmol) in toluene (79 mL) was heated at 100° C. for 21 hours. The reaction mixture was filtered through CELITE® then concentrated under vacuum. The residue was purified by column chromatography (0-30%, EtOAc/heptane) to give 2-(benzyloxy)-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)-6-methylpyridine-3-carbonitrile (Cpd I, 6.5 g, 74%) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1OC[C@@H](O)CN1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Temperature: 21 °C
Yield: 49 %

Procedure:
N-[2-({(2S)-3-[4-(5-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-methoxyphenyl]acetamide, obtained in Example 32iii), (300 mg, 0.6 mmol) was dissolved in dichloromethane (5 ml) and stirred under nitrogen (N2) at ambient (20-22° C.) temperature. Boron tribromide solution (1 M in dichloromethane, 2 ml, 2 mmol) was added dropwise. After stirring at ambient temperature for 17 hr dichloromethane (5 ml) and water (5 ml) were added. After 1 hr the solvent was removed in vacuo. The residue was purified by gradient flash chromatography on silica gel (CH2Cl2/MeOH, 100/0 to 70/30) and lyophilized yielding the title compound as a white solid (134 mg, 49%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]
Reactant: NCCCCCCN1CCOCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCCN5CCOCC5)n4)cc3)cc12

Procedure:
Using 6-morpholin-4-ylhexylamine (reference example 93i) and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates MS (ion spray) m/z 552 (M+H)+.