Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][S:26]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](CO)=[CH:32][CH:31]=1)(=[O:28])=[O:27]>O1CCCC1>[Cl:24][CH2:20][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Cc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
Triphenylphosphine (5.71 g, 21.8 mmol), carbon tetrachloride (8.4 mL, 87 mmol), and tetrahydrofuran (12 mL) were combined in a round bottom flask under argon and stirred at room temperature for 10 minutes. A heterogeneous mixture of (4-methanesulfonylmethyl-phenyl)-methanol (2.18 g, 10.9 mmol) and tetrahydrofuran (37 mL) were added to the reaction mixture, and then the mixture was heated at 75° C. for 3 hours. The reaction mixture was cooled to room temperature, and then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was concentrated over silica gel, and the resulting silica gel supported crude product was loaded onto a RediSep® Flash column. Flash chromatography (25%-40% ethyl acetate in hexanes) afforded 1.59 g (67%) of 1-chloromethyl-4-methanesulfonylmethyl benzene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.47 (d, J=8.2 Hz, 2 H), 7.41 (d, J=8.2 Hz, 2 H), 4.78 (s, 2 H), 4.50 (s, 2 H), 2.91 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][N:20]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=[C:23]2[C:22]2[CH:21]=[N:20][C:19]([Cl:18])=[CH:26][CH:25]=2)=[CH:8][CH:9]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1c2ccccc2nc(-c2ccc(Cl)nc2)n1-c1ccc(Cl)cc1
Temperature: 150 °C
Yield: 4 %

Procedure:
2-Amino-N-(4-chlorophenyl)benzamide (0.500 g, 2.03 mmol) and 6-chloronicotinaldehyde (2.23 mmol), NaHSO3 (0.253 g, 2.44 mmol) and p-TsOH (0.039 g, 0.20 mmol) were dissolved in DMA (20 mL) and heated at 150° C. for 21 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×200 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 70% ethyl acetate/heptane, afforded the title compound as a white solid (4%). 1H-NMR (300 MHz, DMSO-6): δ 8.46 (d, J=2.1 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.92-7.97 (m, 1H), 7.80-7.86 (m, 2H), 7.63-7.68 (m, 1H), 7.47-7.50 (m, 5H). MS (APCI) m/z: 368 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][C:32]([N:38]1[CH2:43][C@H:42]([CH3:44])[NH:41][C@H:40]([CH3:45])[CH2:39]1)=[N:33]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[C@H:42]([CH3:44])[CH2:43][N:38]([C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[CH:37][C:28]=4[Cl:27])[N:33]=3)[CH2:39][C@@H:40]2[CH3:45])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: O[C:2]1[C:3]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:22]>O1CCOCC1>[Cl:22][C:2]1[C:3]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2sc3ncnc(O)c3c2c1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2sc3ncnc(Cl)c3c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Into a 100-mL round-bottom flask containing a solution of ethyl 4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (2.2 g, 4.01 mmol, 1.00 equiv) in 1,4-dioxane (60 mL) was added POCl3 (30 mL) at room temperature under nitrogen. The resulting solution was stirred for 2 h at 90° C. and concentrated under vacuum. The residue dissolved in DCM and poured into a cooled saturated aqueous Na2CO3, extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to give 1.8 g (77%) of the corresponding ethyl 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate as a yellow solid.
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:14][CH2:13][C:12]([OH:18])([CH2:15][NH:16][CH3:17])[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[ClH:1].[OH:18][C:12]1([CH2:15][NH:16][CH3:17])[CH2:13][CH2:14][NH:10][CH2:11]1
Reactant: CNCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCC1(O)CCNC1

Procedure:
6.9 g (23.5 mmol) of 1-benzyl-3-hydroxy-3-methylaminomethylpyrrolidine dihydrochloride in 100 ml of methanol are hydrogenated on 2 g of palladium/active carbon (10%) at 80°C. and 100 bar. The catalyst is filtered off with suction, the solution is concentrated and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(C(F)(F)F)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(C(F)(F)F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[3-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: CNOC
Reactant: COC(C(=O)O)c1cccc2ncccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(C(=O)N(C)OC)c1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(quinolin-5-yl)acetic acid (2.8 g, 12.9 mmol) in anhydrous CH2Cl2 (50 mL) and NMM (3.1 mL, 29 mmol) under argon was added isobutyl chloroformate (1.9 mL, 14 mmol) dropwise. After stirring over an ice bath for 40 min, N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 24 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-100% EtOAc-hexanes) gave N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide as an oil which became crystalline upon standing (1.8 g, 60% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:51])[CH:10]([C:13]1[CH:50]=[CH:49][CH:48]=[CH:47][C:14]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1)[CH2:11][CH3:12]>C(Cl)Cl>[NH:37]1[CH2:38][CH2:39][CH:34]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:19]3[N:18]=[C:17]([CH2:16][CH2:15][C:14]4[CH:47]=[CH:48][CH:49]=[CH:50][C:13]=4[CH:10]([CH2:11][CH3:12])[C:9]([NH2:8])=[O:51])[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=3)=[CH:33][CH:32]=2)[CH2:35][CH2:36]1
Reactant: CCC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Yield: 71.1 %

Procedure:
A solution of TFA (0.84 mL, 11 mmol) and tert-butyl 4-(4-((4-(2-(1-amino-1-oxobutan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A2) (168 mg, 0.275 mmol) in DCM (20 mL) was stirred for 24 hours at room temperature under a nitrogen atmosphere. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH to elute the amine product. The ammoniacal filtrate was evaporated under reduced pressure and the residue was taken up in DCM (˜2 mL). Cyclohexane (˜10 mL) was added and the resulting suspension sonicated for 10 minutes. The precipitate was isolated by filtration to give the title compound 1 as an off-white solid (100 mg, 71%); 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.67 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.51-7.43 (m, 1H), 7.31 (s, 1H), 7.22-7.10 (m, 5H), 6.87 (s, 1H), 3.61 (dd, J=8.8, 6.1 Hz, 1H), 3.22-2.89 (m, 6H), 2.62-2.53 (m, 3H), 2.07-1.91 (m, 1H), 1.67 (d, J=12.0 Hz, 2H), 1.62-1.42 (m, 3H), 0.87-0.80 (m, 3H). LCMS-A: rt 4.973 min; m/z 512 [M+H]+.
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[OH:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16])[CH3:7]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (0.15 g) and 0.36 ml of triethylsilylchloride were added to a solution of 0.32 g of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one in 3.2 ml of dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with 80 ml of ethyl acetate, and the diluted reaction mixture was washed three times with 20 ml of a 10% aqueous sodium chloride solution and was then washed with an a saturated aqueous sodium chloride solution and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resultant solid was suspended in 4 ml of a hexane:ethyl acetate=1:1 solution and was collected by filtration to give 0.33 g of (3S,4R)-3-[(1R)-1-(triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8]CC)=[O:7])C.[OH-].[Li+]>C(O)C.O>[C:23]1([S:22][CH2:21][CH2:20][C:5]([CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)O
Temperature: 49 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
A solution of 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid diethyl ester (5.614 g) in ethanol (100 mL) was treated with lithium hydroxide (2.84 g) in water (10 mL). The reaction mixture was heated at 49° C. for 17 hours followed by 85° C. for 2 hours. The solvents were evaporated at reduced pressure to give a residue that was treated with water (100 mL) and washed with ether. The aqueous layer was cooled on ice, acidified and the product extracted with ethyl acetate. The extracts were dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give acid 2,2-bis-(2-phenylsulfanyl-ethyl)-malonic acid (5.628 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:9][C:6]3[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[C:14]([CH3:28])[O:13][N:12]=1
Reactant: COc1ccc(N)nn1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Temperature: 20 °C
Reaction time: 18 h
Yield: 4.1 %

Procedure:
To a solution of 6-methoxypyridazin-3-amine (125 mg, 1.0 mmol) in pyridine (8 mL) at room temperature, was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (0.302 g, 1.0 mmol). The reaction mixture was stirred at 20° C. for 18 hours. The solvent was evaporated in vacuo and passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol. The crude was then purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-25% methanol gradient), to provide the title compound (16 mg). LCMS (2 min, formic) Rt 0.83 min, m/z (ES+) 391 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]([O:21]CC)=[CH2:20])CCC.Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[C:10]2[CH:11]=[C:2]([C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)CCCc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
A solution of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound 15, 1.20 g, 5.94 mmol) in 20 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (4.29 g, 11.88 mmol) and PdCl2(PPh3)2 (422 mg, 0.60 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10 % HCl was added. The mixture was then stirred for another 30 min, then extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (80:20 hexane/ethyl acetate) afforded the title compound (669 mg, 56% yield) as a colorless oil:
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[N:5]=1.[OH-].[Na+]>CC#N.O>[Cl:10][C:8]1[N:9]=[C:4]([NH:2][CH3:1])[N:5]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[N:7]=1
Reactant: CN
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Cold methylamine (40% (w) in water, 234 μL, 1 equivalent) was added to the crude solution of cis-4-(4,6-dichloro-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (2.7 mmol) in CH3CN/H2O (1/1, 20 ml), followed by 1N NaOH (5.34 ml, 1 equivalent). The reaction mixture was stirred at room temperature for 2-3 hrs. The crude product was used in the next step. MS (ES+): m/e 286.09 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH2:24]O)[N:9]=2)[CH:7]=1.COCCN(S(F)(F)[F:37])CCOC>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH2:24][F:37])[N:9]=2)[CH:7]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CO)n1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CF)n1
Reaction time: 0.25 h
Yield: 141.5 %

Procedure:
To a slurry of N-(7-(5-fluoro-2-methylphenyl)-5-(hydroxymethyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, 0.1 mmol), in dichloromethane (0.7 mL) cooled at −15° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (0.045 mL, 0.2 mmol). After 15 minutes at this temperature, the reaction mixture was diluted with dichlormethane (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (50 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 9.38 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.47-7.33 (m, 2H), 7.21 (m, 1H), 5.99 (s, 1H), 5.88 (s, 1H), 2.37 (s, 3H), 2.11 (m, 1H), 0.89 (m, 4H). LCMS (Method G): RT=14.65 min, M+H+=354.4.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:22]([O:26][C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH2:36])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH:36][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
A solution of 710 mg of 2,4-dichloro-6-methoxyquinazoline in 20 mL of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonylaminocyclohexylamine, and stirred at room temperature for 48 hours. After concentrating, the mixture was combined with water, extracted with methylene chloride, and dried. After solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain 1.20 g of the desirable compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:10]1.F[C:21](F)(F)S(OC)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]1[CH3:21]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2F)c1=O
Product: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2F)c1=O
Yield: 65 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2,4-difluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.6 g, 13 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (2.4 g, 65%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:24])=O>ClCCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([Cl:24])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Yield: 102 %

Procedure:
In 100 ml of 1,2-dichloroethane, 57 g (0.19 mol) of 3,4,5-triacetoxybenzoic acid and 34 g (0.29 mol) of thionyl chloride were reacted at 60° C. for 2 hours. The excess thionyl chloride and 1,2-dichloroethane were distilled away under reduced pressure to obtain 61 g of the desired product.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[C:5]([CH3:11])[N+:6]([O-:10])=[C:7]([CH3:9])[CH:8]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C(Cl)(Cl)Cl>[N:12]1([C:3]2[CH:4]=[C:5]([CH3:11])[N+:6]([O-:10])=[C:7]([CH3:9])[CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(Cl)cc(C)[n+]1[O-]
Reactant: C1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(N2CCCCC2)cc(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A quantity (1.94 g., 0.01 mole) of 4-chloro-2,6-lutidine-1-oxide hydrochloride with 6 ml. piperidine, and 10 ml. water were sealed in a reinforced bottle and heated, with stirring, in an oil bath at the temperature 155° to 160° C. for 41/2 hrs. After cooling the reaction mixture to 25° C. and diluting it with 25 ml. water, several portions of chloroform were used to extract the objective product. The chloroform extracts were combined, dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The filtrate was pale yellow. The chloroform was removed by evaporation under reduced pressure. The solid residue thus obtained was triturated with technical hexane (Skellysolve B, a mixture of isomeric hexanes having a boiling range between 142° and 156° F.) and then crystallized from about 10 ml. ethyl acetate. There was thus obtained 1.06 g. (50% yield) of 4-piperidino-2,6-lutidine-1-oxide as buff-colored crystals having a melting point at 87° to 90° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([CH2:30]O)[CH2:27][O:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:30][CH:28]2[CH2:27][O:26][C:25]([CH3:32])([CH3:24])[O:29]2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC3COC(C)(C)O3)c(Cl)c1Cl)C2
Reaction time: 8 h

Procedure:
A mixture of 2 gm. of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetic acid, 3 ml. of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 0.5 g. of p-toluenesulfonic acid hydrate are heated on the steam bath for 3 hours. The dark reaction mixture then is chromatographed on 300 g of silica, and eluted with acetic acid-acetone-toluene (5:5:90). Fractions containing a single component (Rf~0.4) are pooled and concentrated to a yellow oil. On standing overnight, a mixture of crystalline solid and yellow oil resulted. The mixture is filtered and the solid recrystallized from tetrahydrofuran-ether-petroleum ether (5:15:25). The yield of pure product is 0.3 g., m.p. 143°-145° C.