Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7][CH:8]=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[F-].[Cs+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C.CC#N>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[N:7]([CH2:18][CH2:19][OH:20])[CH:8]=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1
Reactant: OCCBr
Reactant: COc1ccc2c(c1)S(=O)(=O)N=CN2
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N=CN2CCO
Reaction time: 2 h

Procedure:
To a solution of 7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide (4.0 g, 18.8 mmol) in a mixture of 30 ml of DMF and 30 ml of CH3CN there are added 8.6 g (56.6 mmol) of CsF and 1.47 ml (18.8 mmol) of 2-bromoethanol. Stirring is carried out for 2 hours at 75° C. and 1.47 ml (18.8 mmol) of 2-bromoethanol are added. After 6 more hours at 75° C., a further 1.47 ml (18.8 mmol) of 2-bromoethanol and then 2.8 g (18.8 mmol) of CsF are added and stirring is continued at 75° C. overnight. The salts are filtered off at ambient temperature and rinsed with CH3CN; the filtrate is evaporated to dryness. The residue is taken up in CH2Cl2, and the organic phase is washed with saturated NaCl solution and dried (MgSO4). After evaporation, the sticky residue is taken up in a mixture of ethyl ether/CH2Cl2. The gum is triturated until a solid is obtained, which is filtered off to obtain the title compound.
Reaction SMILES: C(O)(=O)C.FC(F)(F)C(O)=O.[BH4-].[Na+].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27](O)[C:28]#[CH:29])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>C(Cl)Cl>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[CH:29])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: C#CC(O)c1ccc(N2CCN(C)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: C#CCc1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred mixture of glacial acetic acid (72 ml) and trifluoroacetic acid (8 ml), NaBH4 (79.1 mmol) is added slowly under nitrogen at 15° C. The solution of 1-[4-(4-methyl-piperazin-1-yl)-phenyl]-prop-2-yn-1-ol (11.3 mmol) in CH2Cl2 (80 ml) is added dropwise over 0.5 h and the mixture is stirred at room temperature for 1 h. The solvents are removed under reduced pressure and the residue is added to saturated sodium bicarbonate. The aqueous solution is extracted with CH2Cl2. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to silica gel column chromatography, which is eluted with following solvents: CH2Cl2 and 5% MeOH in CH2Cl2. The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 86.8%, Rf=0.52 (CH2Cl2:MeOH=9:1).
Reaction SMILES: [NH:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.O>CS(C)=O>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2-c2c1cccc2C1=NC2CCCCC2N1
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2c([nH]1)CCCC2
Temperature: 200 °C
Yield: 64.1 %

Procedure:
In a 20 ml sealed tube, dissolve 330 mg of 4-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained in the previous stage, in 12 ml of dimethyl sulphoxide and then heat at 200° C. for one hour. After cooling, add 30 ml of water and then extract 3 times with 100 ml of ethyl acetate. The crude solid obtained is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (97/3 by volume). In this way, we obtain 210 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.CCOC(C)=O>[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cccc2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Temperature: 90 °C
Yield: 75 %

Procedure:
A microwave vial was charged with 5-bromo-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (Intermediate W) (0.508 g, 1.395 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (0.469 g, 2.092 mmol), potassium phosphate (0.888 g, 4.18 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.099 g, 0.139 mmol). The vial was sealed with a septum cap and flushed with N2. Dioxane (3.49 mL) and water (1.162 mL) were added and the mixture was sparged for 5 min with N2. The mixture was heated in a microwave at 90° C. for 30 min. The resulting mixture was diluted with EtOAc (5 mL) and decanted from insoluble solids. The resulting solution was concentrated for purification by MPLC. The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a 98:2 Heptane:EtOAc (with 5% EtOH additive) to 100% EtOAc (5% EtOH additive) gradient to afford 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (0.485 g, 1.046 mmol) as a orange amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CS(O[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: CS(=O)(=O)OCCN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 443 mg; 1.30 mmol), 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (Intermediate 43; 400 mg; 1.93 mmol), Cs2CO3 (1.30 g; 3.99 mmol) in DMF (10 mL) was stirred at 90° C. overnight. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 285 mg (48%) of the title compound as a brown solid, which was used directly used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[CH2:8][CH2:7]1
Reactant: COCCCC1CCNCC1
Reactant: N#CCBr
Product: COCCCC1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 4-(3-Methoxy-propyl)-piperidine (commercially available from ChemBridge Corporation) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=197.2; 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.30 (t, 2H), 3.00 (s, 3H), 2.75-2.70 (m, 2H), 2.10-2.00 (m, 2H), 1.65-1.40 (m, 4H), 1.20-1.00 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11](=[O:28])[C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](N(CC)CC)[CH3:31].ClCCl>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11](=[O:28])[C:10]=1[CH:30]=[CH2:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)c(I)c2=O)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1c(OCc2ccccc2)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-(4-(benzyloxy)-3-iodo-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (2.4 g), potassium vinyl trifluoroborate (0.945 g), triethylamine (1.3 mL), a dichloromethane adduct of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.269 g), and ethanol (47 mL) was stirred overnight at 90 C in a nitrogen atmosphere. After cooling to room temperature, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the organic layer was separated. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (1.48 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.[H-].[Na+].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CN(C)C=O>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][N:6]1[C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)NC(=O)C(C)(C)N1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)NC(C)(C)N(CC(O)CO)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
2,2,5,5-Tetramethylimidazolidin-4-one (3.54 g, 24.9 mmol), prepared as described in U.S. Pat. No. 5,126,057 (Worely et al., Jun. 30, 1992), was dissolved in N,N-dimethylformamide (150 ml). To the stirring room temperature solution was added sodium hydride (60%, 913 mg, 22.8 mmol), in 4 portions over 10 minutes. After an additional one hour of stirring at room temperature, the glycidol (1.4 ml, 21.1 mmol) was added to the reaction mixture. After the reaction mixture was stirred for 18 hours at room temperature, the mixture was concentrated in vacuo, and crude material is purified by silica gel column chromatography (0 to 20% methanol in dichloromethane) to give 250 mg (5%) the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11](#[N:15])[CH:12]([CH3:14])[CH3:13].Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1>C1(C)C=CC=CC=1.CCOCC>[Br:23][C:19]1[N:18]=[C:17]([C:12]([CH3:14])([CH3:13])[C:11]#[N:15])[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 200 ml, 100 mmol) was added slowly to a solution of isobutyronitrile (8.55 ml, 95.26 mmol) in toluene (200 ml) cooled down to 0° C. After complete addition, the reaction mixture was allowed to warm up to room temperature over 1 hour. The resulting mixture was added to a solution of 2,6-dibromopyridine (56.42 g, 238.15 mmol) in toluene (100 ml). The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was diluted with ether, washed with a saturated aqueous solution of ammonium chloride and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as an oil (14.04 g, 65% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH2:13][N:14]3[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15]3)[C:10]([CH3:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Cl:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH2:31])[CH:29]=2)[N:24]([CH:32]2[CH2:34][CH2:33]2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[CH:12]=[C:11]([CH2:13][N:14]5[CH2:18][CH2:17][C@@H:16]([OH:19])[CH2:15]5)[C:10]([CH3:20])=[N:9]4)[CH:5]=[CH:4][N:3]=3)[CH:29]=2)[N:24]([CH:32]2[CH2:34][CH2:33]2)[CH:23]=1
Reactant: Cc1nn(-c2ccnc(Cl)n2)cc1CN1CC[C@@H](O)C1
Reactant: Nc1ccc2c(c1)c(Cl)cn2C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)cn4C3CC3)n2)cc1CN1CC[C@@H](O)C1
Temperature: 100 °C
Yield: 69.9 %

Procedure:
A round bottomed flask was charged with (R)-1-((1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)pyrrolidin-3-ol (268 mg, 1.6 mmol), 3-chloro-1-cyclopropyl-1H-indol-5-amine (430 mg, 1.3 equiv.), potassium carbonate (0.66 g, 3.0 equiv), palladium acetate (18 mg, 0.05 equiv.), Xantphos (0.1 equiv.) and 50 mL of anhydrous dioxane. After being degassed by nitrogen bubbling, the reaction mixture was heated at 100° C. for 5 hours. Volatiles were removed in vacuo and then the resulting residue was extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM/MeOH) to give 519 mg (70%) of the desired Compound 142 as a pale yellow solid. MS (ESI) m/z 464 [M+H]+.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Brc1ccccc1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
7.80 g (0.32 mol) of iodine-activated magnesium turnings in 20 ml of anhydrous THF are heated briefly to 60° C. Then 47.1 g (0.30 mol) of bromobenzene and 80 ml of THF are added dropwise over 30 min and the mixture is heated for 1.5 hours to 65° C. After cooling, the Grignard solution is added over 1 hour to a mixture of 51.6 g (0.28 mol) of cyanuric chloride and 140 ml of THF, while keeping the temperature of the mixture in the range from 10° to 20° C. When the addition is complete, the mixture is stirred at for 3 hours at 25° C. The mixture is then diluted with 280 ml of toluene, the resultant suspension is poured into 300 g of 12% aqueous HCl, the organic phase is separated, washed with a total amount of 400 g of water and concentrated. The resultant material (melting point 117°-120° C.) is recrystallised from hexane, giving the title compound in a yield of 61%.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16](OC(C)(C)C)=[O:17].[O-]CC.[Na+]>CCO.O>[OH:17][N:16]=[C:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: O=C(Cc1cccnc1)c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(C(=NO)c1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of 1-phenyl-2-(pyridine-3-yl)ethanone (0.494 g, 2.505 mmol) in EtOH (36.8 mL) at room temperature was added tert-butyl nitrite (0.586 mL, 4.93 mmol) dropwise followed by sodium ethoxide (0.435 g, 2.55 mmol). The reaction was stirred at room temperature overnight. Upon completion, the solvent was evaporated to give a yellow oil. This oil was then diluted with H2O (25 mL), extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (0.214 g). LCMS m/z=227.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10][C:9]=2[N:8]=[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=12)=[O:3].[ClH:26].O1CCOCC1>O1CCOCC1.CO>[ClH:26].[ClH:26].[C:2]([NH:4][C:5]1[C:14]2[CH2:13][NH:12][CH2:11][CH2:10][C:9]=2[N:8]=[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=12)(=[O:3])[CH3:1]
Reactant: CC(=O)Nc1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1c2c(nc3ccccc13)CCNC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10-Methylcarbonylamino-2-t-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (0.5 g, 1.47 mmol) was suspended in a mixture of dioxane (4.5 ml) and methanol (1 ml), followed by adding thereto 4N-hydrogen chloride/dioxane (7.35 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to obtain the desired compound (0.369 g, quant.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:16]([C:15]1[CH:14]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of compound 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)benzoic acid (100 mg, 0.34 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (70 mg, 0.34 mmol), BOPCl (100 mg, 0.41 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at 25° C. for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and the residue was purified by prep-TLC to give the title product which was used directly in next step (150 mg, Yield 93%). LCMS (m/z): 480.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([OH:28])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1.O>CN(C)C=O>[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([O:28][CH2:7][CH3:8])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1
Reactant: CCI
Reactant: Cn1nc(O)c(CSC2=NOC(C)(C)C2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(C)c(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
0.20 g (1.3 mmoles) of anhydrous potassium carbonate and 0.20 g (1.5 mmoles) of ethyl iodide were added to a solution of 0.30 g (1.0 mmoles) of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.30 g (yield: 92.0%) of intended 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.Cl[CH2:18][C:19]([OH:21])=[O:20].O>C1(C)C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:11][CH2:18][C:19]([OH:21])=[O:20])([CH3:9])[CH3:10]
Reactant: CC(C)(O)C1CC2C=CC1C2
Reactant: O=C(O)CCl
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(OCC(=O)O)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 31.4 %

Procedure:
2-(5-norbornen-2-yl)-2-propanol (15.20 g, 0.10 mole) (JSR Corp., Japan) and toluene (100 ml) were added to a three-necked 500 ml round bottomed flask equipped with a magnetic stirrer, an addition funnel, and a condenser with a nitrogen inlet. The addition funnel was charged with n-butyl lithium (1.6M in hexane, 62.50 ml, 0.10 mole). The n-butyl lithium was added drop wise while stirring at room temperature. An exothermic reaction occurred. Afterwards, chloroacetic acid (4.75 g, 0.05 mole) in toluene (100 ml) was added drop wise. The contents were heated to reflux for about 20 hours. After cooling to room temperature, water (200 ml) was added cautiously and stirred. The water phase was collected, washed with ether (100 ml) and neutralized with 2 molar hydrochloric acid solution. The cloudy solution was extracted twice with ether (100 ml) and the combined ether solutions was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was recrystallized from a small amount of hexane to give 3.3 g of white crystalline material (Melting Point: 48.5-49.50° C).
Reaction SMILES: [H-].[Na+].[CH2:3]1COC[CH2:4]1.[OH:8][C:9]1[C:14](/[CH:15]=[CH:16]/[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=1[C:18](=[O:20])[CH3:19].C(Cl)(=O)C>O>[CH3:3][C:4]1[O:8][C:9]2[C:10]([C:18](=[O:20])[CH:19]=1)=[CH:11][CH:12]=[CH:13][C:14]=2/[CH:15]=[CH:16]/[CH3:17]
Reactant: C/C=C/c1cccc(C(C)=O)c1O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: O
Product: C/C=C/c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
12.52 g (313.2 mmol) of 60% sodium hydride (suspension in mineral oil) are introduced into 300 ml of absolute THF under argon at 10° C. 18.4 g (104.4 mmol) of 1-{2-hydroxy-3-[(1E)-prop-1-en-1-yl]phenyl}ethanone are slowly added dropwise to the suspension. After 15 min, 9 g (114.9 mmol) of acetyl chloride are added. The reaction mixture is stirred at room temperature ovemight. Hydrolysis is carried out with 300 ml of water, and the mixture is extracted several times with ethyl acetate. Washing of the organic phase with saturated sodium chloride solution is followed by drying over sodium sulfate. The solvent is then removed in vacuo. The residue is taken up in 200 ml of methanol and heated with 50 ml of 20% strength hydrochloric acid at 80° C. for 30 min. The solvent is then removed in vacuo, and the residue is mixed with 400 ml of water. Several extractions with dichloromethane are carried out. After the organic phase has been dried over magnesium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 98:2). 10.5 g (50.2% of theory) of the title compound are obtained as a yellow oil.