Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:6]([N:11]=[C:12]=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([C@@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24])[CH2:15][CH2:16][CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH:1]1([C@H:6]([NH:11][C:12]([O:24][C@@H:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Reactant: COC(=O)[C@@H](N=C=O)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCCC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A solution of methyl (2S)-cyclopentyl(isocyanato)acetate (1.57 g, 8.56 mmol) and (1R,2R)-2-pent-4-en-1-ylcyclopentanol (Intermediate A9) (1.20 g, 7.78 mmol) in PhMe (56 mL) was treated portionwise with DMAP (0.95 g, 7.78 mmol). The resulting mixture was stirred for 5 hours at 85° C., then cooled to 20° C., and diluted with EtOAc and HCl(aq.) (1N). The organic layer was separated, washed with brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography (gradient elution, 4-40% Et2O/petroleum ether) to afford the title compound (1.97 g, 76%) as an oil. LCMS (ES+) m/z, 338 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.N.[OH:29]O>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:29])=[CH:22][CH:21]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc(C#N)cc4)s3)n2)c1
Reactant: OO
Agent: N
Solvent: CCO
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc(C(N)=O)cc4)s3)n2)c1
Temperature: 40 °C
Reaction time: 60 h

Procedure:
4-(5-(6-(4-methylpyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzonitrile (Example 51, 40 mg, 0.11 mmol) was suspended in EtOH (8 ml). Aqueous ammonia (28-30%, 4 ml) was added followed by H2O2 (35%, 1 ml). The reaction mixture was stirred at 40° C. for 2.5 days. Aqueous ammonia (2 ml) and H2O2 (0.250 ml) were added and the reaction mixture was stirred a further 24 hours at 40° C. The reaction was partitioned between H2O (30 ml) and EtOAc (70 ml). After separation, the aqueous phase was extracted again with EtOAc (70 ml). After evaporation, and purification of the crude product by dry flash chromatography over SiO2 eluting with EtOAc/MeOH (5%-10%)/NEt3 (0.5%), 4-(5-(6-(4-methylpyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzamide was obtained as a yellow solid (46 mg, 74%). 1H NMR (300 MHz, DMSO-d6) δ 9.72 (br s, 1H), 8.59 (br s, 1H), 8.20-7.98 (m, 6H), 7.95 (d, J=8.6 Hz, 1H), 7.78-7.70 (m, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.57-7.45 (m, 3H), 2.25 (s, 3H). (APCI+) m/z 388 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:24](O)[CH2:25][CH3:26]>>[CH2:24]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:22][CH:23]=1)=[O:3])[CH2:25][CH3:26]
Reactant: CCCO
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1
Product: CCCOC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 4--CH3 (CH2)2OOCC6H4 ], m.p. 54° C., from 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole (Example 16) and n-propyl alcohol; MIC vs. rhinovirus Type 2 in vitro=0.07 μg/ml.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:32][C:30]3[CH:29]=[CH:28][C:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:26]([F:25])[CH:31]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (0.43 mmol, 1.0 eq.) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 152 mg (0.65 mmol, 1.5 eq.) of tert-butyl 2-fluoro-4-aminophenylcarboxylate were reacted according to General Method 5C. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 20%-50% mixtures). Yield: 250 mg (purity 93%, 99% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)c(F)c1F
Reaction time: 48 h
Yield: 41.6 %

Procedure:
To a stirred solution of ethyl 4-amino-2,3-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF—MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,3-difluorophenylacetic acid (200 mg, 42%) as a white solid. 1H-NMR (CDCl3) δ2.30 (s, 3H), 3.35 (s, 2H), 6.98 (m, 1H), 7.04 (m, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.90 (m, 1H); MS FAB) m/z 321 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CCCOC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
Tert-butyl 4-[3-(4-chlorophenyl)propoxy]-piperidine-1-carboxylate (0.151 g, 0.427 mmol) prepared in Reference example 114 was dissolved in methylene chloride (4 ml), to which trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride twice. The extracts were combined and washed with brine. The organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dried in vacuo to afford 4-[3-(4-chlorophenyl)propoxy]piperidine (0.109 g, yield 92%) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:25]([CH3:26])[NH:28][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=N)N
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c2c1-c1nc(C)[nH]c1CC2
Yield: 30 %

Procedure:
To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.66 mmol) in 15 mL 1,4-dioxane is added acetamidine hydrochloride (3.32 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. To the residue is added 14 mL CHCl3 and 2 mL MeOH and the mixture is stirred for 10 min. The solid is filtered off. The mother liquid is concentrated and is chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 2-methyl-3,4,5,6-tetrahydro-imidazo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (30%). 1H NMR (DMSO-d6) 1.30 (t, 3H), 2.28 (s, 3H), 2.70 (t, 2H), 2.79 (t, 2H), 4.22 (q, 2H), 7.20 (s, 1H), 10.58 (s, 1H), 11.43 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]([CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:29])[CH3:12])=[O:10].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:29][C@@H:15]1[C@@H:14]([CH2:13][N:11]([CH3:12])[C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16]1)(=[O:32])[CH3:31]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN(C)C(=O)Cc3ccccc3Br)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CN(C)C(=O)Cc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.05 g of 5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine was dissolved in 2 ml of dry pyridine and the solution was treated with 0.12 ml of acetic anhydride. The mixture was stirred at room temperature for 5 hours and then evaporated. The residue was re-evaporated with toluene to give a solid which was triturated with diethyl ether and then removed by filtration. There was obtained 0.03 g of 3'-O-acetyl-5'-[2-(2-bromophenyl)-N-methylacet-amido]-2',5'-dideoxy-5-ethyluridine of melting point about 170° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[Cl:27]Cl.O>C(O)(=O)C>[Cl:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: ClCl
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiazin-3-one in 12.5 liters of glacial acetic acid was added 1.25 kg of potassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 liters of H2O with vigorous stirring. The 4-chloro-3H-phenothiazin-3-one precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chloro-3H-phenothiazin-3-one which was recrystallized from toluene, m.p. 221°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)O
Product: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)propanoic acid, gave (S)-2-amino-N-(4-(4-chlorophenoxy)phenyl)-3-(4-fluorobenzyloxy)propanamide (200 mg, 50%).
Reaction SMILES: [C-:1]#[N:2].[K+].[C-]#N.[Na+].[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][C@H:17]([CH2:20]OS(C)(=O)=O)[CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([O:11][C:12](=[O:13])[NH:14][C@H:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][C:1]#[N:2])[CH2:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COS(C)(=O)=O)C1
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC#N)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
In a round-bottomed flask, methanesulfonic acid (cis)-3-tert-butoxycarbonylamino-cyclopentylmethyl ester (crude from Step 4, 779 mg) was dissolved in DMF (5 ml). Potassium cyanide (277 mg, 4.25 mmol) was added and the reaction mixture was stirred at 80° C. overnight. Sodium cyanide (104 mg, 2.12 mmol) was added and the reaction mixture was stirred at 80° C. for 48 h. The reaction was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 190 mg (38%, 2 steps) of (cis-3-cyanomethyl-cyclopentyl)-carbamic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: OCCCCCCCl
Product: O=C1CCN(CCCCCCO)CC1

Procedure:
1-(6-Hydroxyhexyl)4-piperidone is prepared from 4-piperidone and 6-chloro-1-hexanol essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)O)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC/C=C/c1ccc(NS(C)(=O)=O)cc1)CCC1CCCC1

Procedure:
In the process as described in Example 2 the product of Example 9 is treated with trifluoroacetic acid to give the titled compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:34][C:33]([F:36])([F:35])[C:29]1[N:28]=[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
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: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3cccc(C(F)(F)F)n3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (190 mg, 0.52 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (10 mg, 0.5 mmol/g, 0.005 mmol) was added along with 2-Bromo-6-trifluoromethylpyridine (174 mg, 0.78 mmol) and 500 μl of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 95 mg of title compound were recovered as whitish solid (47%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-{(2S)-5-[6-(trifluoromethyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide.
Reaction SMILES: [C:1]([C:5]1[C:10]2[S:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:20])[CH2:17][CH2:18][CH3:19]>>[C:1]([C:5]1[C:10]2[S:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc2c1SCC2(C)C
Reactant: CCCC(=O)O
Product: CCCC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CS2

Procedure:
Substantially the method described in Example 1 is employed for the reaction between 7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]thiophene and butanoic acid, to provide 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]thiophen-5-yl)-butan-1-one as a colorless oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCOc2ccc(-c3ccc(=O)[nH]n3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][CH2:18][N:19]1[C:28](=[O:29])[CH2:27][C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]1=[O:30]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]2[C:20](=[O:30])[CH2:21][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:27][C:28]2=[O:29])[CH2:14][CH2:15]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Solvent: CCOCC
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2cc(F)c(F)cc2F)CC1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (0.94 g, 4.35 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione (1.00 g, 4.35 mmol) was heated with stirring at 160° C. for 7 hours. The residue was partitioned between ethyl acetate (40 mL) and saturated aqueous sodium carbonate (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL) and the combined ethyl acetate fractions dried over sodium sulfate. The solvent was removed and the residue was purified by flash chromatography over silica gel, eluting with a gradient of hexane to hexane/ethyl acetate (1:1). The solvent was removed from the desired product [Rf=0.7, hexane/ethyl acetate (1:1)], leaving a pale tan oil which slowly solidified (0.652 g, 1.60 mmol, 37%, mp 230-234° C.). 1H NMR (300 MHz, CDCl3) δ6.89 (ddd, 1H, J=11.7, 10.2, 7.5 Hz), 6.74 (dt, 1H, J=12.0, 8.1 Hz), 3.95 (t, 2H, J=6.6 Hz), 2.97 (t, 4H, J=4.7 Hz), 2.65 (t, 4H, J=4.7 Hz), 2.60 (s, 4H), 2.54 (t, 2H, J=6.5 Hz), 1.74-1.70 (m, 4H), 1.55-1.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ172.7, 151.0 (ddd, J=243.8, 8.5, 1.7 Hz), 146.9 (ddd, J=241.6, 12.2, 3.2 Hz), 144.7 (ddd, J=242.3, 13.9, 12.4 Hz), 137.4 (ddd, J=9.6, 6.1, 2.9 Hz), 107.9 (dd, J=20.7, 4.1 Hz), 106.4 (dd, J=26.6, 21.5 Hz), 55.9, 53.6 (2C), 51.3 (d, 2C, J=3.0 Hz), 45.4 (2C), 40.1, 38.0 (2C), 36.9, 24.7 (2C); ESI-MS m/z 410 (MH+). The title compound was dissolved in ether and precipitated by addition of 1N HCl in ether, giving a white solid. The solid was recrystallized from hot methanol/chloroform (4:1) (with hexane added to cloudiness), giving white flakes (0.43 g, 0.96 mmol, 22%): mp 234-236.5° C., Anal. Calcd. For C21H26N3F3O2·1.2 HCl: C, 55.66; H, 6.05; N, 9.31; F, 12.58. Found: C, 56.06; H, 6.09; N, 9.21; F, 12.20.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[N:11]#[C:12][NH2:13]>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]([NH2:13])=[NH:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1N
Reactant: N#CN
Agent: Cl
Solvent: O
Product: COc1cc(Br)ccc1NC(=N)N
Temperature: 60 °C
Reaction time: 6 h
Yield: 99.2 %

Procedure:
To a solution of 4-bromo-2-methoxyaniline 7.1 g (35.1 mmol) in HCl 25% m/v 20 mL, cyanamide 20.6 g (494.3 mmol) was added in portion (1.6 g every half hour). The reaction was stirred at 60° C. for 6 hours, then cooled down to room temperature, diluted with H2O (20 mL), extracted with AcOEt (10 mL). NaOH 35% (30 mL) was added to pH>>14. The aqueous phase was extracted with AcOEt (3×50 mL), dried over Na2SO4 and concentrated to afford 8.5 g (quantitative yield) of the title compound.
Reaction SMILES: CO[C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1(C)C(C)=CC=CC=1>[N:11]1([C:3]([CH:4]2[NH:5][C:6](=[O:9])[CH2:7][CH2:8]2)=[O:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Solvent: Cc1ccccc1C
Product: O=C1CCC(C(=O)N2CCOCC2)N1
Temperature: 140 °C

Procedure:
A mixture of 143 g of pyroglutamic acid methyl ester (1 mol) and 139 g morpholine (1.60 mol) in 900 ml of xylene is heated to 140° C. for 20 h. The xylene is evaporated to a volume of 500 ml. From the suspension obtained, the precipitate is filtered off, washed with THF to yield the desired compound after drying in vacuo. From the filtrate the solvent is evaporated completely. This crude product [(R/S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one] is filtered over 800 g silica gel with THF as the solvent and evaporated to dryness to yield a second crop of the desired compound. This compound is used directly in the next step. HPLC analysis shows the material to be in an enantiomeric ratio: 55.8:44.2 [(4-a, R1=H; R4=morpholine): (4-b, R1=H; R4=morpholine), respectively].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ncccc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccnc1N
Yield: 78 %

Procedure:
A stirred suspension of 2-amino-nicotinic acid (12.15 g, 87.95 mmol) in a mixture of MeOH (175 mL) and THF (500 mL), under nitrogen at room temperature, was added a solution of trimethylsilyldiazomethane (2M in hexane, 50 mL, 99.5 mmol)) dropwise. After completion of the reaction the volatiles were removed in vacuo and the crude product triturated with disisopropyl ether, filtered and dried to give 2-amino-nicotinic acid methyl ester (10.44 g) as a yellow solid.