Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([F:15])[C@@H:13]([CH2:16][O:17]CC2C=CC=CC=2)[O:12][C@@H:11]1[O:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[C:1]([O:9][C@@H:10]1[C@H:14]([F:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@@H:11]1[O:25][CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](F)[C@H]1OC(=O)c1ccccc1
Solvent: O
Product: CO[C@H]1O[C@H](CO)[C@@H](F)[C@H]1OC(=O)c1ccccc1
Yield: 79.9 %

Procedure:
A solution of 10% formic acid in MeOH (50 mL) was degassed under vacuum for 5 min, and then 20 mL of this solution was added under argon to Pd/C (450 mg). To this suspension, compound 35.10 (450 mg, 1.25 mmol) dissolved in 25 mL of the same solution was added dropwise while stirring. The reaction was monitored by LC-MS. When completed, 50 mL of water was added to the mixture. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 0-50% EtOAc in Hexane to give compound 35.11 (270 mg, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](O)(=[O:15])[CH2:12][CH:13]=[CH2:14]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:9][CH3:10])[C:11](=[O:15])[CH2:12][CH:13]2[CH3:14]
Reactant: COc1ccccc1OC
Reactant: C=CCC(=O)O
Product: COc1cc2c(cc1OC)C(C)CC2=O
Temperature: 60 °C

Procedure:
A mixture of 1,2-dimethoxy-benzene (Compound 47a) (19.1 mL, 0.150 mole) and but-3-enoic acid (Compound 49a) (19.2 mL, 0.225 mole) was stirred under argon in an ice bath. Polyphosphoric acid (230 g, 1.05 mole) was added slowly. After addition was complete, the ice bath was removed and the reaction heated for 16 hours at 60° C. The reaction was added to ice water and extracted with ether. The organic extracts were washed with 3N NaOH, water, brine and dried over Na2SO4. The solvent was then removed in vacuo to yield a yellow solid containing a racemic mixture of the title compounds. The crude material was purified on a silica gel column using 1:2 EtOAc:hexane as the eluents. The pure fractions were combined and concentrated to yield the racemic mixture of the title compound (Intermediate X) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH3:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:20]([CH3:27])[CH:21]=1)#[N:24]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: Cc1cc(C#N)ccc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a mixture of methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6, 112 mg, 0.51 mmol), 4-(hydroxymethyl)-3-methylbenzonitrile (83 mg, 0.56 mmol), PPh3 (268 mg, 1.02 mmol) and THF (6 mL) cooled in ice-water bath, DIAD (207 mg, 1.02 mmol) was added. The mixture was stirred overnight at room temperature. It was then concentrated and purified by flash column chromatograph to give 112 mg of the title compound (63%). [M+H] Calc'd for C19H16N4O3, 349; Found, 349.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]2[O:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[CH3:22].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C@H:2]2[C@H:7]3[O:8][C@H:4]([CH2:5][CH2:6]3)[C@H:3]2[C:9]([O:11][CH3:12])=[O:10])=[CH:16][C:15]=1[CH3:22]
Reactant: COC(=O)[C@H]1[C@@H](N)[C@@H]2CC[C@H]1O2
Reactant: Cc1cc(C=O)ccc1F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H]1[C@@H](NCc2ccc(F)c(C)c2)[C@@H]2CC[C@H]1O2
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a stirred solution of methyl (1R,2S,3R,4S)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate (400 mg, 2.34 mmol) in methanol (8 mL) under a nitrogen atmosphere, 4-fluoro-3-methyl-benzaldehyde (0.29 mL, 2.34 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (368 mg, 5.85 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S,3R,4S)-3-[(4-fluoro-3-methylbenzyl)amino]-7-oxabicyclo[2.2.1]heptane-2-carboxylate (610 mg, 2.08 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.40 (2H, m), 1.76 (2H, m), 2.27 (3H, d, J=2.0 Hz), 2.86 (1H, d, J=7.6 Hz), 3.16 (1H, d, J=8.4 Hz), 3.64 (1H, d, J=13.2 Hz), 3.74 (3H, s), 3.79 (1H, d, J=13.6 Hz), 4.46 (1H, d, J=5.2 Hz), 4.73 (1H, d, J=4.8 Hz), 6.92 (2H, m), 7.07 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC(Cl)=O)C.ClC1C=CC(OC2C=CC(OCCC(=O)OC(=O)OCC)=CC=2)=CC=1.[BH4-].[Na+]>O.C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: CCOC(=O)OC(=O)CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
13.8 ml. of triethylamine are added, at 10° C., to a solution of 29.25 g. of 2-[4-(4-chlorophenoxy)-phenoxy]-propionic acid in 200 ml. of THF. The mixture is cooled to -10° C., a solution of 9.8 ml. of chloroformic acid ethyl ester in 60 ml, of THF is added dropwise and the mixture is stirred for 1 hour at -10° C. The solution contains 1-[4-(4-chlorophenoxy)-phenoxy]-4,6-dioxa-octane-3,5-dione, which is not isolated. 7.4 g. of NaBH4 are then introduced in portions. The mixture is stirred for 30 minutes at -10° C. and for 30 minutes at 0° C., poured into water and extracted with chloroform. After evaporation of the extract, the residue is boiled for 1 hour with 200 ml. of 6% ethanolic potassium hydroxide solution, the mixture is evaporated and worked up with water and ether to give 2-[4-(4-chlorophenoxy)-phenoxy]-propanol.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]=[C:8]2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]OS(F)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:14])[C:8]2=[NH:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)F
Reactant: NC1=NC(=O)CN1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1C(=N)N(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.2 g. of 1-phenyl-2-amino-4-oxo-2-imidazoline, 15 ml. methylene chloride and 3.6 ml. of methylfluorosulfonate was left to stir at room temperature for 20 hours. The reaction was stopped and filtered to give 1.9 g. (94%) of the acid salt of the product. The isolation of the free base (m.p. 164°) is made by treating the salt with aqueous sodium hydroxide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20](Cl)=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[O:29])=[CH:26][C:25]=3[O:40][CH3:41])=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CC(C)C(=O)N2C
Yield: 51.8 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-9-benzyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-42), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.046 g (0.00024 mole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0451 g of (rac)-4-(9-benzyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-42) as white powder. HRMS (ES+) m/z Calcd for C30H37N7O3+H [(M+H)+]: 544.3031. Found: 544.3031.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:17][CH3:18])[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)propanoate (10.0 g, 49.2 mmol) was dissolved in THF (100 mL) and cooled to 0° C. under nitrogen. Sodium hydride (60% susp. in mineral oil, 3.00 g, 75.1 mmol) was added in portions over 2 min. The reaction mixture was stirred for 5 min at 0° C. and EtI (4.80 mL, 59.5 mmol) was added. It was allowed to warm to room temperature over the period of 1 h, stirred at room temperature overnight and at 70° C. for 7 d. The reaction mixture was cooled, filtered and concentrated in vacuo. The solid was triturated with hexanes (2×70 mL), the triturates were concentrated in vacuo and the residue was purified using flash column chromatography on silica gel (330 g SiO2, hexanes:ethyl acetate 19:1-9:1) to afford the title compounds as an oil (4.40 g, 39%). [M+H] calc'd for C11H21NO4, 232; found, 232.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:14]([CH3:16])[NH2:15])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4]([N:14]([CH3:16])[NH2:15])=[N:3]1
Reactant: Cc1nc(N(C)N)nnc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1N=C(N(C)N)NN=C1c1ccccc1

Procedure:
5-Methyl-3-(1-methylhydrazino)-6-phenyl-1,2,4-triazine (2.9 g) was dissolved in ethanol (50 ml) containing anhydrous hydrogen chloride and hydrogenated over 5% palladium on carbon (0.33 g) under atmospheric pressure at room temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was neutralized with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from ethanol to give colorless crystals of 5-methyl-3-(1-methylhydrazino)-6-phenyl-2,5-dihydro-1,2,4-triazine, mp 139.5°~141° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([OH:22])=O)=[CH:13][CH:12]=3)[CH2:4][CH3:5])[CH3:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N.O>CN(C)C=O>[CH2:4]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([NH2:25])=[O:22])=[CH:13][CH:12]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)O)ccc3n12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(N)=O)ccc3n12

Procedure:
1-(1-Ethylpropyl)-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxyic acid as synthesized in above Example 13, 300 mg was dissolved in 10 mL of N,N-dimethylformamide, and to the solution 1,1′-carbonyldiimidazole 275 mg was added little by little in nitrogen atmosphere. After another hour's stirring, ammonia gas was injected into the reaction liquid for 30 minutes, followed by an hour's stirring. Water 30 mL was added and the formed precipitate was recovered by filtration. The crystals were washed with water and dried by heating under reduced pressure to provide 250 mg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:12]I>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[I:12][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[NH:1][N:2]=1
Reactant: c1n[nH]c2c1CCCC2
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a suspension of 4,5,6,7-tetrahydroindazole (700 mg, 5.7 mmol) and KOH (1.2 g, 21.5 mmol) in DMF (20 mL) was added I2 (2.9 g, 11.5 mmol) at 0° C., and the reaction was stirred overnight while warming to rt. The reaction mixture was diluted with sat. Na2S2O3, extracted with EtOAc (50 mL×3), washed with brine (50 mL), dried (MgSO4), and concentrated to give 1.2 g (83%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.73-1.84 (4H, m), 2.40 (2H, t, J=5.6 Hz), 2.54 (2H, t, J=6.0 Hz).
Reaction SMILES: [Mg].[Br-].II.[CH:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C1COCC1.O>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19]/[CH:18]=[CH:17]\[CH2:16]/[CH:15]=[CH:14]\[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([OH:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC=O
Agent: Cl
Agent: II
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C/C/C=C/CCCCC
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 139.4 %

Procedure:
A 100 mL round bottom flask, charged with magnesium turnings (355 mg, 14.6 mmol) and a stir bar, was dried with a high temperature heat gun for 5 minutes. Upon cooling under nitrogen, THF (6 mL) was added followed by linolaidyl bromide (6.02 g, 18.3 mmol). The mixture was heated to 45° C. and a single grain of iodine was added. The reaction was refluxed for 2.5 hours then cooled to room temperature where upon a solution of (10Z,13Z)-nonadeca-10,13-dienal (3.4 g, 12.4 mmol) in THF (10 mL) was added. The solution was stirred for 1.5 hours at room temperature then poured into water (150 mL) and 5% HCl (50 mL) was added. Upon dissolution of the magnesium, the solution was extracted with ether (2×150 mL). The combined ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% hexanes) to afford the title compound as a colorless oil (4.57 g, 71%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[S-2].[Na+].[Na+]>>[CH:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [S-2]
Product: Nc1ccc(Nc2ccccc2)cc1

Procedure:
aniline method, where p-nitro-chlorobenzene and aniline as raw materials react in the presence of a catalyst to produce 4-nitrodiphenylamine, then, 4-nitrodiphenylamine is reduced by sodium sulfide to form 4-aminodiphenylamine;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][CH2:12][C:13]1[N:18]=[C:17](Cl)[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][CH2:12][C:13]1[N:18]=[C:17]([O:30][CH3:29])[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CCc2cc(Br)ccc2OCc2ccccc2)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CCc2cc(Br)ccc2OCc2ccccc2)nc1OC
Temperature: 140 °C
Yield: 88.9 %

Procedure:
A mixture of methyl 6-[2-benzyloxy-5-bromophenethyl]-2-chloro-3-pyridinecarboxylate (7.0 g) and sodium methoxide (2.5 mole equivalents) in methanol was heated at 140° C. for 5 hours in a Carius Tube. The solvent was evaporated and the residue extracted with ethyl acetate and washed with saturated aqueous NH4Cl, water and brine. The organic solution was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on 7734 silica gel, eluting with 1% MeOH/CH2Cl2, to give methyl 6-[2-benzyloxy-5-bromophenethyl]-2-methoxy-3-pyridinecarboxylate (6.16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[S:6][N:5]=1)[CH3:2].[CH3:24][NH:25][CH3:26]>CN(C)C=O>[CH3:24][N:25]([CH3:26])[C:15]([NH:14][C:7]1[S:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:23]
Reactant: CNC
Reactant: CCOC(=O)c1c(OCC)nsc1NC(=O)Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)nsc1NC(=O)N(C)C
Yield: 26.5 %

Procedure:
In the manner of Example II B, 8.4 g of phenyl (3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)carbamate in 20 ml of dimethylformamide were treated with 2.3 g of dimethylamine. The solid from the reaction mixture was recrystallized from ethanol to yield 1.9 g of 1,1-dimethyl-3-(3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)urea, mp 164°-165°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>>[NH:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[CH2:37][N:13]1[C:12](=[O:24])[C:11]2([CH2:25][CH2:26][N:8]([C:6](=[O:7])[C:5]3[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=3)[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:14]1=[O:23]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(Cc2nc3ccccc3[nH]2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=630.0 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 2-(chloromethyl)-benzimidazole.
Reaction SMILES: C(O[C:4](=[O:24])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:24])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1O

Procedure:
250 g of [[[1-(2-furyl)methyl-5-pyrazolyl]amino]methylene]-malonic acid diethyl ester (0.75 mol) is dissolved in 1 liter of diphenyl ether and heated to 240° for 2 hours. The ethanol formed is continuously distilled off. The solvent is removed in vacuo. The 4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester remains and is recrystallized from methanol, yield 248 g (86%), m.p. 103°-106°.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:23](O)(C)C>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH:6]([CH3:23])[CH3:7])=[O:4]
Reactant: CC(C)O
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [Ti+4]
Agent: CC[O-]
Product: CC(C)OC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 0 °C

Procedure:
To a chilled (0° C.), stirred solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (0.68 g) in anhydrous isopropyl alcohol (10.2 ml) was added titanium (IV) ethoxide (0.17 ml) via syringe under a nitrogen atmosphere. The solution was warmed to room temperature and refluxed for 6.5 hours. The isopropyl alcohol was removed under reduced pressure and the residue dissolved in ethyl acetate (100 ml). The solution was washed twice with 50 ml portions of saturated aqueous NH4Cl solution, twice with 50 ml portions of saturated aqueous NaHCO3 solution and once with 50 ml of brine. The organic and aqueous phases were separated and the organic phase dried (Na2SO4), filtered, and concentrated to an oil. The crude mixture was purified using preparative HPLC (silica gel, 35% ethyl acetate in dichloromethane as the loading solvent and eluent). The appropriate fractions were combined and the solvents were removed under reduced pressure yielding 0.54 g of 1,2,3,3 a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, isopropyl ester, as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3Br)[CH2:5][C:4]=2[N:3]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:28]3[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1Br)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1-c1cccnc1F)C2
Yield: 86.9 %

Procedure:
To a 10 mL recovery flask was added 2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one (33 mg, 0.0942 mmol, 1.0 eq.), 2-fluoropyridine-3-boronic acid (27 mg, 0.188 mmol, 2.0 eq.), DME (2 mL), potassium carbonate (2.0M aq., 94 μL, 0.188 mmol, 2.0 eq.), and palladium tetrakis triphenylphosphine (5 mg, 0.00471 mmol, 0.05 eq.). The reaction was refluxed overnight whereupon LC/MS analysis judged the reaction to be complete. The reaction mixture was filtered through Celite and concentrated to a residue. The residue was purified via preparatory-HPLC to give the product white solid (30 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (dd, J=3.54, 1.77 Hz, 1H) 2.89 (br. s., 1H) 3.06 (t, J=12.51 Hz, 2H) 3.18 (br. s., 1H) 7.18 (dd, J=9.60, 2.78 Hz, 1H) 7.31-7.53 (m, 4H) 7.72 (dd, J=8.84, 5.81 Hz, 1H) 7.98 (ddd, J=9.79, 7.52, 1.89 Hz, 1H) 8.28 (d, J=4.80 Hz, 1H). ESI-MS: m/z 367.3 (M+H)+. ESI-MS: m/z 367.3 (M+H)+.