Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (7.1 g, 21 mmol) was dissolved in DCM (70 ml). To this was added diisopropylethylamine (7.3 ml, 42 mmol) in one portion followed by the drop wise addition of acryloyl chloride (1.54 ml, 19 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to give the title compound (5.3 g, 20% yield) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:11](Cl)[CH:12]=[C:13]([CH3:15])[CH3:14]>>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)=CCCl
Reactant: CC(C)C(O)C(C)(C)CO
Product: CC(C)=CCOCC(C)(C)C(O)C(C)C
Yield: 92 %

Procedure:
Treatment of 2,2,4-trimethylpentan-1,3-diol with prenyl chloride employing the alkylation reaction conditions described above provided 1-(3-methyl-2-butenyloxy)-2,2,4-trimethylpentan-3-ol in 92.0% yield (393.8 g, b.p.=82–84 C./0.8 mmHg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNC(=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.10 g, 326 μmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (98mg, 326 μmol), and tetrakis(triphenylphosphine)palladium (19 mg, 16 μmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (488 μl, 977 μmol). The resulting mixture was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (0.11 g) as a pale yellow solid. Found MS(ES+): 402(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc2ccc(Cl)cc12
Reactant: O=C1CCC(=O)N1Br
Product: Clc1ccc2cccc(CBr)c2c1

Procedure:
Using general procedure A (Exp. 1.3.), 7-chloro-1-methyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-7-chloro-naphthalene as a white solid. MS: 253.9 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C1C(=O)N([Br:32])C(=O)C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:21])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCNC(=O)c1ccc(-n2ncc(C(=O)O)c2OC)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Yield: 97.1 %

Procedure:
Combined 5-methoxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (2.19 g, 6.55 mmol), NBS (1.749 g, 9.83 mmol), and sodium bicarbonate (1.651 g, 19.65 mmol) in DMF (20 mL) and stirred at 20° C. for 1 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL, then 2×50 mL). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on a 120 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.348 g, 97% yield) as a white solid. MS m/z 369, 371 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (quin, J=6.6 Hz, 2H) 3.25 (s, 3H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.3 Hz, 2H) 4.05 (s, 3H) 7.79 (dd, J=8.6, 0.5 Hz, 1H) 7.85 (s, 1H) 8.38 (dd, J=8.6, 2.3 Hz, 1H) 8.74 (t, J=5.6 Hz, 1H) 8.96 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[C:27]([O:26][C:24]([CH2:23][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
Sodium hydride (115 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (600 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. t-Butyl bromoacetate (562 mg) was added thereto and stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized and then extracted with dichloromethane. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-t-butoxycarbonylmethyl-1H-indole-5-carboxylate (944 mg, Y.: quant.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Nc1ccncc1N
Product: Cc1cccc(-c2nc3cnccc3[nH]2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield according to the procedure in Example 1 using 3-methylbenzoic acid and 3,4-diaminopyridine. Crystallization from methanol/water afforded light tan crystals, m.p. about 202.5°-204° C.
Reaction SMILES: [OH:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[C:25]([O:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12)(=[O:27])[CH3:26]
Reactant: O=c1nnc2c(O)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c2nnc(=O)n-2c2ccc(Cl)cc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.4 g of 4-hydroxy-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml of methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[N:59]=[C:58]([NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:66])[CH3:65])[CH:57]=[C:56]([N:67]3[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)[N:55]=2)=[CH:50][CH:49]=1>CN1C(=O)CCC1>[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]2[N:59]=[C:58]([NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:66])[CH3:65])[CH:57]=[C:56]([N:67]3[CH2:72][CH2:71][N:70]([C:1]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[O:13])[CH2:69][CH2:68]3)[N:55]=2)=[CH:52][CH:53]=1
Reactant: CC(=O)NCCNc1cc(N2CCNCC2)nc(-c2ccc(Cl)cc2)n1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1cc(N2CCN(C(=O)c3ccc4ccccc4n3)CC2)nc(-c2ccc(Cl)cc2)n1
Reaction time: 12 h

Procedure:
A solution of quinaldic acid (60 μl of a 0.3M solution in NMP), HATU (60 μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 5 min. N-(2-{[2-(4-chlorophenyl)-6-piperazin-1-ylpyrimidin-4-yl]amino}ethyl)acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hr. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:5]2[C:4]=1O)#[N:2].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[C:5]2[N:6]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=2)[N:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Product: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Temperature: 75 °C
Yield: 48 %

Procedure:
To a round bottom flask was added POCl3 (200 mL) and ethyl 3-cyano-4-hydroxypyrrolo[1,2-b]pyridazine-6-carboxylate (20 g, 80 mmol). The reaction was heated under nitrogen at 75° C. for 2 hours. The reaction was cooled to room temperature and POCl3 was removed under vacuum. The residue was poured onto ice-water. The aqueous solution was extracted with CH2Cl2. The organic layer was washed with saturated sodium carbonate solution, dried and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 10 g (48%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm: 8.33 (1H, d, J=1.3 Hz), 8.11 (1H, s), 7.41 (1H, d, J=1.6 Hz), 4.41 (2H, q, J=6.8 Hz), 1.41 (3H, t, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:24])[CH3:23])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:23])[CH3:24])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([C:36]([F:35])([F:46])[F:47])=[CH:38][CH:39]=3)=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred suspension of [4,6-bis-dimethylamino-2-(4-aminobenzyl)pyrimidin-5-yl]acetic acid methyl ester (100 g, obtained according to step C) in 700 mL of methanol in a 1500 mL double jacketed vessel at 20±5° C. is added diisopropylethylamin (41.4 g) over a period of 30 minutes while heating the reaction mixture to 50±5° C. 4-Trifluoromethylbenzoic acid chloride (63.8 g) is added during further 30 minutes. The reaction mixture is stirred for 15 minutes at 50±5° C. and subsequently heated to 65±5° C. (reflux conditions) and stirred for another 30 minutes. The resulting suspension is gradually cooled to 5±5° C. over a period of 2 hours and stirred at this temperature for 1 hour. The solid is filtered off, washed with 200 mL of isopropanol and dried in vacuo at 50° C. to yield [4,6-bis-dimethylamino-2-[4-(4-trifluoromethylbenzoylamino)benzyl]pyrimidin-5-yl]acetic acid methyl ester in an amount of 135.8 g (yield: 90%; HPLC-purity: 99.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:20][CH:17]1[CH2:19][CH2:18]1
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1ccc2[nH]cc(C[C@H]3CCCN3CC3CC3)c2c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
5-Bromo-3-(pyrrolidin-2(R)-ylmethyl)-1H-indole (1.84 g, 6.3 mmol) (see Preparation 55), cyclopropylmethyl bromide (0.67 ml, 6.9 mmol), sodium carbonate (0.73 g, 6.9 mmol) and sodium iodide (1.0 g, 6.7 mmol) in 1,2-dimethoxyethane (10 ml) was refluxed under nitrogen for 14 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and aqueous sodium carbonate. The organic phase was washed with more aqueous sodium carbonate, dried (Na2SO4) and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide (90:10:0.05) to yield the title compound as a foam (2.09 g). Found: C,61.22; H,6.40; N,8.39. C17H21BrN2 requires: C,61.26; H,6.35; N,8.41%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 58.8 %

Procedure:
To a solution of 0.73 g (1.5 mmol) of (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(tri-fluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 6) in ˜25 mL dry toluene was added 0.166 g (1.7 mmol) cyclopentane-1,3-dione and 0.03 g (0.15 mmol) of PTSA. The resulting mixture was heated at reflux for 2 hr. The solvent was removed under vacuum and the residue was purified by prep TLC eluting with CHCl3/2N NH3 in MeOH (9/1) to afford 0.49 g the title compound. The compound could be further purified by chiral HLPC on CHIRACEL AD column eluting with hexanes/EtOH (9/1). The compound could be crystallized (mp=216.5-217.5° C.) from hexanes/EtOAc or hexanes/EtOH. 1H-NMR (CDCl3): δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz), 4.89, 4.48 (1H, s), 4.47 (1H, m), 3.71, 3.48 (1H, m), 3.35 (1H, m), 3.28-3.17 (1H, m), 2.95 (1H, m), 2.95, 2.81 (1H, m), 2.68 (2H, m), 2.45 (2H, m), 2.37 (2H, m), 2.15 (1H, m), 1.93 (2H, m), 1.60 (1H, m), 1.38 (1H, m), 1.36 (3,H, t, J=6.0 Hz). MS: (MH)+556.0.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at −78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at −78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
Reaction SMILES: [CH:1]1[NH:8][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]=1[F:9].C(N(CC)CC)C.[C:17]([O:25][CH2:26]Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>CC(N(C)C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([O:25][CH2:26][N:8]2[CH:1]=[C:2]([F:9])[C:3](=[O:4])[NH:5][C:6]2=[O:7])=[O:24])[CH:19]=1
Reactant: O=C(OCCl)c1cccnc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(OCn1cc(F)c(=O)[nH]c1=O)c1cccnc1
Reaction time: 24 h

Procedure:
5-FU (1.31 g, 0.01 mol) was dissolved in 5 mL of dimethylacetamide and treated with triethylamine (2.78 mL, 0.02 mol). Chloromethyl nicotinate (2.95 g. 0.012 mol) in 5 mL of dimethylacetamide was added in one portion, and the mixture was stirred for 24 hours, filtered, washed with ethyl acetate and evaporated. The residue was chromatographed on a column of silica gel, using as eluent first benzene, then 3:1 benzene/chloroform, then 1:1 benzene/chloroform, then 3:1 chloroform/benzene, then chloroform and finally 99:1 chloroform/methanol. Unreacted nicotinate was eluted initially, followed by the 1,3-bis-isomer and finally the 1-isomer. The 1-isomer (1.3 g, 50%) melted at 190°-192° C. and had the formula ##STR158## as confirmed by NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:22])=[C:4]([CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:10])=[C:6]([NH2:9])[C:7]=1[I:8].[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl.C(#N)C>[C:23]([O:26][CH2:27][C:28]([NH:9][C:6]1[C:5]([I:10])=[C:4]([CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:3]([I:22])=[C:2]([NH:1][C:12](=[O:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:7]=1[I:8])=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(Cc1c(I)c(N)c(I)c(N)c1I)OC(C)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Yield: 64 %

Procedure:
The product in Example 64e, 3,5-diamino-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene was acylated using acetoxyacetyl chloride according to the general procedure in Example 24i. After chromatography on silica gel using methylene chloride/acetonitrile (3/1) as the eluent the product was isolated in 64% yield.
Reaction SMILES: O=C1C2C=CC=CC=2NC2=CC(C(O)=O)=NN12.F[C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24]3=[CH:29][C:30]([C:32]([NH2:34])=[O:33])=[N:31][N:23]3[C:22](=[O:35])[C:21]=2[CH:20]=1>N1C=CC=CC=1.S(Cl)(Cl)=O>[O:35]=[C:22]1[C:21]2[CH:20]=[CH:19][CH:28]=[CH:27][C:26]=2[NH:25][C:24]2=[CH:29][C:30]([C:32]([NH2:34])=[O:33])=[N:31][N:23]12
Reactant: NC(=O)c1cc2[nH]c3ccc(F)cc3c(=O)n2n1
Agent: O=C(O)c1cc2[nH]c3ccccc3c(=O)n2n1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc2[nH]c3ccccc3c(=O)n2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4,9-dihydro-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid (5 g; 0.022 mole), thionyl chloride (250 ml) and four drops of pyridine is stirred at room temperature for 24 hrs. The reaction mixture is evaporated to dryness under reduced pressure in a water bath at 30°-40° C. The residue is treated with cold (0° C.) concentrated ammonium hydroxide solution (200 ml) and allowed to come to room temperature. The product is filtered off, washed with ether and used in the next step without further purification. Yield 3.2 g; mp 315°-325° C. An analytical sample, recrystallized from dimethylformamide, melts at 335°-340° C. By the same procedure, starting with the corresponding 7-fluoro compound, the product obtained is 4,9-dihydro-7-fluoro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[N:21]([CH2:14][C@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]1[OH:20])=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](COS(C)(=O)=O)[C@H](O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](O)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
To a solution of cis-1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine (4.44 g) in dimethylformamide (60 ml) were added sodium azide (1.4 g) and ammonium chloride (1.15 g), and the resulting mixture was stirred at 60° C. for 6 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to give 3.4 g of cis-4-azidomethyl-1-tert-butoxycarbonyl-3-hydroxypiperidine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:22]([CH3:32])[C:23](=[O:31])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21]2[N:22]([CH3:32])[C:23](=[O:31])[CH:24]=[CH:25][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (0.192 g, 1.01 mmol) in THF (5 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. Methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for one hour at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to pH 7 with saturated NH4Cl and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g (65%) pure desired product as a white crystalline solid.