Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:16]=3)[S:12][C:11]=2[CH:31]=1)=[O:6].[BH4-].[Na+]>CO.ClCCl>[CH3:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([CH3:1])[CH2:29][CH2:30]4)[N:16]=3)[S:12][C:11]=2[CH:31]=1)=[O:6]
Reactant: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCNCC4)ncc3C)sc2c1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCN(C)CC4)ncc3C)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous formaldehyde (37.4% or 13.5 M, 0.711 mL, 9.60 mmol) is added to a stirred solution of 2-[5-methyl-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid methylamide (346 mg, 0.845 mmol) in CH3OH (10 mL) and dichloromethane (10 mL) at room temperature. The resultant mixture is stirred for 90 minutes. After being cooled to 0° C., the mixture is treated with powdered sodium borohydride (211 mg, 8.00 mmol) and stirred for 60 minutes. The mixture is allowed to stir at room temperature for 3 hours, concentrated and subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-8%, to give the title compound as a yellowish foam (280 mg, 78% yield). ES+(m/z) 424 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17]2)[CH:7]=1)[C:10]#[C:11][CH2:12][CH3:13]
Reactant: FC(F)(F)C1CCCNC1
Reactant: CCC#CCOc1cc(Cl)ncn1
Product: CCC#CCOc1cc(N2CCCC(C(F)(F)F)C2)ncn1
Reaction time: 10 h
Yield: 47.1 %

Procedure:
0.2 g of 4-chloro-6-(2-pentynyloxy)pyrimidine and 0.23 g of 3-trifluoromethylpiperidine were mixed and left for 10 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.15 g of 6-(2-pentynyloxy)-4-(3-trifluoromethylpiperidino)pyrimidine (hereinafter, referred to as Compound (25)).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62]C=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].C[O:65]C(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:58]1[CH2:59][CH2:60][O:65][CH2:62][CH2:63]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C5CCOCC5)[nH]3)cc2CO4)[nH]1)C(C)C

Procedure:
This compound was made in an analogous manner to methyl (S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amide coupling. LCMS-ESI+: calculated for C47H54N8O8: 858.98; observed [M+1]+: 860.02.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[NH4+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: N#C[S-]
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a well-stirred mixture of 108 g of o-nitroaniline and 128 g of ammonium thiocyanate in 400 ml of acetic acid there is added dropwise a solution of 128 g of bromine in 160 ml of acetic acid below 20° C. The mixture is stirred for 4 hours at room temperature and then poured into 4 liters of water. The resulting solid is filtered off and crystallized from ethanol to yield 86.7 g, m.p. 111°-114° C.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCC.[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[C:8]1([CH:14]([Br:27])[CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(CCCOc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCC
Solvent: Oc1ccccc1
Product: BrC(CCOc1ccccc1)c1ccccc1

Procedure:
Following the above procedure but using phenol in place of m-methoxyphenol, there was prepared 1-phenyl-3-phenoxypropane distilling at 146°-9° C. at 6 torr. This propane derivative was brominated α to the phenyl group with N-bromosuccinimide and benzoyl peroxide to yield 1-phenyl-3-phenoxypropylbromide which compound was in turn reacted with dimethylamine in a sealed reaction vessel to yield N,N-dimethyl 1-phenyl-3-phenoxypropylamine boiling in the range 116°-118° C. at 0.3 torr. The hydrochloride salt was prepared by the above procedure to yield N,N-dimethyl 1-phenyl-3-phenoxy-propylamine hydrochloride melting at 165°-167° C. after recrystallization from an ethyl acetate/acetone solvent mixture.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H][H]>[Pd].CO>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:58]([O:60][CH3:61])=[O:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])[CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[C@@H:19]([CH3:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)[C@@H](C)OC(C)(C)C

Procedure:
4.0 g of Z-Tyr(tBu)-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH3 in 100 ml of absolute pre-hydrogenated N,N-dimethylformamide are decarbobenzoxylated with hydrogen at room temperature with the addition of 1.4 g of 10 % strength palladium on charcoal. After completion of the hydrogen uptake the mixture is diluted with 400 ml of methanol, filtered and evaporated in vacuo. The colourless solid residue is used for the next stage without further purification.
Reaction SMILES: [C:1]([CH:5]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].[Br:29][C:30]1[C:35]([O:36][CH2:37][O:38][CH3:39])=[CH:34][C:33]([O:40][CH2:41][O:42][CH3:43])=[C:32]([C:44]2[O:45][C:46]([CH:49]=O)=[CH:47][CH:48]=2)[C:31]=1[CH2:51][C:52]([O:54][CH3:55])=[O:53]>C1(C)C=CC=CC=1>[Br:29][C:30]1[C:31]([CH2:51][C:52]([O:54][CH3:55])=[O:53])=[C:32]([C:44]2[O:45][C:46]([CH:49]=[CH:5][C:1]([O:3][CH3:4])=[O:2])=[CH:47][CH:48]=2)[C:33]([O:40][CH2:41][O:42][CH3:43])=[CH:34][C:35]=1[O:36][CH2:37][O:38][CH3:39]
Reactant: COCOc1cc(OCOC)c(-c2ccc(C=O)o2)c(CC(=O)OC)c1Br
Reactant: COC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COCOc1cc(OCOC)c(-c2ccc(C=CC(=O)OC)o2)c(CC(=O)OC)c1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
(Carbomethoxymethylene)triphenylphospholane (0.17 g, 0.51 mmol) was added to toluene (4.0 mL) solution of methyl 2-bromo-6-(5-formylfuran-2-yl)-3,5-bis(methoxymethoxy)phenylacetate (0.11 g, 0.25 mmol) obtained in the step 3 in Example 265, and stirred at 60° C. for 4 h ours. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (n-hexane to ethyl acetate/n-hexane=1/2) to obtain methyl 3-{5-[3-bromo-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)phenyl]furan-2-yl}acrylate (0.12 g, 93%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.CCO.O.[NH2:23][NH2:24]>O>[F:8][C:7]1[C:2]([NH:23][NH2:24])=[N:3][C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][CH:6]=1
Reactant: COc1cccc(COc2ncc(F)c(Cl)n2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cccc(COc2ncc(F)c(NN)n2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 125 mL Erlenmeyer flask was charged with 4-chloro-5-fluoro-2-(3-methoxybenzyl-oxy)pyrimidine (1.50 g, 5.58 mmol) and EtOH (50 mL). Hydrazine monohydrate (900 μL, 18.5 mmol) was added, and the resulting mixture was allowed to stir at room temperature. After 22 h, the reaction was transferred to a 500 mL Erlenmeyer flask and diluted with water (200 mL), whereupon a white solid began to precipitate from solution. After stirring for 7 h, solid product was collected in a fritted funnel and rinsed with excess water. After drying on the frit, the title compound was obtained (1.23 g, 83%) as a white solid: mp 103-106° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (bs, 1H), 7.86 (d, J=3.6 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.94-7.01 (m, 2H), 6.87 (dd, J=2.4, 7.9 Hz, 1H), 5.24 (s, 2H), 4.46 (bs, 2H), 3.74 (s, 3H); MS (ESI) m/z 265.2 (M+H)+, 263.2 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2
Reactant: COc1ccc(CN2C(=O)C(N)c3ccccc3-c3ccccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1C(=O)Nc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.1 g (0.29 mmol) (RS)-7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one in 8 ml of dichloromethane at 0° C. temperature 0.67 ml (8.7 mmol) of trifluoroacetic acid and 0.25 ml of trifluoromethansulfonic acid (2.9 mmol) were added and the mixture was stirred for 4 hours at room temperature. After concentration of the mixture at 40° C. in vacuo an aqueous NaHCO3 solution was added and the mixture extracted two times with ethyl acetate. The combined organic layers were dried (MgSO4). After evaporation of the solvent a light yellow oil was obtained, that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[CH:35]=[N:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:36]2[CH:35]=[C:34]([CH3:33])[CH:38]=[N:37]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)c1
Yield: 62.6 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylpyrazole (0.48 g) and dimethylformamide (25 ml), the title compound (0.74 g) was obtained as an amorphous solid, MS, m/z: 403.2 (M+H)+, 425.2 (M+Na)+, 805.3 (2M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]=3)[CH:9]=2)[N:4]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[N:3]=1.[C:41]1([C:47]2[CH:51]=[C:50]([CH2:52][N:53]3[CH2:58][CH2:57][CH:56]([CH2:59][NH2:60])[CH2:55][CH2:54]3)[O:49][N:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:41]1([C:47]2[CH:51]=[C:50]([CH2:52][N:53]3[CH2:54][CH2:55][CH:56]([CH2:59][NH:60][C:2]4[C:10]5[C:5](=[CH:6][CH:7]=[C:8]([C:11]6[N:15]=[CH:14][N:13]([C:16]([C:29]7[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=7)([C:23]7[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=7)[C:17]7[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=7)[N:12]=6)[CH:9]=5)[N:4]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][O:36]5)[N:3]=4)[CH2:57][CH2:58]3)[O:49][N:48]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(CN3CCC(CNc4nn(C5CCCCO5)c5ccc(-c6ncn(C(c7ccccc7)(c7ccccc7)c7ccccc7)n6)cc45)CC3)on2)cc1
Temperature: 100 °C

Procedure:
3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(1-trityl-1H-1,2,4-triazol-3-yl)-1H-indazole (0.25 g, prepared according to the reported preparation in US 2004/0127536), the compound prepared in Example 9 (0.29 g), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.040 g), and sodium tert-butoxide (0.20 g) were suspended in toluene (6 mL) and purged with argon. Tris(dibenzylideneacetone)dipalladium(0) (0.019 g) was added and the system was sealed and heated at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (0.13 g) having the following physical data.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 62.2 %

Procedure:
170 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 268 mg of 5-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Br)[C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:18][NH:19][C:20]#[N:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:21]=[C:20]([NH:19][CH3:18])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(Br)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CNC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
3.6 g (0.01 mol) of 2,2-dimethylpropionyl bromide 2,4,6-trichlorophenylhydrazone and 0.6 g (0.01 mol) of N-methylcyanamide were added to 50 ml of toluene. Then, 1.1 g (0.011 mol) of triethylamine was dropwise added under stirring at room temperature. After the dropwise addition, stirring was continued at the same temperature for further 1 hour. After washing the reaction mixture with water, the toluene layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 2.8 g (yield: 85%) of 3-(tert-butyl)-5-(N-methylamino)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole as power having a melting point of from 165° to 166° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[CH3:15].CCCCCC.C([Li])CCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>O1CCCC1>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH3:15])[CH:4]=1)[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOCCOc1cc(C)c(Br)c(C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCOc1cc(C)c(B(O)O)c(C)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of 2-bromo-5-(2-ethoxyethoxy)-1,3-dimethylbenzene (10.0 g, 36.6 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium hexane solution (1.6 M, 25.1 mL, 40.2 mmol) at −78° C. with stirring. The reaction mixture was stirred at the same temperature for 30 min. and triisopropyl borate (10.5 mL, 45.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 3 hrs. 5 N Hydrochloric acid (20 mL) was added to the reaction mixture and the mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/diethyl ether and dried to give the title compound (5.9 g, yield 68%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[Li]CCCC.[CH:13]([C@@H:15]1[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:14].[NH4+].[Cl-]>C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[S:3][C:4]([C@@H:13]([OH:14])[C@@H:15]2[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:5][CH:6]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Brc1ccc(Br)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
To a −78° C. solution of 2,5-dibromothiophene (7.2 g, 29.6 mmol, 1.02 equiv) in anhyd. THF (100 mL) was added dropwise a solution of n-BuLi (1.6M in hexane, 18.5 mL, 29.6 mmol, 1.02 equiv) keeping the reaction temperature below −70° C. The resulting brown solution was stirred for 2.5 h. A solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 5.9 g, 29.1 mmol) in benzene (30 mL) was added, keeping the reaction temperature below −70° C. The reaction mixture was diluted with THF (30 mL) and after 30 min was treated with a saturated NH4Cl solution (150 mL). The resulting mixture was extracted with EtOAc (200 mL) and CH2Cl2 (2×200 mL) and dried (Na2SO4). The combined organic layers were concentrated under reduced pressure. The crude product was triturated (MeOH) to give (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenyl-pyrrolidin-2-one (6.2 g) as a white solid. The filtrate was treated with silica gel (15 g), concentrated under reduced pressure and purified by flash chromatography to afford an additional 0.92 g of product (total 7.12 g, 67%) as an off-white solid: TLC (60% EtOAc/hex) Rf 0.39; 1H NMR (CDCl3) δ 2.24 (dd, J=6.2, 15.1 Hz, 1H), 2.42 (s, 3H), 2.95 (t, J=13.8 Hz, 1H), 3.76-3.85 (m, 1H), 4.15 (d, J=8.0 Hz, 1H), 4.36 (d, J=4.5 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 6.70-7.15 (m, 1H), 7.02 (dd, J=1.9, 4.0 Hz, 1H), 7.22-7.44 (m, 5H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CN(C(OC)OC)C>[CH3:8][N:10]([CH3:12])/[CH:11]=[CH:2]/[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]([CH3:11])[CH3:12])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)N(C)C)cc1
Agent: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Yield: 139.6 %

Procedure:
A mixture of 4-acetyl-N,N-dimethylbenzamide (9.80 g, 51.2 mmol) and DMF dimethyl acetal (60 mL) was heated to reflux for 15 h, cooled to room temperature and concentrated. The residue was recrystallized from ethyl acetate to give (E)-4-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzamide as a brown solid (8.80 g, 70%). MS (E+) m/z: 247 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:7]([O:23][CH3:22])=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Reaction time: 1 h

Procedure:
To a solution of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitrobenzenamine (Intermediate 12. 700 mg, 1.7 mmol) in THF (20 mL) was added NaOMe solution at −78° C. (which was prepared by dissolving Na metal (39 mg, 1.7 mmol) in 4 mL of methanol). The reaction mixture was brought to rt and stirred for 1 h at same temperature. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography to yield 2,5-difluoro-N-(2-fluoro-4-iodophenyl)-3-methoxy-6-nitrobenzenamine as yellow solid (597 mg). 1H-NMR (400 MHz, CDCl3): δ 3.95 (3H, s), 6.51-6.56 (1H, m), 6.57-6.65 (1H, m), 7.34 (1H, d, J=8.8), 7.42 (1H, dd, J=1.6, 10), 7.7 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[NH:17][C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12].Br[CH2:21][CH:22]=[CH:23][CH3:24]>>[CH2:21]([N:17]1[C:13]([C:11](=[O:12])[CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]([CH3:19])=[C:16]1[CH3:18])[CH:22]=[CH:23][CH3:24]
Reactant: CC=CCBr
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2F)[nH]c1C
Product: CC=CCn1c(C(=O)CCc2ccc(F)cc2F)cc(C)c1C
Yield: 55.4 %

Procedure:
The title compound (cis/trans=23/77) was prepared as a yellow oil in 55.4% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(2,4-difluorophenyl)propionyl]-2,3-dimethylpyrrole and 1-bromo-2-butene.