Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A slurry of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (10 g, 29.2 mmol) and 2-amino-4,6-difluorobenzoic acid (source: Buttpark Ltd.) (5.06 g, 29.2 mmol) in iPrOH (250 ml) and DIPEA (25.5 ml, 146 mmol) was heated at 95° C. overnight, then distilled 180 mL of solvent off over 4 h, then heated for another 2 h. After allowing to cool to rt, the reaction mixture was diluted with EtOAc (300 mL), washed with a 1N HCl solution (400 mL), a saturated NaHCO3 solution (200 mL), a saturated NaCl solution (200 mL). The organic layer was diluted with Et2O (200 mL). The resulting slurry was filtered, the solid dried in vacuum oven overnight at 80° C. to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzoic acid as a pale yellow solid (5.3 g, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3H), 6.60-6.78 (m, 2H), 7.48 (d, J=8.06 Hz, 2H), 7.77 (d, J=3.85 Hz, 1H), 7.98 (d, J=8.42 Hz, 2H), 8.23-8.36 (m, 1H); ESIMS (M+H)+=478.94.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.OP=O.C(O[C:19]([CH2:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([OH:36])[C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=2)=[O:24])=O)C>O.C(Cl)Cl>[C:1]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[O:22][C:23](=[O:24])[C:25]3[CH:26]=[C:27]([OH:36])[C:28]4[C:33]([C:34]=3[CH:19]=2)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)COC(=O)c1cc(O)c2ccc(C)cc2c1
Agent: O=P(O)(O)O
Agent: O=PO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(O)cc3c(=O)oc(C(c4ccccc4)c4ccccc4)cc3c2c1

Procedure:
Toluene, 1000 milliliters (mL), heptanes, i.e., a C7 distillate having a boiling range of from 82 to 98° C., (1000 mL), methylene chloride (1000 mL), phosphoric acid, 20.0 grams of an 85 weight percent solution, 5.0 grams of hypophosphorus acid and 625.0 grams of 3-(ethoxycarbonyl)methoxycarbonyl-1-hydroxy-6-methylnaphthalene were added to a reaction flask. The reaction flask was a 5 liter four necked round bottom reactor equipped with an overhead mechanical stirrer, thermometer, electric heating mantle, heavier than water Barrett water trap, Fredrich's condenser and bottom outlet. The mixture was heated to reflux (~55° C.) and about 2 mL of water was removed. 1,1-Diphenyl-2-propyn-1-ol, 903.25 grams of a 61 weight percent solution in methylene chloride, was added to the reactor and the mixture was heated at reflux (~57° C.) for about 8 hours. The hot mixture was filtered to separate the insoluble desired product from the other products of reaction. The crystals were washed with 1 liter of a 1:1:2 mixture of toluene:heptanes:methylene chloride and dried to yield 144 grams of 2-diphenylmethyl-6-hydroxy-9-methyl-4-oxo-4H-naphtho[2,1-c]pyran.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S-:14][C:15]#[N:16].[NH4+].C(OCC)(=O)C>CC(C)=O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:16]=[C:15]=[S:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)N=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-tert-butylbenzoyl chloride (6 g, 198 mmol) in acetone (250 mL) was added ammonium thiocynate (28 g, 237 mmol). The resulting yellow suspension was stirred at room temperature for 2 hours, condensed to dryness and then reconstituted through the addition of ethyl acetate (200 mL). The organic portion was washed with a saturated sodium bicarbonate solution (2×200 ml) and brine (200 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated to a sticky liquid. The residue was chilled in a −10° C. freezer to give 37 grams of Intermediate A as a yellow solid (88%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20]>O1CCOCC1.C(O)C>[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20].[CH2:13]([NH:17][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCNCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
18 g of D-glucose are suspended in 200 ml of dioxane and 100 ml of ethanol, and 7.3 g of butylamine are added. The mixture is warmed to 70° C. and, after 10 minutes, 9.0 g anhydrous oxalic acid is added. The temperature is maintained for 4 hours. After cooling to room temperature, the product crystallizes out. The solid is filtered off with suction, rinsed five times with 50 ml of ethanol each time and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[N:36]1[C:41]2[NH:42][C:43]3[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=3[NH:45][CH2:46][C:40]=2[CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([N:45]1[C:44]2[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=2[NH:42][C:41]2[N:36]=[CH:37][CH:38]=[CH:39][C:40]=2[CH2:46]1)=[O:6]
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1

Procedure:
In the manner of Example 5, Step D, employing 2-chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid of Step B (0.971 g, 4.1 mmol), triethylamine (0.57 mL, 4.1 mmol), 2,4,6-trichlorobenzoylchloride (0.63 mL, 4.0 mmol), 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (0.67 g, 3.4 mmol) and 4-dimethylamino pyridine (0,42 g, 3.4 mmol) in dichloromethane (20 mL), was obtained a compound identical to that of Example 1, Step E.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[I:13]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([I:13])=[C:4]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)cc(Br)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (20 g, 83 mmol) in acetic acid (150 ml) was treated portionwise with N-iodosuccinimide (20.62 g, 92 mmol). The reaction was stirred 24 h at ambient temperature. The reaction was diluted with ethyl acetate (600 mL) and was washed with aqueous sodium bisulfie (100 mL) and brine (100 mL). The organic layer was dried with magnesium sulfate and evaporated. The residue was purified on a silica gel column with a gradient of ethyl acetate/hexanes from 7% to 15% to give 23.5 g (77%) of slightly impure product. 1H-NMR (CDCl3, 400 MHz) δ 7.21 (d, J=1.3 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 4.57 (bs, 2H); LC/MS (HPLC method 4): tR=3.578 min, 365.80(MH)+.
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N:16]([CH2:2][C:3]([CH3:5])=[CH2:4])[C:17](=[O:19])[CH3:18]
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
At 25° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added dropwise to a solution of N-(2-bromo-5-nitrophenyl)acetamide (3.6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 mL). The reaction mixture was stirred at 25° C. overnight. The reaction mixture was then filtered and the filtrate was treated with sat. Na2CO3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to provide N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide as a golden solid (3.1 g, 85%). ESI-MS 313 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][CH:23]([CH3:26])[CH2:24]C)=[CH:19][CH:18]=[CH:17][C:16]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:12]=[C:11]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[C:39]([OH:44])[CH:38]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(OCC)(=O)C>[C:45]([NH:43][C:40]1[CH:41]=[CH:42][C:37]([C:11]2[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])=[C:2]([NH2:1])[N:14]=[C:13]([C:15]3[C:16]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH:23]3[CH2:26][CH2:24]3)[CH:12]=2)=[CH:38][C:39]=1[OH:44])(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)COc1cccc(OCc2ccc(OC)cc2)c1-c1cc(-c2ccc(N)c(O)c2)c(C(=O)OC(C)(C)C)c(N)n1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-amino-4-(4-amino-3-hydroxyphenyl)-6-[2-[(4-methoxybenzyl)oxy]-6-(2-methylbutoxy)phenyl]nicotinate (2.46 g, 4.21 mmol) was added acetic anhydride (0.44 mL, 4.63 mmol). The mixture was stirred at room temperature for overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-[4-(acetylamino)-3-hydroxyphenyl]-2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}nicotinate. (2.65 g, 100%); LC-MS (M/z=626, M+1)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=O>>[CH:1]1([NH:4][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(CNC2CC2)cc1OC

Procedure:
prepared by reaction of cyclopropylamine with 3,4-dimethoxy-benzaldehyde
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3(O)[CH2:13][O:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(S(F)(F)[F:21])CC)C>C(#N)C.[N+](C)([O-])=O>[F:21][C:10]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][NH:2][CH2:3]3)[CH2:13][O:12][CH2:11]1
Reactant: OC1(c2ccc3c(c2)CNC3)COC1
Reactant: CCN(CC)S(F)(F)F
Solvent: CC#N
Solvent: C[N+](=O)[O-]
Product: FC1(c2ccc3c(c2)CNC3)COC1
Temperature: 0 °C
Yield: 67 %

Procedure:
To 0.58 mmol 3-(2,3-dihydro-1H-isoindol-5-yl)-oxetan-3-ol in 2 ml acetonitrile and 2 ml nitromethane at −60° C. was added 1.15 mmol diethylaminosulfur trifluoride and the mixture was allowed to warm to 0° C. over 30 min. The reaction mixture was re-cooled to −60° C. and quenched by addition of 5 ml saturated aq. sodium carbonate solution. The mixture was warmed to RT and diluted with THF and ethyl acetate, then washed sequentially with water and with brine. The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a brown oil (67% yield). MS (m/e): 194.3 ([M+H]+, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Reactant: c1cn[nH]c1
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[NH2:13][NH2:14]>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:13][NH2:14])=[O:5]
Reactant: COC(=O)c1ccccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccccc1F
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Methyl 2-fluorobenzoate (27) (25 g, 160 mmol) was dissolved in ethanol (200 mL) and hydrazine monohydrate (11.8 mL, 240 mmol) was added. The mixture was heated to reflux for 4 hr then allowed to cool to room temperature overnight. The reaction was incomplete. After heating for a further 2 hr, starting material still remained. Additional hydrazine monohydrate (4 mL) was added. After heating for 2-3 hr the reaction was nearly complete. The mixture was cooled and concentrated under reduced pressure. Water (50 mL) was added to the residue and the aqueous layer was saturated with solid NaCl. The product was extracted with EtOAc (3×100 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with heptane (100 mL), filtered, and dried to provide 23.8 g (95%) of 13 as a pinkish solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[CH3:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37].CCCCCC>C(CC(C)(C)C)(C)C>[C:36]([O:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5])(=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=[CH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: CC(C)CC(C)(C)C
Solvent: CCCCCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of farnesol and 750 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 107 mg of farnesyl eicosapentaenoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-n3ccnc3)ccc2N1
Temperature: 90 °C

Procedure:
A mixture of 1.0 g of 6-bromo-3,4-dihydrocarbostyril, 300 mg of imidazole, 40 mg of cuprous iodide and 600 mg of potassium carbonate in 4 ml of N,N-dimethylformamide was heated at 90° C. for 48 hours. The reaction mixture was poured into water and extracted with a mixture of 10% methanol in methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride, giving 6-(imidazol-1-yl)-3,4-dihydrocarbostyril, m.p. 205°-208° C.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[Br:12]Br>CC(O)=O>[Br:12][CH:7]1[C:6](=[O:11])[CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][C:8]1=[O:10]
Reactant: CC(C)C1CC(=O)CC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)C1CC(=O)C(Br)C(=O)C1
Yield: 96.8 %

Procedure:
To a stirred solution of 5-isopropylcyclohexane-1,3-dione (2 g, 12.9 mmol) in AcOH (20 mL) at r.t. was added bromine (2.06 g, 0.66 mL, 12.9 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound (2.91 g, 96%) as a white solid. δH (DMSO-d6) 2.55-2.48 (4H, m), 2.38-2.32 (1H, m), 1.91-1.82 (1H, m), 1.79-1.54 (1H, m), 0.87 (6H, d, J 6.7 Hz). LCMS (ES+) 234.9 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:17])C(F)(F)F.C([OH:20])C.[OH-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([OH:17])=[O:20]
Reactant: O=C(c1cccn1Cc1ccco1)C(F)(F)F
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccn1Cc1ccco1

Procedure:
1-Furfurylpyrrole (2.3 g, 15.6 mMol), 15 ml of trifluoroacetic anhydride (22.35 g, 106 mmol), 50 ml of nitromethane and 25 ml anhydrous diethylether were combined in a 100 ml round bottom flask. The mixture was stirred overnight under positive argon. The reaction was heated and the excess solvents distilled off. The mixture was evaporated to dryness under reduced pressure to give 3.9 g of a dark oil. The oil was distilled in a Kugel-rohr apparatus. The fraction collected at 80° C. to 90° C. at 0.2 mm Hg pressure gave 3.0 g of the colorless oil. 1-(2-furanylmethyl)-2-trifluoroacetyl-1H-pyrrole. This oil was combined with 50 ml ethylalcohol in a 100 ml round bottom flask equipped with a reflux condenser. The mixture was heated to reflux. Sodium hydroxide, 3.0 g in 15 ml of water, was added, and the reaction mixture was refluxed for 3 hours. The ethanol was distilled off and 50 ml of water was added. The mixture was cooled and acidified by addition of 5.0 g malonic acid. A precipitate formed which was collected by filtration. The solid precipitate was recrystallized from acetonitrile to give the title compound a white powder, mp=117° C. to 118° C., infrared spectrum absorption at 3400 cm-1, 1675 cm-1, 1530 cm-1, 1440 cm-1, 750 cm-1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][C:21]=1[F:26])(=[O:3])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) were added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 4-bromo-2-fluoroaniline (0.891 g, 4.69 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.42 g, 82%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])(=O)=O.[I-:19].[Li+].CN1CCCC1=O>O>[I:19][C:7]1[C:8]([F:16])=[CH:9][CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: [I-]
Reactant: O=[N+]([O-])c1cccc(F)c1OS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(F)c1I
Reaction time: 18 h
Yield: 47 %

Procedure:
A mixture consisting of 2-fluoro-6-nitrophenyl trifluoromethanesulfonate (62.0 g, 0.215 mol), lithium iodide (60 g, 0.451 mol) and 1-methyl-2-pyrrolidinone (400 mL) was heated with stirring at 130°-132° C. (oil bath temperature) for 18 hours. Upon cooling it was poured into water (1200 mL) and extracted with diethyl ether. The combined extracts were washed with 1N NaOH, water and with brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo to give 27.0 g of the title compound as a brown-colored solid title compound (m.p. 54°-57° C.).
Reaction SMILES: [CH2:1]([NH:3][C:4](F)=[O:5])[CH3:2].[C:7]([N:11]1[CH:15]=[C:14]([OH:16])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([NH:3][C:4](=[O:5])[O:16][C:14]1[CH:13]=[N:12][N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:15]=1)[CH3:2]
Reactant: CCNC(=O)F
Reactant: CC(C)(C)n1cc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC(=O)Oc1cnn(C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
4.6 g (0.05 mol) of N-ethylcarbamoyl fluoride were added to a mixture of 7 g (0.05 mol) of 1-tert.-butyl-4-hydroxypyrazole, 10.4 g (0.075 mol) of potassium carbonate and 100 ml of acetonitrile. The mixture was stirred for a further 3 hours at 20° C. It was then filtered under suction. The filtrate was concentrated by evaporation in vacuo. 9 g (85% of theory) of 1-tert.-butyl-pyrazol-4-yl N-ethylcarbamate were obtained in the form of beige crystals with a melting point of 77° C.
Reaction SMILES: I[CH2:2][C:3]#[C:4][CH2:5][O:6][CH2:7][C:8]([O-:10])=[O:9].[K+].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].Cl>C(O)C.O>[C:8]([CH2:7][O:6][CH2:5][C:4]#[C:3][CH2:2][N:16]1[C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]2[C:12]1=[O:22])([OH:10])=[O:9]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C([O-])COCC#CCI
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: CCO
Solvent: O
Product: O=C(O)COCC#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Potassium 7-iodo-3-oxa-5-heptynoate is added to a solution of potassium phthalimide (equimolar quantity) in ethanol at 25° C. The resulting solution is stirred and maintained at 25° C. until alkylation is complete. Evaporation of the reaction mixture in vacuo at 40° to 50° C. leaves a residue which is suspended in water. The aqueous suspension is acidified to Congo Red with dilute hydrochloric acid and extracted three times with ether. The combined organic extract is washed with saturated aqueous brine, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate at 40° to 50° C. leaves the desired title compound.