Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccccc1Cl
Product: CCOC(=O)C(C#N)c1ccccc1OC
Yield: 86.4 %

Procedure:
Method B of the above general procedure was followed using 2-chloroanisole (143 mg, 1.01 mmol) and ethyl cyanoacetate (125 mg, 1.11 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (191.4 mg, 87%) as a colorless oil: 1H NMR (CDCl3) δ 7.40-7.35 (m, 2H), 7.03-6.99 (m, 1H), 6.93 (d, 8.0 Hz, 1H), 5.03 (s, 1H), 4.30-4.22 (m, 2H), 3.86 (s, 3H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.19, 156.48, 130.73, 129.44, 121.11, 119.11, 115.92, 111.12, 62.97, 55.72, 38.18, 13.97.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Se](=O)=[O:14]>O1CCOCC1>[CH:1]([C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:14]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1C=O

Procedure:
A solution of ethyl 2-methylnicotinate (2.0 g, 12.12 mmol), selenium dioxide (20.0 g, 18.18 mmol) and dioxane (10 ml) is heated at 135° for 4 hours. The reaction mixture is filtered and the filtrate is concentrated and purified by prep. TLC to give ethyl 2-formylnicotinate.
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.F[C:21]1[CH:22]=[C:23]([C:29]#[N:30])[C:24](=[CH:27][CH:28]=1)[C:25]#[N:26].F[C:32](F)(F)[C:33](O)=O>ClCCl>[C:29]([C:23]1[CH:22]=[C:21]([N:18]([CH2:27][CH2:28][CH2:21][CH2:22][CH2:23][CH2:32][CH3:33])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26])#[N:30]
Reactant: N#Cc1ccc(F)cc1C#N
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)c(C#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 4-fluorophthalonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile) to give the title compound.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[O:44][CH3:45])[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[O:44][CH3:45])[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(NC2CCCc3cccc(OC)c32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3cccc(OC)c32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.23, 6.78, 5.32, 4.31, 3.71, 2.89–2.77, 2.50–2.35, 1.81–1.65, 1.32, 1.18; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1172.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8]/[C:9](=[C:16]1\[CH2:17][O:18][C:19]2[C:24]([C:25]\1=O)=[CH:23][C:22]([F:27])=[CH:21][CH:20]=2)/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[NH2:29][NH2:30].[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([N:29]1[C:9]([CH2:8][CH2:7][CH:2]2[O:1][CH2:6][CH2:5][CH2:4][O:3]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]2[CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[C:25]2=[N:30]1)(=[O:33])[CH3:32]
Reactant: NN
Reactant: O=C1/C(=C(/CCC2OCCCO2)c2ccccc2)COc2ccc(F)cc21
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1N=C2c3cc(F)ccc3OCC2C1(CCC1OCCCO1)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 225 mg (0.61 mmol) 5-3 in 10 mL of pyridine was added 45 μL (0.92 mmol) hydrazine hydrate and the reaction was heated for 1 h at 90° C. After cooling to room temperature, and then to 0° C., 220 μL (3.05 mmol) of acetyl chloride was added, the cooling bath was removed, and the reaction was stirred at room temperature overnight. The reaction was dumped into a separatory funnel containing EtOAc and brine, the layers were separated, the organic phase was washed again with brine, dried over Na2SO4, and concentrated. The residue was then resuspended twice in toluene and concentrated to azeotrope off any remaining pyridine, and then purified by silica gel chromatography with EtOAc/hexanes to provide 5-4 as a mixture of diastereomers. These were again purified on silica gel with a careful gradient of EtOAc/hexanes to provide the individual isomers, each as an off-white solid. Data for the first diastereomer of 5-4 to elute from silica: LC-MS: rt=2.67 min, m/z=425 (M+1). Data for the second diastereomer of 5-4 to elute from silica: LC-MS: rt=2.63 min, m/z=425 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CCl
Reactant: Oc1ccc(Cn2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cn2cccn2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 60 g of 4-(1-pyrazolyl)methylphenol, 54.9 g of ethyl chloroacetate, 95.1 g of potassium carbonate, and 500 ml of anhydrous dimethylformamide was heated at 50° C. under stirring for 5 hours, followed by cooling to room temperature. The reaction mixture was poured into 1 liter of water, which was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with water, saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 4-(l-pyrazolyl)methylphenoxyacetate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[C:7]#N.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:24]CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=[O:24]
Reactant: N#Cc1cc(Br)ccc1I
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=Cc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-2-iodobenzonitrile (7.4 g, 24.2 mmol) in. THF (40 mL) at −78° C. was added diisobutylaluminium hydride (1M in hexanes; 24.2 mL, 24.2 mmol) over 5 minutes, and the reaction was allowed to warm to room temperature and monitored by analytical tlc. After stirring overnight at room temperature, starting material was still present, so the mixture was cooled to 0° C. and additional diisobutylaluminium hydride (1M in hexanes; 10.0 mL, 10.0 mmol) was added. After stirring for 2 hours at room temperature, no starting material was seen by analytical tlc, so the mixture was carefully quenched with freshly saturated aqueous Na2SO4 and diluted with EtOAc. The mixture was stirred vigorously for 1 hour and then filtered through Celite. The filtrate was concentrated, and the resulting oil solidified on standing. The solid was stirred vigorously in CH2Cl2 and 1N aqueous HCl, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: OC([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:22]([O:24][CH3:25])=[O:23])[CH:5]=1)C.C[C:27]([CH3:29])=[O:28].[OH:30]S(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:22]([C:6]1[CH:5]=[C:4]([CH2:29][C:27]([OH:30])=[O:28])[C:13]2[C:8]([CH:7]=1)=[CH:9][C:10]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:11][CH:12]=2)([O:24][CH3:25])=[O:23]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(C(C)O)c2ccc(OCc3ccccc3)cc2c1
Agent: O=[Cr](=O)=O
Product: COC(=O)c1cc(CC(=O)O)c2ccc(OCc3ccccc3)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.08 g (0.24 mmol) of 1-hydroxyethyl-3-carbomethoxy-6-benzyloxynaphthalene in 10 ml of acetone at 0° C. is added Jones reagent until a green precipitate forms. After stirring at 0° C. for 10 minutes, the mixture is partitioned between ethyl acetate and H2O. The organics are dried (MgSO4) and concentrated in vacuo to afford 0.081 g of 3-carbomethoxy-6-benzyloxy-1-naphthyl acetic acid in the form of a light tan solid which is used directly in the next step.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:26]>CO.O>[NH2:26][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C)n2)cc1
Reactant: N
Solvent: O
Solvent: CO
Product: Cc1nc(C(O)CNC(C)Cc2ccc(OCC(N)=O)cc2)cs1

Procedure:
1 g (0.0027 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine is dissolved in 5 ml of methanol and stirred with 5 of concentrated ammonia at room temperature for 3 hours. The mixture is then diluted with water and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol =9:1 as eluant.
Reaction SMILES: [CH3:1]OP(CC(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+].O=[CH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1>CC#N.CO>[CH2:20]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)[CH2:19][C:18]#[CH:1]
Reactant: COC(=O)Cc1ccc(CCC=O)cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C#CCCc1ccc(CC(=O)OC)cc1
Reaction time: 2 h

Procedure:
Dimethyl-2-oxopropylphosphonate (1.2 equiv, 1.5 g, 9.1 mmol) was added to a suspension of K2CO3 (3 equiv, 3.1 g, 23 mmol) and p-TsN3 (1.2 equiv, 1.8 g, 9.1 mmol) in MeCN (144 mL). The mixture was then stirred for 2 h. A solution of the methyl 2-(4-(3-oxopropyl)phenyl)acetate (1 equiv, 1.56 g, 7.6 mmol) in MeOH was then added in one portion and the reaction was stirred overnight. The solvent was evaporated under reduced pressure. The residue was partitioned between Et2O (100 mL) and water (100 mL). The aqueous phase was separated and extracted with Et2O (25 mL) twice. The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column eluting with 0-30% EtOAc in hexanes to afford methyl 2-(4-(but-3-ynyl)phenyl)acetate in 980 mg (64%). LRMS: 202.5 (calc) 225.1 (found)(MNa)+.
Reaction SMILES: IC1C(=O)N[C:5](=[O:8])NC=1.Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([I:18])=[CH:13][N:12]=1.P(Cl)(Cl)(Cl)=O.[CH3:24][O-:25].[Na+]>>[CH3:5][O:8][C:11]1[N:16]=[C:15]([O:25][CH3:24])[C:14]([I:18])=[CH:13][N:12]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ncc(I)c(OC)n1

Procedure:
As illustrated in Scheme 2, 5-iodouracil was converted to 2,4-dichloro-5-iodopyrimidine with phosphorus oxychloride, which on treatment with sodium methoxide yielded 2,4-dimethoxy-5-iodopyrimidine (2a). The latter was coupled with trimethylsilylacetylene in the presence of (Ph3P)2PdCl2 /CuI, Et3N in CH2Cl2 to give 3a, followed by deprotection of the trimethylsilyl group with n-Bu4NF to give 2,4-dimethoxy-5-ethynylpyrimidine (4a). The coupling of decaborane with the alkyne was first conducted at 110° C. in toluene in the presence of propriononitrile as an activating agent for the decaborane, which is known to give very good yields (>70%) with a variety of terminal alkynes. Unfortunately, when these conditions were applied to the compound 4a, the formation of two products in equal proportion was observed by TLC. The less polar component corresponded to a product which had the two methoxy groups, but no signal for the B-C-H proton by 1H NMR, whereas the second more polar product corresponded to the desired compound 5a. A kinetics study of this reaction monitored by TLC showed the initial exclusive formation of the desired product. However, when the reaction was maintained at 110° C., the formation of the less polar product occurred and increased if the reaction was maintained at the same temperature. These observations were confirmed by 1H-NMR after quenching the reaction with MeOH at different times. The temperature at which the reaction was performed appeared critical since it had been reported by Heying, T. L. et al. , "A new series of organoboranes. (I) Carboranes from the reaction of decaborane with acetylenic compounds," Inorg. Chem. 1963, 2, 1089-1092, that formation of the decaborane-propriononitrile complex occurs only at high temperature. Surprisingly, when the coupling reaction was conducted in the absence of propriononitrile, the formation of the only desired compound 5a was obtained in 60% yield. Demethylation of the methoxy groups using iodotrimethylsilane gave after crystallization in MeOH the desired pure 5-carboranyluracil (6a) exclusively in the closo-form. The absence of the nido-compound [(nido-7,8-C2B9H11)- ] was confirmed by mass spectroscopy and a stain test (spraying the TLC plate with 0.1% PdCl2 in concentrated HCl and heating, produces a gray color for the closo-form and a black color for the nido-form of carboranes) as a white crystalline solid. The availability of 5-carboranyluracil (6a) provided a versatile intermediate for the synthesis of a number of nucleoside analogues described below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH2:17])=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CNc1nc(Nc2ccc(Cl)cc2)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc(Nc2ccc(Cl)cc2)ncc1N
Reaction time: 0.5 h

Procedure:
3.0 g of 2-(4-chlorophenylamino)-4-methylamino-5-nitro-pyrimidine are hydrogenated in 300 ml of methanol and 150 ml of dimethylformamide in the presence of 1 g of platinum on charcoal (5% platinum) for one hour at a hydrogen pressure of 50 psi. The reaction mixture is filtered and the filtrate is evaporated to dryness in vacuo. The residue is combined with 40 ml water and stirred for 30 minutes. The solid is suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([Cl:1])[C:3]([C:13]([F:14])([F:16])[F:15])=[N:4]3)[CH2:32][CH2:31]2)=[CH:38][CH:37]=1
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)c(Cl)c1-c1ccccc1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.82–7.84 (m, 2H), 7.4–7.48 (m, 3H), 6.9–7.04 (m, 2H), 6.88–6.94 (m, 2H), 5.22 (s, 1H), 3.76–3.88(m, 2H), 3.6–3.68 (m, 2H), 3.1–3.22 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.2, 130.4, 128, 126, 118.2, 116.4, 52.2, 50, 44, 41.8.
Reaction SMILES: [Na].[CH3:2][C:3](=O)[CH2:4][CH2:5][C:6](=O)[CH3:7].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.O>CO>[CH3:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[C:10]2[C:11]=1[CH:12]=[CH:13][CH2:14]2
Reactant: CC(=O)CCC(C)=O
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc(C)c2c1C=CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23 g (1.0 mol) of sodium were dissolved in portions in 250 ml of absolute methanol. A mixture of 45.6 g (0.40 mol) of 2,5-hexanedione and 39.7 g (0.60 mol) of cyclopentadiene was then added dropwise at 0° C. in the course of 1 hour. After the mixture had been stirred at room temperature for 1 hours, 50 ml of water were added and the mixture was extracted with about 2 1 of diethylether. The residue which remained after the solvent had been stripped off was chromatographed on 1.4 kg of silica gel 60. 38 g (65%) of 4,6-dimethylindene (yellowish oil) were eluted with hexane/methylene chloride (10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].Br[C:32]1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.CC1C=CC=CC=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:32])[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.28 mmol) and 2-methyl aniline (0.28 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[C:11]=2[CH3:19])[CH:6]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:18][C:12]1[C:11]([CH3:19])=[C:10]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)=[O:32])[O:9][N:8]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1c(-c2cc(CCN)on2)ccc(C#N)c1Cl
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(-c2cc(CCNC(=O)c3cc(-c4cccnc4)n[nH]3)on2)ccc(C#N)c1Cl
Yield: 16.3 %

Procedure:
N-(2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxamide was prepared from 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chloro-3-methylbenzonitrile hydrochloride (54.8 g, 0.184 mmol), 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (34.8 mg, 0.184 mmol), HOBt hydrate (42.2 mg, 0.276 mmol), DIPEA (0.096 ml, 0.551 mmol) and EDCI (53 mg, 0.276 mmol) using DCM as solvent as described in previous Example. The crude product was purified by preparative HPLC to give the title compound 13 mg. 1H-NMR (400 MHz; CDCl3): δ 2.47 (s, 3H), 3.23 (t, 2H), 3.89 (m, 2H), 6.30 (s, 1H), 7.09 (bs, 1H), 7.22 (bs, 1H), 7.40 (m, 2H), 7.57 (d, 1H), 7.98 (d, 1H), 8.62 (bs, 1H), 8.95 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6](S(Cl)(=O)=O)[CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1.[NH2:23]C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([NH:23][S:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Product: O=S(=O)(Nc1cc(Br)ccc1Cl)c1cccnc1

Procedure:
This compound is prepared analogously to Intermediate E (step 2), by replacing 5-bromo-2-chloro-benzenesulfonyl chloride in this procedure with pyridine-3-sulfonyl chloride and aniline with S-bromo-2-chloroaniline to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.C(OC(C1(N)C=[CH:58][C:57]([NH2:60])=[CH:56][CH2:55]1)=O)(C)(C)C>>[NH2:60][C:57]1[CH:58]=[CH:24][C:23]([NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]2[C:14](=[O:15])[CH:8]([CH2:7][C:6]3[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]2)=[O:17])[CH2:31][CH3:32])=[O:21])=[CH:55][CH:56]=1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C1(N)C=CC(N)=CC1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(N)cc1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, 1-(tert-butoxycarbonyl)-1,4-phenylenediamine was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31].FC(F)(F)S([O-])(=O)=O.[Sm+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C1COCC1.C(Cl)Cl>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][CH2:31][N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])[CH3:35]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: C=CC(=O)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sm+3]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 160 °C
Yield: 32.5 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.6 mg, 0.0723 mmol), ethyl acrylate (73.7 mg, 0.728 mmol, Aldrich) and samarium(III) trifluoromethanesulfonate (34.9 mg, 0.0572 mmol) in THF (1.5 mL) were heated for 3 h at 160° C. in a microwave tube. The reaction mixture was then diluted with CH2Cl2, extracted with water, and saturated NaCl. The organic phase was separated, dried over Na2SO4, and purified by flash column to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-propionic acid ethyl ester (12.3 mg, 32.5%).