Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1.CCCCCC>[CH2:19]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a 2 liter three-neck flask equipped with a stirrer and a thermometer, 100 g (0.6 mol) of fluorene was dissolved in 1 l of tetrahydrofuran and the flask was cooled sufficiently to −78° C. With an injector, 264 ml (1.32 mol) of 2.5M n-butyl lithium which was diluted in hexane was slowly added dropwise into the flask. When the addition of the same was finished, the above cooled temperature was maintained for thirty minutes, and then the flask was stirred at room temperature for one hour. Then again the resultant material was cooled down to −78° C. 88.44 ml (1.26 mol) of hexyl bromide was added into the flask using an injector. When the above procedure was finished, after keeping the temperature for thirty minutes, the flask was stirred at room temperature for 24 hours. When the reaction was finished, a small amount of cooled distilled water was poured to the resultant solution and the resultant solution was stirred for 2 to 3 minutes. When layers were separated, the organic layer was extracted using ether three times and it was washed by water several times. Then the resultant materials were dried using anhydrous magnesium sulfate and after removing the solvent, the resultant materials were purified with column, to obtain 132 g (88% t yield) of the entitled product as a pale yellowish viscous oil. 1H-NMR (CDCl3) δ 0.6-1.41 (m, 8H, CH2, 3H, CH3), 2.08-2.12 (m, 4H, CCH2), 4.07-4.18 (t, 1H, CH), 7.39-7.92 (m, 8H, Aromatic).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([C@@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc([C@@H](O)c2c(C(C)C)nc3c(c2C2=CCOCC2)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(4-isopropoxyphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 5:1.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([O:11]C)=[CH:4][CH:3]=1.[ClH:13].N1C=CC=CC=1>>[Cl:13][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: COc1ccc(Br)c2ccsc12
Solvent: c1ccncc1
Product: Oc1ccc(Cl)c2ccsc12
Yield: 40.6 %

Procedure:
4-Bromo-7-methoxybenzo[b]thiophene (prepared as described in J. Chem. Soc. (Perkin Trans I), 1983, 2973-2977) (1.2 g, 4.96 mmol) and pyridine hydrochloride (1.95 g, 16.87 mmol) was heated at 210° C. in a microwave for 15 min. The mixture was partitioned between HCl (aq.) (20 mL) and EtOAc (20 mL). The aqueous phase was washed with additional EtOAc (3×20 mL) and the organic phase was dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography on silica gel with EtOAc:heptane (1:10 to 1:5, v/v) as eluent to give the title compound as a red oil (372 mg, 41%).
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[S:11][C:12]2[C:13](=[CH:15][CH:16]=[C:17]3[C:25]4[S:24][C:23]([C:26]5[S:27][CH:28]=[CH:29][C:30]=5[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][C:21]=4[CH:20]=[CH:19][C:18]=23)[CH:14]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.CN([CH:43]=[O:44])C.[C:45](=O)([O-])[OH:46].[Na+]>ClCCl>[CH2:1]([C:5]1[CH:9]=[C:8]([CH:43]=[O:44])[S:7][C:6]=1[C:10]1[S:11][C:12]2[C:18]3=[CH:19][CH:20]=[C:21]4[C:25]([S:24][C:23]([C:26]5[S:27][C:28]([CH:45]=[O:46])=[CH:29][C:30]=5[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22]4)=[C:17]3[CH:16]=[CH:15][C:13]=2[CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCc1ccsc1-c1cc2ccc3c(ccc4cc(-c5sccc5CCCC)sc43)c2s1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1cc(C=O)sc1-c1cc2ccc3c(ccc4cc(-c5sc(C=O)cc5CCCC)sc43)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of benzothiophenobenzothiophene 20 (300 mg, 0.58 mmol) in 7 ml of dichloromethane is added a solution of 1.1 ml (11.4 mmol) of phosphorus oxychloride and 0.94 ml (12.2 mmol) of DMF in 7 ml of DCM. The reaction mixture is refluxed for 16 h, then sat. sodium hydrogencarbonate solution (50 ml) is added and the mixture is stirred at room temperature for 2 h. After phase separation, the organic phase is dried over sodium sulfate. After the solvents have been distilled off, the residue is recrystallized from toluene to obtain 172 mg (52%) of product. 1H NMR (TCE-d2, 375 K): 9.83 ppm (s, 2H), 8.01 (d, 2H), 7.90 (s, 2H), 7.61 (s, 4H), 2.92 (dd, 4H), 1.72 (m, 4H), 1.44 (qa, 4H), 0.95 (t, 6H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][Cl:15].CCN(CC)CC>O1CCOCC1.CCOCC>[Cl:15][CH2:14][CH2:13][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: ClCCCBr
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: ClCCCN1CCCc2ccccc21
Temperature: 70 °C
Reaction time: 17 h
Yield: 23.5 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (505 mg, 3.79 mmol) and 1-bromo-3-chloro propane (1.77 g, 11 mmol) in 1,4-dioxane (6 mL) was added Et3N (1.90 g, 19 mmol). The reaction mixture was stirred at 70° C. for 17 h, and quenched by addition of H2O (2 mL). Reaction was diluted with Et2O (100 mL) and washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (hexanes:EtOAc 49:1) yielded 1-(3-chloropropyl)-1,2,3,4-tetrahydroquinoline (187 mg, 24%) as a colorless oil. The title compound was isolated as a yellow oil (22 mg, 43%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(3-chloropropyl)-1,2,3,4-tetrahydroquinoline (51 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.77-2.19 (m, 10H), 2.24-2.41 (m, 2H), 2.61-2.69 (m, 1H), 2.75-2.84 (m, 3H), 2.91-3.02 (m, 1H), 3.10-3.21 (m, 2H), 3.26-3.34 (m, 5H), 3.52-3.61 (m, 1H), 3.77-3.96 (m, 1H), 6.49-6.65 (m, 3H), 6.85 (d, 1H, J=7.3 Hz), 6.92-6.96 (m, 2H), 6.99-7.05 (m, 1H) ppm.
Reaction SMILES: O.[NH2:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CN(C)C=O>[N:2]1([CH2:3][CH:4]2[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=43)[C:7](=[O:17])[NH:6][CH2:5]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CNC(=O)c2cccc3[nH]cc1c23
Reactant: BrCCCCCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCC(CN2CCCCC2)c2c[nH]c3cccc1c23
Temperature: 25 °C

Procedure:
4 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-Cd]indole hydrate (for preparation see Example 1C) were dissolved in 40 ml of dimethylformamide. 2.6 ml of triethylamine were added to the solution and subsequently, while stirring at room temperature, 2 4 ml of 1,5-dibromopentane were added. The reaction mixture was heated at 50° C. for 3.5 hours. The reaction mixture was worked up by evaporating it under reduced pressure (water pump vacuum) and taking up the residue in a 9:1 dichloromethane/methanol mixture. Then saturated aqueous sodium carbonate solution was added until pH 11 was reached. The organic phase was separated and the aqueous phase was washed twice more with 50 ml portions of the dichloromethane/methanol mixture. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in ethanol, and diethyl ether was added to the solution until a slight turbidity appeared. The resulting crystals were filtered out and dried. 3.5 g of crystalline 3-(1-piperidinylmethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole were obtained with a melting point of 119° to 122° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](OC)(OC)[O:16]C.O.[CH3:23]O>Cl(O)(=O)(=O)=O>[CH3:23][O:8][C:1]([O:16][CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: CO
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: COC(OC)(c1ccccc1)c1ccccc1
Temperature: 27.5 °C

Procedure:
In a round bottom flask, (10 g) Benzophenone in 20 ml methanol was taken. 12 ml (2 equiv.) trimethyl orthoformate was added into the reaction mixture in a single lot and the reaction mixture was stirred at 25-30° C. 3-4 drop perchloric acid (HClO4 as a catalyst) was added and reflux it for 9 hr. After completion of the reaction, the reaction mass was dumped into water. Subsequently, the reaction mass was stirred for 15 min, filtered it and wash the solid mass with water to obtain white solid product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH2:12][OH:13].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]=[O:13]
Reactant: Cn1cc2c(CO)c(Br)ccc2n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: Cn1cc2c(C=O)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
(5-Bromo-2-methyl-2H-indazol-4-yl)methanol (324 mg, 1.34 mmol) and o-iodoxybenzoic acid (414 mg, 1.48 mmol) were dissolved in dimethyl sulfoxide (6.7 mL), and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (311 mg, yield 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.C(C1C=CC([NH:46]C(=O)C)=C(Br)C=1)(=O)C.[OH-:51].[K+]>C(O)C>[NH2:46][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:34])=[O:51])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:7][C:2]=1[Br:1]
Reactant: [OH-]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1Br
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1Br
Yield: 15 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with N-(4-acetyl-2-bromo-phenyl)-acetamide (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (16 mg, 15% yield).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Al:21]>O.[Cl-].C([N+](CC)(CC)CC)C.CO>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Al+3:21].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: [Al]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Al+3]
Yield: 4.9 %

Procedure:
To a reaction flask was charged 12.0 g (0.0422 mole) of stearic acid, 220 g methanol and 0.40 g of tetraethylammonium chloride hydrate. Aluminum foil was used as the anode and a graphite rod as the cathode. After passing 2,780 coulombs of electricity, 0.56 g (0.021 mole) of aluminum was consumed. A greyish solid precipitated out during the reaction which was filtered, washed with methanol and dried. This gave a grey solid aluminum stearate containing 4.9% aluminum.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:29][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:22])[CH2:28][CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NC1CCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CCC3)cc2n1
Yield: 80 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using cyclobutylamine instead of aminomethylcyclopropane, to the title compound (89 mg, 80%) which was obtained as a light yellow foam. MS: m/e=373.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O>>[C:9]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.4 %

Procedure:
To a mixture of p-chlorophenol (19.0 g, 147.8 mmol) and tert-butanol (21.9 g, 295.6 mmol) was added concentrated sulfuric acid (15 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into ice water (300 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 95:5) to give the title compound (14.3 g, yield 54%) as a brown oil.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[S:7][C:8](=[C:11]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:12]([O-:14])=[O:13])[S:9][CH:10]=1.[CH:21]1[CH:26]=CC=C[CH:22]=1.C(N(CC)CC)C>O>[S:9]1[CH:10]=[CH:6][S:7][C:8]1=[C:11]([S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:12]([O:14][CH:21]([CH3:26])[CH3:22])=[O:13]
Reactant: CC(C)S(=O)(=O)C(C(=O)[O-])=C1SC=C(O)S1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)C(=C1SC=CS1)S(=O)(=O)C(C)C

Procedure:
After dropwise addition of 13.5 g of thionyl chloride to a mixture of 32.7 g of 4-hydroxy-1,3-dithiol-2-ylidene-isopropylsulfonylacetate and 100 ml of benzene, the reaction mixture was refluxed for 30 minutes. Subsequent to its cooling, 13.0 g of triethylamine was added to the reaction solution, followed by further reflux for 3 hours. The resultant reaction mixture was cooled. Water was added to the reaction mixture and the resulting organic layer was separated. Upon removal of the solvent by distillation under reduced pressure, 28.3 g of the title compound was obtained as pale brown crystals. Upon recrystallization from a mixed solvent of benzene and n-hexane, they turned to white crystals. Melting point: 124.5°-125° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]3[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>C(O)(=O)C>[CH3:4][CH2:3][CH2:2][CH:1]([CH3:7])[CH3:6].[Br:18][C:15]1[C:14](=[O:17])[NH:13][C:12]2=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][CH:10]=[C:11]2[CH:16]=1
Reactant: BrBr
Reactant: O=c1ccc2cnnc(-c3ccccc3)c2[nH]1
Solvent: CC(=O)O
Product: CCCC(C)C
Product: O=c1[nH]c2c(-c3ccccc3)nncc2cc1Br
Temperature: 25 °C

Procedure:
8-Phenyl-1H-pyrido[2,3-d]pyridazin-2-one (46 mg) and bromine (0.11 ml) were stirred together in acetic acid (3 ml) at 90° C. for 7 days, adding a fresh aliquot of bromine (0.11 ml) every 24 h. The mixture was allowed to cool to room temperature, precipitating a solid. This was separated by filtration and purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate:isohexane, then 100% ethyl acetate, yielding 3-bromo-8-phenyl-1H-pyrido[2,3-d]pyridazin-2-one as a pale yellow solid (10 mg). 1H NMR (400 MHz, CDCl3) δ7.67 (5H, m), 8.29 (1H, s), 9.02 (1H, br s), 9.21 (1H, s); MS (ES+) m/e 302, 304 [MH]+.
Reaction SMILES: O[C:2]1([O:21][CH3:22])[C:7]([O:8][CH3:9])=[CH:6][CH:5]([CH:10]([CH:16]=[CH2:17])C(OCC)=O)[C:4](=O)[CH:3]1[O:19][CH3:20].[OH2:23].[NH2:24][NH2:25]>>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:10]2[NH:25][N:24]=[C:17]([C:9]([O:8][CH2:7][CH3:6])=[O:23])[CH:16]=2)[CH:4]=[C:3]([O:19][CH3:20])[C:2]=1[O:21][CH3:22]
Reactant: NN
Reactant: C=CC(C(=O)OCC)C1C=C(OC)C(O)(OC)C(OC)C1=O
Reactant: O
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)[nH]n1

Procedure:
Ethyl 4-hydroxy-2-oxo-3,4,5-trimethoxyphenyl-3-butenoate (5.0 g) and hydrazine monohydrate (0.8 mL) were treated in the same manner as in Preparation Example 26 to obtain the title compound.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:34])[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1.[Cl:35][C:36]1[N:41]=[C:40]([Cl:42])[C:39]([CH2:43]I)=[CH:38][N:37]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:34])[CH:19]([C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1)[CH2:43][C:39]1[C:40]([Cl:42])=[N:41][C:36]([Cl:35])=[N:37][CH:38]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 10 minutes, a solution of 3,5-bis-trifluoromethylphenylacetic acid methyl ester (2.20 g, 7.7 mmol) (from Example 8a supra) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 10 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 2 hours then slowly allowed to warm up to −20° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-(3,5-bis-trifluoromethyl-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester as a colorless oil. (Yield 1.71 g, 76.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Li][CH:18]1C2N=CC(C)=CC=2CCC1.[C:29](=[O:31])=[O:30]>CCOCC>[CH3:18][O:30][C:29]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:31]
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: O=C=O
Reactant: [Li]C1CCCc2cc(C)cnc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)C1CCCc2cc(C)cnc21
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-methyl-5,6,7,8-tetrahydroquinoline (147 g., 1 m) in dry ether (700 ml.) was treated with a freshly prepared solution of butyl lithium (860 ml. of a 1.4 M solution i.e. 1.2 m) under nitrogen. The reaction mixture was stirred for an additional 15 min. The resulting 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline was treated in situ with a slow stream of dry CO2 gas which was bubbled into the reaction mixture until it became colourless. The reaction mixture was processed as described in Example 19 of our copending U.S. Ser. No. 460,265 to give methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:10]=[C:9]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[CH:8]=1)=O.CO.Cl>C1COCC1.O1CCOCC1>[OH:4][CH2:5][C:7]1[N:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:10]=[C:9]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[CH:8]=1
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(CO)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A 2M solution of lithium borohydride in THF (22.4 ml, 44.8 mmol) was added to a mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (4.0 mg, 8.96 mmol) in anhydrous THF (200 ml). The reaction mixture was stirred at ambient temperature for 3 hours and then heated at reflux for 1 hour. The mixture allowed to cool and methanol was added until effervescence ceased, a 4M solution hydrogen chloride in dioxane (30 ml) was then added and the mixture heated at reflux for 1 hour. The volatiles were removed by evaporation, the residue was dissolved in water and the resulting solution adjusted to pH 9 by careful addition of 10M aqueous sodium hydroxide solution. The aqueous mixture was extracted with DCM and purification by chromatography on silica gel, eluting with DCM/methanol (100:0 increasing in polarity to 90:10) to give the title compound (3.4 g, 91%).