Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2.COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC.Cl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2
Reactant: O=C(O)C1CCc2cc(F)ccc21
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCc2cc(F)ccc21
Yield: 10.5 %

Procedure:
The combined mother liquors from the resolution of Intermediate T3 were concentrated under reduced pressure until no acetone remained and acidified to pH 3 with 0° C. 5N HCl. This solution was extracted 3 times with Et2O (200 ml portions) and the combined Et2O portions were washed successively with 1N HCl, H2O and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow solid (71 g). This residue was recrystallized from hexane to give pure 5-fluoro-indan-1-carboxylic acid (Intermediate 2a, 58.6 g, 325.5 mmol) which was enriched in the R enantiomer. To Intermediate 2a in refluxing acetone (1 L) was added pulverized brucine (128.4 g, 325.5 mmol). After most solids had dissolved the solution was hot filtered and reheated to reflux as H2O (1 L) was added gradually. Excess acetone was boiled off until the solution became hazy. The solution was allowed to stand in a recrystallization dish for 1 month before solids appeared. The resultant solids were broken up, filtered off and recrystallized four more times in similar manner from acetone and H2O to give a buff colored solid which was taken up in 0° C. 1N HCl (150 ml). This solution was extracted 3 times with Et2O (75 ml portions) and the combined Et2O portions were washed successively with 1N HCl, H2O and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 6.13 g of (R)-5-fluoro-indan-1-carboxylic acid (Intermediate T4) as a pale solid which rotates sodium light at 20° C. with [α]20D +31.8 (c=4.49, benzene).
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:15]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:16]=3[N:17]=2)=[C:7]([O:42][CH3:43])[CH:6]=1)([CH3:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(N)CN>[CH3:4][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])[C:15]3[CH:20]=[CH:19][NH:18][C:16]=3[N:17]=2)=[C:7]([O:42][CH3:43])[CH:6]=1)([CH3:1])=[O:3]
Reactant: COc1cc(P(C)(C)=O)ccc1Nc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c2ccn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COc1cc(P(C)(C)=O)ccc1Nc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c2cc[nH]c2n1
Temperature: 60 °C

Procedure:
To a solution of compound N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine in THF (1 mL) was added tetrabutylammonium fluoride (TBAF) in THF (1.0 M, 3 mL) and ethylenediamine (0.1 mL). The solution was heated at 60° C. for 24 hrs. About 40% conversion was observed by HPLC monitoring. Volatile components were removed on rotavap and the residue was subjected to prep-HPLC purification. The desired product was determined by NMR to be contaminated with TBAF, which was removed by water wash (4 times). Evaporation of EtOAc gave the pure compound (14 mg). MS/ES+: m/z=514.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][OH:20])[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:3]1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1S,2R,4R)-4hydroxy-2-(hydroxymethyl)cyclohexylcarbamate (8.78 g, 31.42 mMol) was dissolved in anhydrous CH2Cl2 prior to the addition of triethylamine (11 mL, 78.55 mMol) followed by DMAP (0.05 g) and then trityl chloride (10.52 g, 37.7 mMol) in one portion. The reaction mixture was stirred at rt overnight. The reaction was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried (MgSO4), filtered, concentrated and chromatographed. Benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate was obtained as a white foamy solid (9.85 g, yield=60%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:6])=O.[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[C:9]=1[C:10]([O:12][CH3:13])=[O:11].N>C(O)(=O)C>[C:22]([NH:21][S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:8]([NH:7][CH:4]([CH3:6])[CH3:3])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:20])=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)=O
Reactant: COC(=O)c1c(N)cccc1S(=O)(=O)NC(C)(C)C
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(NC(C)C)cccc1S(=O)(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At a temperature of 5-10° C., 925 mg (24.4 mmol) of sodium borohydride are stirred into 14 ml of acetic acid. After 1 h, this mixture is admixed first with 1.42 g (24.4 mmol) of acetone and then with 700 mg (2.44 mmol) of methyl 2-amino-6-[(tert-butylamino)sulfonyl]benzoate and stirred at 5-10° C. for 2.5 h. For work-up, the reaction mixture is poured into ice-water, neutralized with aqueous ammonia solution and extracted with dichloromethane. The organic phase is concentrated and the residue that remains is triturated with diisopropyl ether. After filtration with suction and drying, 700 mg (89% of theory) of methyl 2-[(tert-butylamino)sulfonyl]-6-(isopropylamino)benzoate remain as a white solid of m.p. 110-112° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:24])[CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:24])[CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(O)CCCN
Reaction time: 3 h

Procedure:
TFA (2 mL) was added to a solution of 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester in methylene chloride (10 mL) and the mixture was stirred for 3 h and then concentrated under reduced pressure to give crude 5-amino-2-hydroxy-pentanoic acid methyl ester (1 g).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1([CH3:19])[O:18][CH2:17][CH2:16][O:15]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[C:8]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(c2cc(F)ccc2Br)OCCO1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cc(F)ccc2B(O)O)OCCO1
Temperature: -78 °C
Yield: 75 %

Procedure:
A solution of t-butyl lithium (19.0 mL) was added dropwise to a solution of 2-(2-bromo-5-fluorophenyl)-2-methyl-1,3-dioxolane (4.02 g, 15.40 mmols) and triisopropyl borate (4.6 mL, 19.93 mmols in anhydrous THF (40 mL), stirring under an inert atmosphere at −78° C. The resulting yellow solution was stirred at −78° C. for ½ h and then allowed to warm to −15° C. The resulting boronic ester was hydrolyzed in situ with sat'd NH3Cl (aq) at room temperature. The reaction mixture was transferred to a separatory funnel, diluted with H2O (50 mL), and extracted with EtOAc (3×50 mL). The combined organics were washed with H2O, brine, dried over Na2SO4, and concentrated. The resulting residue was recrystallized from EtOAc and hexanes to give 4-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)phenylboronic acid as an orange solid (2.62 g, 75%). 1H NMR (DMSO, 300 MHz) δ1.60 (s, 3H), 3.61-3.67 (m, 2H), 3.87-3.93 (m, 2H), 7.02-7.08 (m, 2H), 7.24-7.30 (m, 1H), 7.59 (s, 1H) ppm; 1H NMR (DMSO+D2O, 300 MHz) δ1.61 (s, 3H), 3.61-3.67 (m, 2H), 3.78 (brs, 2H) 3.89-3.94 (m, 2H), 7.04-7.10 (m, 2H), 7.26-7.31 (m, 1H) ppm.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.C(Cl)Cl>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][CH2:12][NH:11][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirring solution of salicylic acid (2.0 g, 14.5 mmol) and t-butyl N-(2-aminoethyl)carbamate (2.32 g, 14.5 mmol) in dry THF (15 mL) was added a solution of 1,3-dicyclocarbodiimide (3.29 g, 16.0 mmol) in CH2Cl2 (5 mL) dropwise at 0° C. The reaction was stirred for 18 h and then filtered. The filtrate was conc in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 5% NaHCO3, dried with MgSO4, and conc in vacuo to a white solid. The solid purified by silica gel chromatography (gradient: 0-70% EtOAc in hexanes) to yield 2.88 grams (71%) of the product as white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:20](=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH:22]1[CH2:24][CH2:23]1)=[O:10])[CH3:7].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH:22]2[CH2:24][CH2:23]2)=[N:13][C:14]2[C:19]([C:20]=1[Cl:3])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C2CC2)[nH]c2ccccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Temperature: 75 °C
Yield: 10.2 %

Procedure:
Phosphorus oxychloride (0.77 ml, 0.082 mols) was added in one portion to a suspension of 2-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.0 g, 0.041 mols) in acetonitrile and the mixture was heated at 75° C. for 90 minutes (becomes a clear solution above 65° C.). The resulting light brown solution was poured into saturated sodium bicarbonate (100 ml); the suspension was extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo to leave 4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 106%) as an off-white solid. Rf (AcOEt)=0.73. Step 3 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([O:18][CH2:19][C:20](O)=[O:21])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.O>[CH2:16]([O:18][CH2:19][C:20]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:21])[CH3:17]
Reactant: CCOCC(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CCOCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 25 mL of dichloromethane was cooled to 0° C. and was successively treated with ethoxyacetic acid (0.26 mL, 1.1 eq.), dimethylaminopyridine (30 mg, 0.1 eq.) and dicyclohexylcarbodiimide (560 mg, 1.1 eq.). The reaction mixture was stirred at 0° C. for two hours then at room temperature for two hours, diluted with 25 mL water and extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid/oil was triturated in ether, the solid removed and the volatiles removed in vacuo, to give 674 mg (95%) of 2-ethoxy-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (35) as a pale yellow solid, which was used without purification.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1>>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3]3)[CH2:6]2)=[O:26])=[C:23]([CH3:30])[CH:22]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: COc1ccc(C(=O)O)c(C)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cnc5ccccc5n4)CC3C2)c(C)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4-methoxy-2-methyl-benzoic acid. MS (ESI): mass calculated for C23H24N4O2, 388.47; m/z found 389.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17]1)[CH3:12]
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Reactant: Sc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
58 G. of 4-chlorothiophenol and a solution of 26.5 g. of 85% potassium hydroxide in 1500 ml. of ethanol were each placed in a 3 l. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 105 g. of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary evaporator), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue, weighing 128 g., was distilled in vacuo. A forerun weighing 28.7 g. was collected at 100°-190° (1 mm.), while 76.4 g. of a main fraction collected at 190°-222° (1 mm.). A gas chromatographic determination of the main fraction showed that 3-(4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester was present.
Reaction SMILES: C(C1C=C(O)C(=CC=1)O)(C)(C)C.S(Cl)([Cl:15])=O.CN(C)C=O.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:33])(=O)=[O:31])=[CH:26][CH:25]=1.[Na+]>O>[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([Cl:15])(=[O:33])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 2.0 parts of 4-tert-butylcatechol, 565 parts of thionyl chloride and 400 parts of dehydrated N,N-dimethylformamide were fed, and then stirred under ice cooling. To the solution obtained, while this was kept at 0° C. or below, 150 parts of formula-(18) sodium p-styrenesulfonate was dividedly added thereto. After its addition, the reaction solution was stirred for 24 hours while keeping the liquid temperature. After the reaction was completed, the reaction solution was poured into 1,500 parts of water to carry out extraction with toluene, and the organic layer formed was washed with ion-exchanged water. This organic layer was then dried with sodium sulfuric anhydride, followed by evaporation of the solvent under reduced pressure to obtain 128 parts (quantitative) of formula-(19) p-styrenesulfonic acid chloride.
Reaction SMILES: N1C=CC=CC=1C(Cl)=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([N:40]=[C:41]=[S:42])=[O:39]>C1(C)C=CC=CC=1.C(O)C>[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([N:40]=[C:41]=[S:42])=[O:39].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:41]([NH:40][C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[O:39])=[S:42])=[CH:27][CH:26]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccn1
Agent: O=C(N=C=S)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccn4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Pyridinecarbonyl isothiocyanate was prepared using commercially available 2-pyridinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.C(O[CH:14](OCC)[CH2:15][CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)C.Cl>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:9][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18]
Reactant: NNc1ccccc1Cl
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: CCO
Product: NCCc1c[nH]c2c(Cl)cccc12

Procedure:
A 10.0 g sample of 2-chlorophenylhydrazine hydrochloride and 17.9 g of 4-phthalimidobutyraldehyde diethyl acetal were stirred in 200 mL ethanol with 1 mL 5N HCl. The mixture was concentrated to a residue which was slurried in a small amount of methylene chloride. A yellow solid was collected and vacuum dried at 40° C. The solid was stirred in 500 mL ethanol. Hydrazine hydrate (14 g) was added and the mixture was heated at reflux for 14 hours. A 60 mL sample of 5N HCl was added and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool and was concentrated to a residue. The residue was partitioned between 1N NaOH and chloroform. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined extracts were dried (Na2SO4) and concentrated to an oil. The oil was chromatographed on silica gel using a gradient of 0-10% methanol in chloroform containing 0.2% ammonium hydroxide. Fractions containing product were concentrated to an oil which was taken up in a small amount of methanol and added to ethereal HCl. A solid was collected, washed with diethyl ether, and vacuum dried at 50° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Nc2cc(Cl)ncn2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CN3C(=O)c4ccccc4C3=O)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.739 g 2-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-isoindole-1,3-dione (prepared in Example 67) (4.79 mmol) was suspended in 50 cm3 abs. DMF and the flask was filled with argon properly. 347 mg Tetrakis(thriphenylphosphine) palladium[0] (0.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 968 mg 2-methoxyphenyl-boronic acid (6.50 mmol) and 2.123 g K3PO4 (3 mmol) was added. The mixture was ferluxed for 6 hours while slow argon flow was being applied. The reaction mixture was evaporated under reduced pressure, 150 cm3 5% NaHCO3 solution was added and it was extracted three times with 100-100 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated under reduced pressure. The residual oil was chromatographed on silica gel eluting with chloroform containing 1% ethyl-alcohol. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product as a yellow solid. Yield: 1.652 g (79%). For analitical results and compound identification see Table 1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[F:7][C:8]1[CH:9]=[C:10]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)[CH:11]=[C:12]([F:14])[CH:13]=1>>[C:23]([O:22][C:21](=[O:27])[NH:20][C@@H:16]([CH2:15][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=1)[C@H:17]([OH:18])[CH2:19][N:1]=[N+:2]=[N-:3])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN=[N+]=[N-]
Temperature: 77.5 °C
Reaction time: 16 h

Procedure:
Sodium azide (0.22 g, 4 mmole) and ammonium chloride (2 eq) are added to tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 0.6 g, 2 mmole). The reaction is heated to 75-80 degrees C. and stirred for 16 hours. The reaction is monitored by TLC to insure completion. The solvent is removed under reduced pressure. The concentrate is partitioned between ethyl acetate and water, the phases are separated and the organic phase is washed with bicarbonate and saline, dried over anhydrous sodium sulfate and concentrated to give the title compound, TLC (ethyl acetate/hexane) Rf=0.45; MS (MH+)=343.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:34])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate [(Example 1, Step 6) 580 mg, 1.49 mmol] was suspended in toluene (5 mL) and dioxane (5 mL), placed into an oil bath preheated to 110° C. and treated in one portion with Lawesson's Reagent (603 mg, 1.49 mmol, 1 equiv). After stirring for 30 minutes, the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 50:50; hexanes:ethyl acetate), providing the titled compound.