Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([C:22]([O:24]C)=O)=[N:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CO.[NH3:35]>>[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([C:22]([NH2:35])=[O:24])=[N:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: N
Reactant: COC(=O)c1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Solvent: CO
Product: Cc1c(C(N)=O)nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1C
Temperature: 130 °C
Yield: 77 %

Procedure:
A solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate [that was prepared in a manner analgous to that described for Example 51] (80 mg, ˜90% purity, 0.170 mmol, 1.0 eq) in 2.41 ml 7N ammonia in MeOH (˜100 eq of NH3) was heated for 2 hours at 130° C. by the use of a single mode microwave oven (Biotage). On cooling the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 11 g SNAP NH2 cartridge: hexane/EtOAc 1:1→EtOAc) to give 54 mg (77% yield) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCCCCC>ClC(Cl)C.CCOC(C)=O>[C:9]([O:8][CH2:7][CH:6]([N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(Cl)Cl
Product: CC(=O)OCC(COC(C)=O)N(C)CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (4.54 g, 26 mmol) in dichloroethane (75 ml) was added tert-butyl 2-(methylamino)acetate HCl. After stirring for 10 minutes sodium triacetoxyborohydride (8.3 g, 39 mmol) was added and stirring was continued for 18 hours and monitored by TLC (1:1 heptane:EtOAc). The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-20% EtOAc:Hept to yield the title compound (1.32 g, 17% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.07-4.33 (4H, m), 3.34 (2H, s), 3.23 (1H, t, 5.9 Hz), 2.49 (3H, s), 1.99-2.19 (6H, m), 1.33-1.55 (9H, m).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[CH3:22][CH:23]([N:25]=[C:26]=[O:27])[CH3:24].C(N(CC)CC)C.O>O1CCCC1>[CH3:22][CH:23]([NH:25][C:26]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=2)[CH2:17]1)=[O:27])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 1.8 g (0.022 mole) of 1-methylethyl isocyanate and after 0.5 hr, 5 ml of triethylamine was added. A clear yellow solution was obtained and was stirred for 18 hr, then treated with 10 ml of water, yielding 5.3 g (87.7%) of pale yellow crystals, m.p. 151°-152° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:17]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][N:16]3[N:15]=2)[CH:11]=[N:12][CH:13]=1.[CH:24]1(B(O)O)[CH2:26][CH2:25]1.C(Cl)Cl>O1CCOCC1.O>[CH:24]1([C:8]2[CH:9]=[C:10]([C:14]3[N:23]=[C:17]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][N:16]4[N:15]=3)[CH:11]=[N:12][CH:13]=2)[CH2:26][CH2:25]1
Reactant: Cc1ccc2nc(-c3cncc(Br)c3)nn2c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2nc(-c3cncc(C4CC4)c3)nn2c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Cesium carbonate (0.45 g, 0.0013 mol) was added to a stirred solution of 2-(5-bromopyridin-3-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (44-2; 0.2 g, 0.00069 mol) and cyclopropylboronic acid (0.119 g, 0.00138 mol) in a mixture of 1,4-dioxan (9 mL) and water (3 mL). The reaction mixture was purged with argon for 20 min. Pd(dppf)2Cl2.DCM (0.028 g, 0.000034 mol) was added and the reaction flask was again purged with argon for 10 min. The reaction mixture was then stirred at 100° C. for 18 h. The reaction mixture was filtered through a filter bed of CELITE and the filter bed was thoroughly washed with ethyl acetate (2×50 mL). The collected organic factions were concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compound. 1H NMR (400 MHz, DMSO) δ 9.08-9.07 (d, J=1.2 Hz, 1H), 8.83 (s, 1H), 8.50-8.49 (d, J=2.4 Hz, 1H), 8.04 (s, 1H), 7.78-7.76 (d, J=8.8 Hz, 1H), 7.57-7.55 (d, J=9.2 Hz, 1H), 2.37 (s, 3H), 2.08-2.05 (m, 1H), 1.08-1.03 (m, 2H), 0.84-0.80 (m, 2H), MS (M+1): 251.2.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1.[FH:40].[K].CCCC[N+](CCCC)(CCCC)CCCC.F.F.[F-].ClC1C=CC=CC=1>C1(C)C=CC=CC=1>[F:40][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CO3)CC2)c2ncnn12
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CF)CC2)c2ncnn12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 4′-({4-[trans-4-(oxiran-2-ylmethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g), potassium hydrogen fluoride (0.075 g), tetra-n-butylammonium dihydrogentrifluoride (0.015 g) and chlorobenzene (1 mL) was stirred at 120° C. for 5 hr. Potassium hydrogen fluoride (0.075 g) and tetra-n-butylammonium dihydrogentrifluoride (0.014 g) were added, and the mixture was stirred at 120° C. for 16 hr. Toluene was added, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH:25]1([NH:28][CH2:29][C@@H:30]2[C@H:34]([F:35])[CH2:33][NH:32][CH2:31]2)[CH2:27][CH2:26]1>>[CH:25]1([NH:28][CH2:29][C@@H:30]2[C@H:34]([F:35])[CH2:33][N:32]([C:11]3[CH:10]=[C:9]4[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]4[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])=[CH:3][C:2]=3[F:1])[CH2:31]2)[CH2:27][CH2:26]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 65 %

Procedure:
Using 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (337 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow powder (309 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C(OCC)(=O)C.[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
Part 1. To a solution of methyl 4-[(tert-butoxy)carbonylamino]-3-nitrobenzoate (0.44 g, 1.5 mmol) in methanol (2 mL), ethyl acetate (3 mL) and triethylamine (0.21 mL, 1.5 mmol) was added 10% Pd on carbon (159 mg, 0.15 mmol). The reaction mixture was hydrogenated under 1 atm H2 for 3.5 hours, filtered, and concentrated in vacuo to yield methyl 3-amino-4-[(tert-butoxycarbonyl)amino]benzoate (0.40 g, 99%) as a white solid. ES-MS (M+H—C4H8)+=211.1.
Reaction SMILES: [CH2:1]([C:9]1([NH:15][CH:16]=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.CC(O)C>[O:12]1[CH2:13][CH2:14][C:9]2([N:15]=[CH:16][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][CH2:1]2)[CH2:10][CH2:11]1
Reactant: O=CNC1(CCc2ccccc2)CCOCC1
Solvent: CC(C)O
Solvent: ClCCl
Product: C1=NC2(CCOCC2)CCc2ccccc21
Yield: 13.9 %

Procedure:
Formamide 20 (3.65 g, 15.7 mmol) from the previous experiment is cyclized according to general procedure C to give imine 22 (0.47 g, 14%) as a yellow oil after FC (10:1 CH2Cl2 /iPrOH). 1H NMR (CDCl3) 8.35(s,1) , 7.50-7.45(m,1) 7.40-7.20(m,3), 4.10-3.95(m,2), 3.85-3.70(m,2), 3.15-3.05(m,2), 2.00-1.95(m,2), 1.85-1.70(m,4); 13C NMR (CDCl3) 157.88, 141.77, 135.23, 132.61, 129.89, 129.66, 126.21, 64.02, 58.32, 38.71, 37.25, 30.13; MS(MW=215.3, CI/CH4, eE=120 eV) m/z 216 [(M+H+), base peak], 199, 189, 171, 143, 117, 100, 83.
Reaction SMILES: C([Li])CCC.[C:6](=[O:8])=O.CC(C)=O.[C:13]1([CH2:19][N:20]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]2[C:30]3[N:31]=[CH:32][N:33]([CH2:34][O:35][CH2:36][CH3:37])[C:29]=3[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)=O.C(Cl)(Cl)(Cl)Cl.C=O>O1CCCC1>[C:39]1([CH2:38][N:20]([CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]2[C:30]3[N:31]=[C:32]([CH2:6][OH:8])[N:33]([CH2:34][O:35][CH2:36][CH3:37])[C:29]=3[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reactant: O=C=O
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOCn1c(CO)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C

Procedure:
Butyllithium (1.6 mL of 2.5M in hexanes, 4 mmole) was added to a chilled (dry ice/acetone bath) solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.7 g, 4 mmole) in tetrahydrofuran. No color change was observed. The reaction mixture was warmed to -20° C. (dry ice/carbon tetrachloride) and the reaction turned red in color. Formaldehyde gas entrained in a flow of nitrogen was added to the reaction mixture. After several minutes the reaction turned to a solid mass and the ice bath was removed. The reaction mixture was allowed to warm to ambient temperature and the color of the reaction mixture changed from red to yellow. The reaction was diluted with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10-20% ethyl acetate in hexanes v/v) to provide 1 g of 4-bis(phenylmethyl)amino-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-2-methanol.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH2:12][C:13]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:14]=1[C:15]([NH:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16].O>O1CCOCC1>[CH2:19]([O:18][N:17]1[C:15](=[O:16])[C:14]2[C:13](=[CH:29][C:28]([F:30])=[C:27]([F:31])[CH:26]=2)[NH:12][C:1]1=[O:2])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)NOCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1

Procedure:
Phosgene, 12.5% solution in toluene, (16 mL, 20 mmol) was added to a solution of 2-amino-N-benzyloxy-4,5-difluoro-benzamide (Example A, 5.54 g, 19.9 mmol) in 160 mL of dioxane. The solution was heated at reflux for 5 hours and then poured into 450 mL of water. The aqueous solution was extracted with ethyl acetate; the combined organic extracts were washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 5.73 g of the title compound as a solid, mp>250° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:13]2[C:14]([CH3:22])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[S:8][C:9]=1[C:10]([NH2:12])=O)([CH3:4])([CH3:3])[CH3:2].COC(OC)[N:26]([CH3:28])C.O.[NH2:32]N>C(O)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:13]2[C:14]([CH3:22])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[S:8][C:9]=1[C:10]1[NH:26][CH:28]=[N:32][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn2ccccc2c1-c1nc(C(C)(C)C)c(C(N)=O)s1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn2ccccc2c1-c1nc(C(C)(C)C)c(-c2nnc[nH]2)s1
Yield: 85 %

Procedure:
Using 4-tert-butyl-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxamide (230 mg, 0.73 mmol), N,N-dimethylformamide dimethyl acetal (25 mL), acetic acid (25 mL) and hydrazine monohydrate (0.5 mL) as starting materials and in the same manner as in Example 13(vi), the title compound (210 mg, 85%) was obtained as a brown solid.
Reaction SMILES: O1CCCC1.B.CO[N:9]=[C:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH:11]1[CH2:13][CH2:12]1.O.[OH-].[Na+]>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]([CH:11]2[CH2:12][CH2:13]2)[NH2:9])=[CH:19][CH:18]=1
Reactant: CON=C(c1ccc(Cl)cc1)C1CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
Borane tetrahydrofuran complex (1N in THF, 65.6 mL) was added to (4-chlorophenyl)(cyclopropyl)methanone O-methyl oxime (Intermediate 2) (2.75 g) in THF (100 mL) at 25° C. under nitrogen. The resulting solution was stirred at reflux for 3 hours, then cooled to 0° C. Water was carefully added, followed by aqueous NaOH (20%, 100 mL). The resulting mixture was stirred at reflux overnight, then allowed to cool to room temperature. The product was extracted into hexane, then dried over sodium sulfate, filtered and evaporated to afford (4-chlorophenyl)(cyclopropyl)methanamine as a clear oil (2.205 g, 93%).
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32].N1C=CC=CC=1>C(Cl)Cl>[Br-:1].[F:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:3]([NH:2][C:30](=[O:33])[CH:31]=[CH2:32])[CH:8]=1
Reactant: Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Br-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.9 %

Procedure:
A suspension of 89 g (0.19 mol) of [(2-amino-4-fluorophenyl)methyl]-triphenylphosphonium bromide in 1.5 L CH2Cl2 was stirred and 17 mL (0.21 mol) of acryloyl chloride was added dropwise. A 22.8 mL sample of pyridine was added dropwise. The mixture was heated under reflux for 45 min. The mixture was cooled, washed with K2CO3 solution, dilute hydrochloric acid and brine. It was dried (Na2SO4), concentrated and triturated with Et2O to give 80 g (81%) of [[4-fluoro-2-[(1-oxo-2-propenyl)amino]phenyl]methyl]triphenylphosphonium bromide as a yellowish solid: 1H NMR (CDCl3) δ 8.0-7.4 (m, 15H); 6.9 (m, 2H); 6.4 (m, 1H); 6.1 (d, 1H); 5.9 (d, 2H); 5.5 (d, 1H). ##STR18##
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[NH:21]([C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1)[NH2:22]
Reactant: COc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nc(NN)nc(-c3ccccc3)c2c1

Procedure:
To a solution of 9.7 g of 2-chloro-4-phenyl-6-methoxyquinazoline in 300 ml of ethanol were added 15 ml of hydrazine hydrate and 8 ml of glacial acetic acid and the mixture was refluxed for 5 hours. After the precipitate was filtered off, the filtrate was concentrated in vacuo to give crystals. The crystals were collected by filtration, washed with ethanol, and dried to give 7.8 g of 2-hydrazino-4-phenyl-6-methoxyquinazoline, a part of which was recrystallized from ethanol to give yellow scales, m.p. 151° - 152° C.
Reaction SMILES: [C:1]1([C:7]2OC(=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].C(=O)=O>ClC1C=CC=CC=1>[C:1]1([C:7]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=c1oc(-c2ccccc2)ns1
Agent: O=C=O
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccccc2)c1C(=O)OC
Yield: 61.6 %

Procedure:
A solution of 412.2 g (2.3 mol) of 5-phenyl-1,3,4-oxathiazol-2-one, 662.7 g (4.66 mol) of dimethyl acetylenedicarboxylate, and 1 l. of chlorobenzene was heated at 135° for 6.5 hours, at which time CO2 evolution became very slow. Infrared and gas chromatography assays also indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to 0.2 mm and 90°. The 680 g of pot residue was crystallized from about 700 ml of methanol to give 393 g of solid dimethyl 3-phenyl-4,5-isothiazoledicarboxylate, m.p. 70°-71.5°. An additional 69.9 g of solid, m.p. 70°-72°, was obtained from the filtrate. The total of 462.9 g mounted to a 72.7% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>COC(C)(C)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)CN2Cc1ccccc1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc2c(c1)c(C)cn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 269 mg portion of methyl 1-benzyl-3-methylindoline-5-carboxylate was dissolved in 10 ml of tert-butyl methyl ether, and 235 mg of o-chloranil was added, followed by stirring at room temperature for 1 hour. After dilution with ethyl acetate and subsequent washing with a 1 M sodium hydroxide aqueous solution, it was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:30 to 1:20 to 1:10) to obtain 433 mg of methyl 1-benzyl-3-methyl-1H-indole-5-carboxylate as a colorless solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:10])([OH:9])[C:5]([F:8])([F:7])[F:6].[C:11](=O)([O:20]N1C(=O)CCC1=O)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.O>[F:6][C:5]([F:8])([F:7])[C:4]([OH:9])([CH3:10])[CH2:3][NH:2][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(O)(CN)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(O)(CNC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring suspension of amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate R) (1.5 g, 8.35 mmol) in DCM (50 ml) was added TEA 93.54 g, 35.0 mmol) followed by benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.983 g, 7.96 mmol). The mixture was stirred at RT for 6 hours and then diluted with water. The organic portion was separated using a phase separator and concentrated in vacuo. Purification by chromatography on silica eluting with 0-70% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 5.98 (1H, s), 5.05 (2H, s), 3.31 (1H, m), 3.18 (1H, m), 1.21 (3H, s)LC-MS: Rt 1.05 min; MS m/z 278.1 [M+H]+; Method 2 min LC_v003.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH:30][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3ccc4ccccc4n3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 37.6 %

Procedure:
Quinoline-2-carboxylic acid (0.502 g, 2.90 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (0.678 g, 2.90 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (894 μL, 6.38 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.54 g, 4.06 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.426 g, 1.09 mmol, 37.7%). ESI-MS m/z calc. 390.2, found 391.2 (M+1)+. Retention time of 3.94 minutes. 1H NMR (400 MHz, CD3CN) δ 1.69-2.15 (m, 8H), 3.62 (d, J=30.1 Hz, 2H), 3.77 (s, 3H), 3.90 (s, 3H), 6.91-7.03 (m, 3H), 7.69 (t, J=8.1 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.99 (t, J=8.8 Hz, 2H), 8.08 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.44 (d, J=8.5 Hz, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([O:10][C:11]2[C:12]([CH3:26])=[C:13](C)[C:14]3[O:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=O)[C:15]=3[C:23]=2[CH3:24])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.CO[CH:47]([O:50]C)[O:48][CH3:49]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:11]2[C:23]([CH3:24])=[C:15]([CH3:16])[C:14]3[O:19][C:18]([CH3:20])([CH3:17])[CH:21]([C:47]([O:48][CH3:49])=[O:50])[C:13]=3[C:12]=2[CH3:26])=[O:9])=[CH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)CC(C)(C)O2
Reactant: COC(OC)OC
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: O
Solvent: CO
Product: COC(=O)C1c2c(C)c(OC(=O)c3ccc([N+](=O)[O-])cc3)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 84 %

Procedure:
A heterogeneous mixture of 30.20 g (0.079 mol) of 3,4-dihydro-6-(4-nitrobenzoyl)oxy-2,2,5,7,8-pentamethyl-2H-1-benzopyran-4-one, 36.86 g (0.083 m) of thallium (III) nitrate trihydrate, 200 ml of trimethylorthoformate, and 200 ml of methanol is stirred at room temperature for 4 days. The resulting solid is collected and washed with methanol. The residue is slurried in 100 ml of chloroform and filtered; this process is repeated three times. The combined filtrates are heated to boiling and the chloroform is gradually replaced by an equal volume of methanol until crystallization occurs to give 27.44 g (84%) of 2,3-dihydro-5-(4-nitrobenzoyl)oxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid, methyl ester, m.p. 215°-216° C. Elemental analysis, IR, UV, and 1H-NMR spectra confirm the structure. This procedure was scaled up to 402 g, and 380.9 g (87.8%) of product was obtained.