Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[S:21][C:22]([CH3:24])=[CH:23][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[N:26]1([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1N2CCN(CC2)C1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[S:21][C:22]([CH3:24])=[CH:23][C:8]=2[C:7]=1[N:29]1[CH2:30][CH2:31][N:26]([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:27][CH2:28]1)=[O:5])[CH3:2]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Yield: 65.8 %

Procedure:
A solution of 4-chloro-7-(3-fluoro-benzyl)-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester (70) (3.0 g, 7.89 mmol), piperazin-1-yl-thiophen-2-yl-methanone (1.78 g, 9.09 mmol), and DABCO (1.02 g, 9.09 mmol) in anhydrous DMF was heated overnight at 110° C. The solution was cooled and poured into a 2% ammonium chloride aqueous solution. The precipitated solid was collected by vacuum filtration. The solid was redissolved in dichloromethane and filtered. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography eluting with 0-5% MeOH in CH2Cl2 gradient to yield 2.8 g (65%) of 7-(3-fluoro-benzyl)-2-methyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.29 (t, J=7.2 Hz, 3H), 2.43 (s, 3H), 3.29 (m, 4H), 3.81 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.23 (s, 2H), 6.99 (d, J=1.2 Hz, 1H), 7.06-7.16 (m, 4H), 7.41 (m, 1H), 7.46 (dd, J=1.2, 4.0 Hz, 1H), 7.79 (dd, J=1.2, 4.8 Hz, 1H); EIMS m/z 540(M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C>[Br:18][C:8]1[NH:7][C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: BrBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring suspension of 3-methylxanthine (7.9 g 47.6 mmol) and sodium acetate (7.81 g, 95.2 mmol) in glacial acetic acid (120 ml) was added bromine (9.14 g, 57.1 mmol). The mixture was stirred at 65° C. for 2 hours. After cooling to room temperature the precipitate was filtered, washed with acetic acid (2×15 ml), water (3×50 ml) and dried under vacuum to give 8-bromo-3-methylxanthine (10.5 g, 90% yield) as a beige powder.
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH2:22])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:22][C:20]3[N:21]=[C:14]4[C:13]([C:10]5[CH:11]=[CH:12][C:7]([S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=5)=[CH:18][CH:17]=[CH:16][N:15]4[N:19]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)cc1

Procedure:
8-[4-(Propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500.0 mg, 2.347 mmol) and 4-isopropylsulfonylbenzeneboronic acid (650.0 mg, 2.850 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.317 g, 42%). MP=175-177° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64 (d, J=6.6 Hz, 1H), 8.39 (d, J=7.4 Hz, 2H), 7.96 (d, J=7.5 Hz, 2H), 7.85 (d, J=7.4 Hz, 1H), 7.06-7.00 (m, 1H), 6.21 (br s, 2H), 3.54-3.42 (m, 1H), 1.19 (d, J=6.5 Hz, 6H). MS=317 (MH)+. 52b) [4-(4-Methyl-piperazin-1-yl)-phenyl]-{8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amine was prepared from 8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.237 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (75.0 mg, 0.294 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (48.0 mg, 0.0877 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.051 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.7 Hz, 1H), 8.25 (d, J=7.8 Hz, 2H), 8.02 (d, J=7.8 Hz, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.49 (d, J=7.8 HZ, 2H), 7.01-6.95 (m, 3H), 6.69 (s, 1H), 3.30-3.15 (m, 5H), 2.63-2.58 (m, 4H), 2.36 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS=491 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.O.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[F:19]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(-c2c(F)cnn2C)c(Cl)s1
Reaction time: 12 h
Yield: 24.3 %

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 0.974 mmol)[prepared according to the procedure in Example 95] in acetonitrile (4.864 ml) and H2O (486 μl) was added selectfluor (449 mg, 1.27 mmol). The resulting solution was stirred at 70° C. in a sealed tube for 1 h after which additional selectfluor (449 mg, 1.266 mmol) was added in one portion. After stirring 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM-THF and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) affording methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol, 24.30% yield) as a yellow solid; LCMS (ES) m/z 274, 276 (M, M+H).
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([OH:18])=[O:17])[NH:4]1)[CH3:2].C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>O.CO>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([OH:18])=[O:17])[N:4]1[C:26]([S:28][CH3:29])=[S:27])[CH3:2]
Reactant: CI
Reactant: CC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC[C@H]1c2[nH]c3ccccc3c2C[C@@H](C(=O)O)N1C(=S)SC
Yield: 52.7 %

Procedure:
In the same manner as described in Example 43, (1RS,3RS)-cis-1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.22 g), triethylamine (1.21 g), carbon disulfide (456 mg), methyl iodide (852 mg), methanol (30 ml) and water (3 ml) are reacted and treated. The product is recrystallized from aqueous ethanol to give the title compound (880 mg, 52.7%) as colorless prisms, m.p. 198°-200° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[CH:15]=[CH:16][N+:17]([O-:19])=[O:18])[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].P([O-])(O)(O)=O.[Na+]>C(OCC)C.C(O)C>[C:1]([O:4][C@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[CH2:15][CH2:16][N+:17]([O-:19])=[O:18])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C[N+](=O)[O-])CC[C@]32O)C1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](CC[N+](=O)[O-])CC[C@]32O)C1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 13.86 g of 3β-acetoxy-21-nitro-5β-pregn-20-en-14β-ol (Eberlein W. et al., Chem. Ber., 1974, 107, 1275) in 440 ml of diethyl ether and 440 ml of ethanol, 2.86 g NaBH4 were added at room temperature. After 1 hr. the mixture was neutralized with aqueous sodium dihydrogenphosphate and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 13.40 g of 3β-acetoxy-21-nitro-5β-pregnane-14β-ol.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[N:10]1([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:14]=[CH:13][CH:12]=[CH:11]1>C(Cl)Cl>[C:1]([C:11]1[N:10]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of acetyl chloride (6.77 ml) in DCM (400 ml) was added tin (IV) chloride (11.14 ml) at -5° C., under nitrogen. 2-(1H-pyrrol-1-yl)-1H-isoindole-1, 3(2H)dione (20.0 g) was then added portion-wise, keeping the temperature below 0° C. The reaction mixture was then stirred at 0° C. for 0.5 hour, at which time it was poured into ice water. The layers were separated and the aqueous phase was extracted with DCM. The combined organics were washed twice with 5% HCl (aq.) and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, DCM) afforded 9.62 g of the product as a solid, m.p. 204°-205° C.
Reaction SMILES: C1C([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH:8]=2)=CC=C(O)C=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:19][C:12]1[CH:13]=[C:14]([O:18][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=2)[CH:15]=[C:16]2[C:11]=1[C:9](=[O:10])[CH:8]=[CH:7][O:17]2)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2cc(O)cc(O)c12
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2cccnc2)c2c(=O)ccoc2c1)c1cccnc1
Temperature: -10 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
In a 500 mL round-bottomed flask fitted with magnetic stirrer were placed apigenin (4′,5,7-trihydroxyflavone (5 g, 18.50 mmol)) and pyridine (250 mL). The mixture was cooled at −10° C. and nicotinoyl chloride HCl (16.5 g, 92.70 mmol) was added. Then the reaction mixture was stirred for 24 h at rt under nitrogen. The solvent was removed under reduced pressure and the residue was dissolved in chloroform, which was washed with water and evaporated. The crude product was purified by crystallization from DCM-MeOH to give 7.5 g of 2-(4-nicotinoyloxy)phenyl)-oxo-4H-chromene-5,7-diyl dinicotinate (69%). MS (ES) m/z: 586.17 (M+1), 481.11, 293.70.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:14][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCNCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A mixture of 6-bromo-2-pyridinecarboxaldehyde (54) (20 g, 108 mmol) and 2-methoxy ethanamine (10.3 mL, 8.88 g, 118 mmol) in DCM (1.3 L) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (25 g, 118 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (400 mL) and acidified to pH=4 with 1M HCl (−140 mL). The two phases were separated and the organic layer was extracted with 0.25M HCl (2×500 mL). The aqueous layers were combined, basified to pH=9 with 4N NaOH, extracted with DCM (1×500 mL), dried over Na2SO4, filtered and concentrated yielding 25.2 g of 55 (96%). MS (m/z): 245.1 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][C:26]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:27]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
1-(4-Chlorophenyl)piperazine dihydrochloride (1.88 g, 6.973 mmol) was dissolved in methylene chloride and, after slowly adding triethylamine (1.9 mL, 13.946 mmol) at 0° C., stirred for 5 minutes. After adding 3-chloropropionyl chloride (0.67 mL, 6.973 mmol), the reaction solution was stirred at room temperature. After extracting with methylene chloride, the organic layer was dried with desiccant and then filtered. The filtrate was concentrated and purified by column chromatography (EtOAc/hexane, 4:1). A target compound (1.03 g, 3.586 mmol, 51.5%) was yielded as white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 120 °C
Yield: 14.3 %

Procedure:
A stirred mixture of tert-butyl 1-piperazinecarboxylate (1.00 g, 5.37 mmol), ethyl 4-fluorobenzoate (903 mg, 5.37 mmol), and K2CO3 (1.11 g, 8.06 mmol) in DMF (10 mL) was heated at 120° C. overnight. After cooling, the mixture was diluted with EtOAc (300 mL), followed by washing with brine (2×200 mL), drying over MgSO4, and evaporation. The residue was chromatographed on silica-gel with CHCl3-EtOAc (20:1 to 4:1, v/v) as eluent to give 257 mg (14%) ethyl 4-[4-(tert-butyloxycarbonyl)-1-piperazinyl]benzoate as a pale yellow amorphous solid. IR (KBr) 1701, 1612 cm−1; 1H-NMR (CDCl3) d 1.37 (3 H, t, J=7.3 Hz), 1.49 (9 H, s), 3.30 (4 H, t, J=5.4 Hz), 3.58 (4 H, t, J=5.4 Hz), 4.33(2 H, q, J=7.3 Hz), 6.87(2 H, d, J=8.8 Hz), 7.94 (2 H, dt, J=8.8, 2.4 Hz); MS (FAB) m/z 335 (M++1); Anal. Calcd for C18H26N2O4: C, 64.54; H, 7.84; N, 8.38. Found: C, 64.39; H, 7.89; N, 8.38.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[NH:6]1[CH2:13][CH2:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[CH2:14]=[C:15]=[O:16]>C(OCC)(=O)C>[C:15]([N:6]1[CH2:13][CH2:12][C:10](=[O:11])[N:9]([C:1](=[O:4])[CH3:2])[C:7]1=[O:8])(=[O:16])[CH3:14]
Reactant: O=C1CCNC(=O)N1
Reactant: CC(=O)[O-]
Reactant: C=C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(=O)N(C(C)=O)C1=O

Procedure:
After adding 1.5 gm of finely pulverized sodium acetate suspended in 1 liter of ethyl acetate, 15 gm (0.13 mol) of 5,6-dihydrouracil were reacted with ketene at boiling temperature (77° C). After the reaction had been completed, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropanol. The melting point was 81.5° C to 83° C, and the elementary analysis resulted in the following values:
Reaction SMILES: [CH2:1]([C:8]1([OH:28])[C:21]2[O:22][C@@H:18]3[C@@:19]45[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]([C@@H:14]4[CH:15]=[CH:16][C@@H:17]3[OH:27])[CH2:12][C:11]([C:20]5=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1>[C:36]([C@:17]1([OH:27])[CH:16]=[CH:15][C@@H:14]2[C@@:19]34[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]2[CH2:12][C:11]2[C:20]3=[C:21]([O:22][C@@H:18]14)[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:9][CH:10]=2)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)[C@]1(O)C=C[C@H]2[C@H]3CC4=CCC(O)(Cc5ccccc5)C5=C4[C@@]2(CCN3C)[C@H]1O5
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of 3-benzylmorphine (12.7 g, 33.9 mmol) in CH2CI2 (300 ml), was added triethylamine (10 ml, 99%, 71.2 mmol), acetic anhydride (7.5 ml, 99%, 78.6 mmol), and 4-dimethylaminopyridine (0.3 g). The reaction mixture was heated under reflux for 2 hr, cooled with an ice--H2O bath, then transferred to a separatory funnel, and washed with cold 10% aqueous NaHCO3 solution (3×100 ml). The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave 6-acetyl-3-benzylmorphine (13.87 g, 96% yield). IR (KBr)(ν, cm-1): 2900 (m, sharp), 1727 (s, sharp, AcO); NMR (δH)(CDCl3): 7.47-7.20 (5, m, --C6H5), 6.68 (1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2, 1-H), 5.63(1, dm, J, 10.1, 7-H), 5.43 (1, dt, J, 10.1 & 2.3, 8-H), 5.25-5.15(1, m, 6-H), 5.14 (2, s, --OCH2Ph), 5.10 (1, dd, J, 6.7 & 1.1, 5-H), 3.34 (1, dd, J, 6.0 & 3.3, 9-H), 3.01 (1, d, J, 18.6, 10-Hβ), 2.79-2.70 (1, m, 14-H), 2.59 (1, dd, J, 12.1 & 3.4, 16-He), 2.43 (3, s, N--CH3), 2.37 (1, td, J, 11.8 & 3.6, 16-Ha), 2.27 (1, dd, J, 18.8 & 6.6, 10-Hα), 2.10 (3, s, AcO), 2.04 (1, td, J, 11.9 & 5.1, 15-Ha), 1.86 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20](O)=[O:21])[CH2:3][CH2:2]1.Cl.Cl.[CH3:25][C:26]1([CH3:37])[CH:31]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH2:29][NH:28][CH2:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:28]2[CH2:29][CH2:30][CH:31]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:26]([CH3:37])([CH3:25])[CH2:27]2)=[O:21])[CH2:2][CH2:3]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Reactant: CC1(C)CNCCC1N1CCCC1
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CCCC2)C(C)(C)C1

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 181A) and 3,3-dimethyl-4-pyrrolidin-1-yl-piperidine dihydrochloride in direct analogy to the general procedure used in example 150. MS: 457.4 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][N:6]=[C:5]([C:11]#[N:12])[CH:4]=1.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1[CH:7]=[N:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[CH2:2]2
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: N#Cc1cc(CBr)c(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cnc(C#N)cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 4,5-bis(bromomethyl)pyridine-2-carbonitrile from Step B (729 mg, 2.52 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (665 mg, 2.52 mmol, described in Intermediate 1) in DMF (75 mL) was added cesium carbonate (2.46 g, 7.55 mmol), portionwise, over 5 min. After 2 h, acetic acid (0.15 mL) was added and the mixture was concentrated to a volume of about 25 mL, then partitioned between CHCl3 (100 mL), saturated aqueous NaHCO3 (30 mL) and brine (50 mL). The organic layer was removed and the aqueous layer was extracted further with CHCl3 (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(O)=O)[CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:22]([Cl:24])=[O:23]>ClCCl.CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:20])([C:22]([Cl:24])=[O:23])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nn(Cc2ccccc2)c2cc(C(=O)O)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C(=O)Cl)NN(Cc2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 1-benzyl-3-methyl-indazole-6-carboxylic acid in dichloromethane (20 ml) was treated with dimethylformamide (2 drops) then with oxalyl chloride (1.69 ml). After stirring for 2 hours the reaction mixture was evaporated and the residue was dried under high vacuum to give the title compound (0.16 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24].[CH3:26]CN(CC)CC>CS(C)=O.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:19]3[CH2:26][CH2:25][CH:22]([CH2:23][OH:24])[CH2:21][CH2:20]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: CC(CO)CCN
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCC(CO)CC2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of compound (7) (540 mg, 2 mmol, Preparation 2) and 4-amino-2-methyl-butan-1-ol (230 mg, 2 mmol) in DMSO (20 mL) was added Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (50 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc: Petrol ether=3:1) on silica gel to give (36). (557 mg, 1.6 mmol, yield 80%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[N:4][C:3]=1[Cl:11].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:18]N(C=O)C>>[CH3:18][O:10][C:8]([C:6]1[CH:5]=[N:4][C:3]([Cl:11])=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)n1
Reactant: CN(C)C=O
Reactant: C1CCNCC1
Product: COC(=O)c1cnc(Cl)c(N2CCCCC2)n1

Procedure:
From a mixture of 1 g (3.98 mmol) 6-bromo-5-chloro-pyrazine-2-carboxylic acid and 0.508 g (5.97 mmol) piperidine in 1 mL DMF 0.61 g (60%) of the title compound were filtered off as slightly yellow crystals. m/z (ES+): 256.4 (M+H).