Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[CH:7][CH:6]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[C:43]([CH2:45][C:46](O)=[O:47])#[N:44]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:46](=[O:47])[CH2:45][C:43]#[N:44])[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[4-(2-fluorophenoxy)phenyl]-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (10 mL), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (80 mg, 0.49 mmol, 1.25 equiv), and 2-cyanoacetic acid (50 mg, 0.59 mmol, 3.80 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (100:1; 50:1) to give 0.05 g (43%) of 3-[(2R)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:9][O:10][CH2:11]CO.S([O-])(O)(=O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][O:10][CH2:11][CH2:1][O:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COCCO
Reactant: COc1sccc1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1sccc1C
Yield: 48.6 %

Procedure:
2-methoxy-3-methyl-thiophene, (1.5 g, 11.7 mmol) 2-methoxy-ethanol (3.8 g, 50.5 mmol, 4.3 equiv.) and sodium hydrogen sulfate anhydrous (100 mg, 0.833 mmol, 0.07 equiv.) were stirred in toluene at 120° C. for 3.5 hours. The mixture was diluted with ethyl acetate and extracted with sodium bicarbonate solution. The organic solvent washed with brine, dried over magnesium sulfate dihydrate, filtered and evaporated. After Kugelrohr distillation, 980 mg of the title compound were obtained as a light yellow oil GC-MS (EI) M=172.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Br:13]Br.O>C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([Br:13])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1sccc1C(N)=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1sc(Br)cc1C(N)=O
Reaction time: 1.5 h

Procedure:
2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide (1.0 g) was dissolved in acetic acid (20 ml) and a solution of bromine (0.35 ml) in acetic acid (5 ml) was added over 5 minutes with rapid stirring. The mixture was stirred for 90 minutes and then added to water (50 ml). The product was filtered off and washed with water and dried under vacuum (0.55 g).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:44][CH:45]([CH3:56])[CH2:46][C@H:47]([NH2:55])[CH2:48][S:49][C:50]1[NH:54][CH:53]=[N:52][N:51]=1.Cl>CN(C=O)C.O.C(Cl)CCl>[CH3:44][CH:45]([CH3:56])[CH2:46][C@H:47]([NH:55][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:7]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:8][C:9]=2[CH:14]=1)=[O:16])[CH2:48][S:49][C:50]1[NH:54][CH:53]=[N:52][N:51]=1
Reactant: CC(C)C[C@H](N)CSc1nnc[nH]1
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](CSc3nnc[nH]3)CC(C)C)ccc21
Reaction time: 20 h

Procedure:
To a solution of 185 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 3 ml of dry DMF 84 mg of HOAT, 151 mg of EDC and 0.47 ml of DIPEA were added at 0° C. After 15 min 133 mg of (S)-3-methyl-1-(4H-[1,2,4]triazol-3-ylsulfanylmethyl)-butylamine-hydrochloride were added and the reaction was stirred at it for 20 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with 2 M aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. After purification by HPLC 64 mg (22%) of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(4H-[1,2,4]triazol-3-ylsulfanylmethyl)-butyl]-amide were obtained.
Reaction SMILES: [C:1]1([CH:7]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[C:35]3[CH:34]=[N:33][CH:32]=[N:31][C:30]=3[N:29]([CH:36]([CH3:38])[CH3:37])[CH:28]=2)=[O:26])[CH:22]=[N:23][CH:24]=1>>[CH:36]([N:29]1[C:30]2[N:31]=[CH:32][N:33]=[CH:34][C:35]=2[C:27]([C:25]([C:21]2[CH:20]=[C:19]([NH:18][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:24]=[N:23][CH:22]=2)=[O:26])=[CH:28]1)([CH3:38])[CH3:37]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)C(OC1CCCCO1)c1ccccc1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(OC3CCCCO3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 using phenyl-[(tetrahydro-pyran-2-yloxy)]-acetic acid (Preparation 236) and (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95) to afford the title compound as a yellow solid in 68% yield, 60 mg.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(N(CC)CC)C>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (5.02 g, 33.4 mmoles) and 1-bromo-3-chloropropane (5.26 g, 33.4 mmoles) in ethanol (100 ml) was added triethylamine (4.66 ml, 33.4 mmoles) and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 5.46 g of the desired product (72.0%, light brown oily product).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]([O:39][CH2:40][CH2:41]O)([CH3:38])[CH3:37].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:36]([O:39][CH2:40][CH2:41][N:7]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6]1)([CH3:38])[CH3:37]
Reactant: CC(C)OCCO
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nn(CCOC(C)C)c(C(=O)OC)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (11.4 g, 50 mmol) was dissolved in tetrahydrofuran (200 mL) and the solution treated with triphenylphosphine (14.4 g, 55 mmol) and 2-isopropoxyethanol (6.36 mL, 55 mmol). The mixture was cooled on an ice bath to 0° C. and diisopropyl azodicarboxylate (10.8 mL, 55 mmol) added dropwise over 10 minutes, keeping the temperature between 20° C. and 30° C. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the crude product azeotroped with dichloromethane to yield the title product. 1H NMR (CDCl3, 400 MHz) δ: 1.02 (d, 6H), 3.45 (m, 1H), 3.72 (t, 2H), 3.90 (s, 3H), 3.94 (s, 3H), 4.74 (t, 2H). MS ES+ m/z 216 [MH]+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1.C[O:24][C:25](=[O:38])[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([SH:37])=[C:33]2[C:29]=1[CH2:30][CH2:31][CH2:32]2>>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:37][C:34]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][C:25]([OH:38])=[O:24])=[C:29]3[C:33]=2[CH2:32][CH2:31][CH2:30]3)=[CH:4][C:5]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1OCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: COc1ccc(CSc2ccc(OCC(=O)O)c3c2CCC3)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 78B and 12C. MS m/z 373 (M−159).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.CN(C)C=O>[CH2:25]([N:21]1[CH2:20][C:19](=[O:32])[N:18]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:23]([CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:22]1=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1C(C(c2ccccc2)c2ccccc2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran) (77 ml) was added portionwise to a stirred solution of 1,4-dibenzyl-2,5-piperazinedione (20.6 g) in a mixture of tetrahydrofuran (400 ml) and N,N-dimethylformamide (200 ml) at 0° C. The whole was stirred at 5° C. for 1 hour and thereto a solution of bromodiphenylmethane (19 g) in tetrahydrofuran (100 ml) was added at −78° C. and the mixture was stirred for 2 hours at the same temperature. After being stirred at 5° C. for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with a mixed solvent of ethyl acetate and isopropyl alcohol, and the resulting solid was collected by filtration to give 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione (10.55 g) as a colorless powder.
Reaction SMILES: Cl.[F:2][C:3]1([F:19])[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[C:23]([CH2:22][CH2:21][C:20]([NH:16][C:15]1[CH:17]=[CH:18][N:11]([C@@H:4]2[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C:3]2([F:2])[F:19])[C:12](=[O:13])[N:14]=1)=[O:26])([OH:25])=[O:24]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 105.2 %

Procedure:
Two hundred mg of 2'-deoxy-2',2'-difluorocytidine, hydrochloride, was dissolved in 2 ml of pyridine, and then 134 mg of succinic anhydride was added. The mixture was stirred at ambient temperature for 1.25 hours, and was then concentrated under vacuum. The residue was dissolved in dichloromethane/methanol, and the solution was absorbed on 1.5 g of silica gel, which was then slurried in dichloromethane and loaded on a 4 g silica gel column. The column was eluted with a gradient solvent, starting with dichloromethane and ending with methanol. The product-containing fractions were combined and freeze-dried overnight to obtain 255 mg of product mixture. It was dissolved in 3 ml of 0.01M ammonium acetate, and was chromatographed on a 22 ml mono-Q fast flow column (Pharmacia Inc.), eluting with the ammonium acetate gradient buffer which has previously been described. Evaporation of the product-containing fractions gave 81 mg of a mixture of the mono-acylated products named in the heading.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Br:16][C:17]1[CH:18]=[C:19]([C:24]([NH:26][C:27]2[C:28]([NH:34][CH2:35][CH3:36])=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:25])[C:20](Cl)=[N:21][CH:22]=1.O>N1C=CC=CC=1>[Br:16][C:17]1[CH:22]=[N:21][C:20]2[N:34]([CH2:35][CH3:36])[C:28]3[N:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=3[NH:26][C:24](=[O:25])[C:19]=2[CH:18]=1
Reactant: CCNc1nc(Cl)ccc1NC(=O)c1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCN1c2nc(Cl)ccc2NC(=O)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A 1 M solution of NaHMDS in THF (167.5 mL, 167.5 mmol) was slowly added to a solution of 5-bromo-2-chloro-N-{2-(ethylamino)-6-choro-3-pyridinyl}-3-pyridinecarboxamide (28.4 g, 72.8 mmol) in pyridine (146 mL) heated to 50° C. The reaction mixture was stirred at 50° C. for 1.5 h. The mixture was then poured into a mixture of water and ice (1 L) and, after 1 h, the resulting suspension was filtered. The solid was washed with water and dried under reduced pressure to give the title compound (23.4 g, 91% yield).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[CH3:21][N:22]=[C:23]=[O:24]>CN(C=O)C.C1COCC1>[CH3:20][C:3]([NH:2][C:23]([NH:22][CH3:21])=[O:24])([C:4](=[O:5])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:17]([CH3:18])[CH3:19]
Reactant: CN=C=O
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide hydrochloride (5 g, 15.58 mmols) dissolved in 50 mL of DMF under nitrogen is cooled to -30° C. Then 10 mL of methyl isocyanate in 10 mL of THF is added at such a rate that temperature is maintained at -30° C., and the reaction mixture is allowed to stir for two hours at -30° C. and then for 16 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH2:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:14][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)CO
Reactant: Brc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)COc1ccccc1Br
Temperature: 100 °C

Procedure:
A vial was charged with 1-bromo-2-iodobenzene (627 μL, 5 mmol), neopentyl alcohol (4.85 g, 55.0 mmol), copper(I) iodide (95 mg, 0.500 mmol), 1,10-phenanthroline (180 mg, 1.000 mmol) and cesium carbonate (2.28 g, 7.00 mmol). The vial was sealed under air atmosphere and heated to 100° C. for 12 h. The reaction mixture was cooled to RT and filtered through a pad of silica gel. The silica gel was washed with Et2O. The filtrate was concentrated and the residue was purified by column chromatography (100% hexanes) to yield the 1-bromo-2-(neopentyloxy)benzene as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Br.Br.[C:28]12[CH2:35][NH:34][CH2:33][C:32]=1[CH2:31][NH:30][CH2:29]2.N12CCCN=C1CCCCC2>C(#N)C>[C:28]12[CH2:35][NH:34][CH2:33][C:32]=1[CH2:31][N:30]([C:7]1[C:2]([F:1])=[C:3]3[C:4]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:18]3[CH:13]=[CH:14][C:15]([F:21])=[CH:16][C:17]=3[F:19])=[CH:5][C:6]=1[F:8])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 74.5 %

Procedure:
1-(2,4-Difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.07 g), 3,7-diazabicyclo [3.3.0] oct-1(5)-ene dihydrobromide (1 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 2 ml) were dissolved in acetonitrile (30 ml) and refluxed for 7 hours. The reaction mixture was kept overnight at room temperature and the produced precipitate was filtered and then suspended in methanol (10 ml) and sonicated for 30 minutes. The insoluble product was collected by filtration to give the title compound (1 g, yield 74%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:25][CH:24]=1.CN(C)C=O>O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10][N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[CH:37][CH:38]=2)[CH:12]=1)[CH3:20]
Reactant: O=C(OCc1ccccc1)c1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.6 %

Procedure:
Sodium hydride (60%, oily, 180 mg) was added to a mixture of ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (1.00 g), benzyl 4-chloromethylbenzoate (1.17 g), and N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred for 2.5 days at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and benzyl 4-[4-(3-ethoxy-3-oxo-1-propyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoate (1.68 g, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]([OH:17])=[O:16]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]([O:17][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C(O)CBr
Product: CC(C)(C)OC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21

Procedure:
Prepared according to the method of Example 15a) from 5-nitroindole (0.207 g) and 2-bromoaceticacid, 1,1 -diemthylethyl ester (0.23 ml) to leave sub-title compound as a yellow oily solid (0.29 g).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[CH3:26][C@H:27]1[CH2:31][CH2:30][C@H:29]([CH3:32])[NH:28]1>>[CH3:26][C@H:27]1[CH2:31][CH2:30][C@H:29]([CH3:32])[N:28]1[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9]
Reactant: C[C@H]1CC[C@H](C)N1
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Product: C[C@H]1CC[C@H](C)N1CC1CCCN1C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:45]2[CH2:46][CH2:47][O:48][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][O:51][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:49][C:43]1[C:44]2[O:48][CH2:47][CH2:46][C:45]=2[C:40]([C@H:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:41][C:42]=1[CH2:50][OH:51]
Reactant: CC(C)(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)OCC2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of compound 65 (1.80 g, 1.9 mmol) in THF (9.5 mL) was added dropwise tetra-n-butylammonium fluoride (1.0M in THF, 4.75 mL, 4.75 mmol) at 0° C. After being stirred for 2 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 66 (1.28 g, 94%) as colorless oil.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10].C(O)C>CS(C)=O.O1CCCC1>[OH:5][CH2:4][CH2:3][CH2:2][C:1](=[O:6])[CH2:10][C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(=O)c1cccnc1
Reactant: O=C1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(CCCO)CC(=O)c1cccnc1
Yield: 110 %

Procedure:
A solution of γ-butyrolactone (1.92 mL, 2.15 g, 25.0 mmol), 60% suspension of sodium hydride in mineral oil (300 mg, 7.50 mmol) and 3-acetylpyridine (551 μL, 606 mg, 5.00 mmol) in dimethylsulfoxyde (4 mL) and tetrahydrofuran (36 mL) was stirred overnight at 25° C. Ethanol (4 mL) was added to destroy excess sodium hydride and the reaction mixture was adsorbed on silica gel (10 g). Flash chromatography on silica gel (75 g), eluting with DCM/MeOH/NH4OH (96/4/1), gave 1.14 g of a yellow oil containing compound 3-A (0.62 g, 60%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>N1C=CC=CC=1>[CH:31]1([C:34]([O:1][C@@H:2]2[C@H:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[S:7][C:6]3[C:17]4[C:22]([CH:23]=[CH:24][C:5]=3[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]2=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)C2CC2)cc1
Reaction time: 17 h
Yield: 99 %

Procedure:
To a solution of 2.0 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one in 25 mL pyridine was added dropwise at ice-bath temperature 0.9 g of cyclopropanecarboxylic acid chloride and the solution was kept at this temperature for 17 hours. The mixture was concentrated and the residue, in water, was made basic with concentrated ammonium hydroxide. The aqueous suspension was extracted with ethyl acetate (3×60 mL). The combined ethyl acetate solutions were washed with brine and dried (magnesium sulfate). Removal of the solvent gave 2.3 g (100%) of (±)-cis-3-[(cyclopropylcarbonyl)oxy]-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one as an amorphous compound.