Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:7]([NH2:9])=[NH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:11](=[CH2:14])[C:12]#[N:13]>>[CH:2]1([C:7]2[N:9]=[C:12]([NH2:13])[CH:11]=[CH:14][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)C1CCCC1
Reactant: C=C(Cl)C#N
Agent: Cl
Product: Nc1ccnc(C2CCCC2)n1
Yield: 25.9 %

Procedure:
This material was obtained in analogy to example 2, step A] via the alternative preparation method from cyclopentanecarboxamidine hydrochloride (CAS 68284-02-6) (500 mg) and 2-chloroacrylonitrile (324 mg) to give 2-cyclopentyl-pyrimidin-4-ylamine as an amorphous glass (142 mg). MS (ESI): 164.6 (MH+). This material was contaminated with several side products that could not be identified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[CH2:7][CH2:6]2.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)CCC2C(=O)O
Product: COc1ccc2c(c1)CCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 86.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-methoxyindan-1-carboxylic acid (0.50 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.80 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-carboxamide (1.00 g) was obtained.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][N:59]([C:62]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[O:63])[CH2:58][CH2:57]2)[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38](=[O:47])[NH:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:36][CH2:37]1)=[O:34])[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]2[CH2:55][CH2:54][CH:53]([N:56]3[CH2:57][CH2:58][N:59]([C:62]([O:64][CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[O:63])[CH2:60][CH2:61]3)[CH2:52][CH2:51]2)=[O:12])[CH:24]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 147.2 %

Procedure:
To a solution of a crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (300 mg) in N,N-dimethylformamide (4.5 ml) were added benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (684 mg) and triethylamine (0.629 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide a crude product of benzyl 4-{1-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-ylcarbamoyl]piperidin-4-yl}piperazine-1-carboxylate as a pale yellow oil (501 mg). This was dissolved in ethanol (10 ml) and N,N-dimethylformamide (5.0 ml). 1,4-cyclohexadiene (0.633 ml) and 10% palladium on carbon (144 mg) were added thereto, followed by stirring at 65° C. for 1.5 hr. The reaction mixture was allowed to cool down to room temperature. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1, then 5:1). Fractions containing the target compound were concentrated to give the residue (56.3 mg). The residue was purified by LC-MS. Fractions containing the target compound were concentrated, which were partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and to the residue was added diethyl ether to suspend a solid. This was collected by filtration, and dried under aeration to provide the titled compound as pale yellow powder (12.7 mg).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=C(F)C=1.C(C1NC(=O)N(CC2C=CC(OC)=CC=2)C1=O)C.[CH3:43][C:44]1[C:45]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([C:59]3[CH:64]=[CH:63][C:62]([N:65]4[CH:69]([CH2:70][CH3:71])[C:68](=[O:72])[N:67](CC5C=CC(OC)=CC=5)[C:66]4=[O:82])=[CH:61][C:60]=3[F:83])=[O:58])[CH2:53][CH2:52]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1>>[CH3:43][C:44]1[C:45]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([C:59]3[CH:64]=[CH:63][C:62]([N:65]4[CH:69]([CH2:70][CH3:71])[C:68](=[O:72])[NH:67][C:66]4=[O:82])=[CH:61][C:60]=3[F:83])=[O:58])[CH2:55][CH2:56]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1
Reactant: CCC1C(=O)N(Cc2ccc(OC)cc2)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Agent: CCC1NC(=O)N(Cc2ccc(OC)cc2)C1=O
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCC1C(=O)NC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (314 mg) described in Preparation Example 114 and 5-ethyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione (176 mg) described in Preparation Example 207 and by the reaction and treatment in the same manner as in Example 508, the title compound (190 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-ethyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:11]([CH3:21])[C:12](=[O:13])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCNC(=O)Nc1ncc(Br)cc1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCn1c(=O)c2cc(Br)cnc2n(C)c1=O
Temperature: 40 °C
Yield: 34.3 %

Procedure:
To a solution of 5-bromo-2-(3-(3-methoxy-3-oxopropyl)ureido)nicotinic acid (15 g, 43.5 mmol) in acetone (150 mL) was added K2CO3 (18 g, 130.4 mmol) followed by CH3I (18 mL, 263.1 mmol). The reaction was heated in a sealed flask at 40° C. for 24 h, cooled to RT, concentrated then diluted with EA (200 mL) and water (100 ml). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by chromatography PE/EA eluted with (10:1 to 2:1) to give methyl 3-(6-bromo-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propanoate (5.1 g, 34.4% yield) as a white solid. LCMS: MH+ 342 and TR=1.266 min. Used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12](Br)=[CH:13][CH:14]=2)[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:6]=1)=[O:4].[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[S:11][C:12]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:32]=3)=[CH:13][CH:14]=2)[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
A mixture of 5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (8.0 g, 20 mmol), 3-methylsulfonylphenylboronic acid (5.0 g, 24 mmol), sodium carbonate (6.0 g, 56 mmol) and palladium tetrakis(triphenylphosphine) (1.2 g, 1.04 mmol) in 1,4-dioxane (100 mL) and H2O (5 mL) was stirred at 90° C. under N2 for 16 h. Solid was filtered off and washed with ethyl acetate. The filtrate was concentrated under vacuum to give a residue, which was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give a crude. It was triturated by DCM to afford 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g). The mother liquors from trituration were combined and concentrated to give a solid, which was purified by flash chromatography on silica gel eluted with EtOAc-hexane (0-60%) to afford another 2.8 g of product. The total yield was 7.6 g (80%). 1H-NMR (CDCl3): δ 8.04 (m, 1H), 7.84 (m, 1H), 7.73 (m, 1H), 7.50-7.58 (m, 4H), 7.47 (m, 1H), 7.23 (d, 1H), 7.20 (s, 1H), 6.82 (d, 1H), 3.98 (s, 3H), 3.07 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][OH:25])=[CH:21][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenylethanol and DBU in dioxane. ES-MS m/e (%): 362 (M{81Br}+H+, 96), 360 (M{79Br}+H+, 100), 258 ([M{81Br}+H-PhCH═CH2]+, 55), 256 ([M{81Br}+H-PhCH═CH2]+, 52).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]#[N:12].P([O-])(OCC)(SCC)=[S:14]>CN(C)C=O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([NH2:12])=[S:14]
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: NC(=S)Cc1nc2ccccc2[nH]1

Procedure:
Using the procedure of Preparation A3, 2.0 g of 2-benzimidazoleacetonitrile and 2.3 ml of diethyl dithiophosphate in 10 ml of dimethylformamide gave 150 mg of the titled compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][CH2:13][C@@H:14]1[O:18][C:17]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:16][C@H:15]1[CH2:24][OH:25].C(N(CC)CC)C>ClCl.C(Cl)Cl.O>[CH3:11][O:12][CH2:13][C@@H:14]1[O:18][C:17]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[O:16][C@H:15]1[CH:24]=[O:25]
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.4 %

Procedure:
A solution of methylsulfinylmethane (20.6 ml, 289 mmol) in CH2 Cl2 (260 mL) at −60° C., was added dropwise to a 2M solution of oxalyl dichloride (15.2 ml, 174 mmol) in CH2Cl2 (80 mL). The mixture was stirred for 20 minutes and then a solution of ((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-yl)methanol (31.3 g, 145 mmol) in CH2Cl2 (80 mL) was added dropwise. The mixture was stirred for 10 minutes and then triethylamine (101 ml, 724 mmol) was slowly added. The reaction mixture was warmed to ambient temperature and water was added. When the mixture became clear, it was extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford crude ((2R,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (34.3 g, 96.2% yield, 87% pure) which was taken on to next reaction without further purification.
Reaction SMILES: [CH3:1][C:2](O)([CH3:9])[CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C-:11]#[N:12].[Na+]>CCCCCC.CCOC(C)=O>[CH3:1][C:2]1([CH3:9])[N:12]=[CH:11][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1
Reactant: [C-]#N
Reactant: CC(C)(O)Cc1ccsc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)Cc2ccsc2C=N1

Procedure:
Treatment of the alcohol 25 from the previous reaction (15.9 g, 102 mmol) with NaCN according to general procedure B gives the cyclized imine directly as a dark liquid after FC (3:1 hexane/EtOAc). Yield: 4.15 g (25%). 1H NMR (CDCl3) 8.17(s,1), 7.36(d,1, J=4.8), 6.88(d,1,J=4.8), 2.75(s,2), 1.28(s,6); 13C NMR (CDCl3) 153.96, 141.02, 131.45, 125.79, 124.39, 56.24, 35.65, 28.03; MS(MW=165.3, EI, eE=70eV) m/z 165 (M+, base peak), 150, 138, 124, 123, 97, 86, 77, 69, 58, 45.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(=O)(O)[O-].[Na+].[CH3:52][O:53][C:54]1[CH:62]=[CH:61][C:60]([N:63]2[CH:67]=[N:66][N:65]=[N:64]2)=[CH:59][C:55]=1[C:56](Cl)=[O:57].C(OCC)(=O)C>CC(C)=O.O.CC(C)=O.CO.ClCCl>[CH3:52][O:53][C:54]1[CH:62]=[CH:61][C:60]([N:63]2[CH:67]=[N:66][N:65]=[N:64]2)=[CH:59][C:55]=1[C:56]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:57]
Reactant: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (1.20 g, 1.77 mmol) and sodium bicarbonate (0.75 g, 8.9 mmol) in acetone/water (5 mL/5 mL). Cool in an ice bath. Add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (0.37 g, 1.6 mmol) in acetone (20 mL). After 30 minutes, warm to ambient temperature. After 5 hours, filter the reaction mixture and extract the filtrate with ethyl acetate. Extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, 3% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound: Rf=0.38 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.1 g, 0.27 mmol) (from Example 25a supra) in acetone (3 mL) was added potassium carbonate (92 mg, 0.68 mmol) (Aldrich), followed by the addition of bromomethyl-benzene (54.7 mg, 0.32 mmol) (Aldrich). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-(1-benzyl-piperidin-3-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 45 mg, 36.3%).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]3[C:30](=[O:40])[C:31]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:32]4[C:33]3=[O:35])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.50 g, 3.53 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (75 ml) were added phthalimide (519 mg, 5.30 mmol), triphenylphosphine (1.39 g, 5.30 mmol) and 40% diethyl azodicarboxylate in toluene solution (2.03 ml, 5.30 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:5) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-phthalimidomethyl-1,3-thiazol-2-yl)azetidine (1.52 mg, yield 78%) as pale yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[CH:32]=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:30]([CH:38]4[CH2:40][CH2:39]4)=[CH:29][C:23]=3[C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[CH:32]=[C:31]([N:33]([C:2]4[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([C:7]#[N:8])[CH:9]=4)[S:34]([CH3:37])(=[O:35])=[O:36])[C:30]([CH:38]4[CH2:40][CH2:39]4)=[CH:29][C:23]=3[C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:16][CH:15]=1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (0.656 mL, 5.73 mmol), 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 4.77 mmol) and K2CO3 (1.980 g, 14.32 mmol) in 1,2-dimethoxyethane (20 mL) and water (5.0 mL) in a seal tube was heated to 80° C. overnight. Cooled down to room temperature, it was diluted with EtOAc. The mixture was washed with water and brine, dried over Na2SO4. It was concentrated to dryness to give the crude product (>99%) as yellow solid which was used for the next step without further purification. LCMS (m/z, ES+)=565 (M+H+).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[NH:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[NH:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH:23][CH:1]=[O:2])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]
Reactant: O=C[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1N2
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC=O)cc(Cl)c1N2
Temperature: 0 °C

Procedure:
Sodium formate (0.074 g, 0.108 mmol) was added to a suspension of compound of Example 37 (0.20 g, 0.547 mmol) in formic acid (2 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (50 mL). The solid precipitated was filtered, washed with water and dried. The crude product was purified by trituration with chloroform/methanol (3:1) to obtain the title compound. Yield: 0.18 g (84%); mp: 280-282° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.48 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.91 (s, 2H, CH2, trans minor isomer), 4.97 (s, 2H, CH2, cis major isomer), 7.30 (d, 1H, Ar, trans minor isomer), 7.47 (d, 1H, Ar, trans minor isomer), 7.56 (s, 1H, Ar, cis major isomer), 7.63 (s, 1H, Ar, cis major isomer), 7.89 (s, 1H, Ar), 7.94 (s, 1H, Ar), 8.26 (s, 1H, CHO, cis major isomer), 8.29 (s, 1H, NH), 8.78 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.46 (s, 1H, NH, cis major isomer); MS: m/e (ES+) 395 (M+1); analysis: C17H14ClNO6S requires C, 51.72H, 3.83; N, 7.10; Cl, 8.98; S, 8.12. found C, 51.24; H, 3.80; N, 6.79; Cl, 9.22; S, 7.84%.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:33]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:33]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (980 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (760 mg, yield: 82%). This was recrystallized from acetone-hexane. Melting point: 161–162° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][C:9](=[CH:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:8](=[O:22])[C:7]2=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:8](=[O:22])[C:7]2=1
Reactant: [H][H]
Reactant: Cc1[nH]cnc1C=C1CCc2[nH]c3c(F)cccc3c2C1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2[nH]c3c(F)cccc3c2C1=O
Yield: 46.7 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl)methylene]-4H-carbazol-4-one (728 mg) in absolute ethanol (30 ml) was added to a suspension of 5% palladium on charcoal (100 mg) in ethanol (30 ml), and the resulting mixture was hydrogenated at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered, and the filtrate was evaporated in vacuo to leave an oil which was purified by FCC eluting with ethanol:ethyl acetate (1:5) to give the title compound (342 mg), m.p. 135°-140°, t.l.c. (ethanol:ethyl acetate, 1:5) Rf 0.175.