Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1>>[N+:22]([C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.54 mmol) and 1-iodo-3-nitrobenzene (146 mg, 0.58 mmol) according to the general procedure IC to give 113 mg (67%) of a pale orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.30 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.36-8.35 (m, 1H), 8.18-8.14 (m, 1H), 7.82-7.79 (m, 1H), 7.55-7.46 (m, 3H), 7.23-7.20 (m, 2H), 3.68 (s, 3H), 3.01-2.96 (t, 2H, J=7.8 Hz), 2.68-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3): δ 173.0, 148.2, 141.8, 137.1, 131.9, 129.3, 128.5, 126.3, 125.2, 122.8, 120.1, 91.9, 86.6, 51.7, 35.3, 30.8; EI-MS m/z 309 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][C:15]([O:18][C:19]([NH:21][C@H:22]([C:31](O)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:20])([CH3:17])[CH3:16].C(Cl)CCl>N1C=CC=CC=1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C@H:22]([NH:21][C:19](=[O:20])[O:18][C:15]([CH3:16])([CH3:14])[CH3:17])[C:31]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:5]=2)=[O:32])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: Cn1nc(-c2ccncc2)cc1N
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 99.1 %

Procedure:
To a 100 ml flask was added 1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine 17.B (540 mg, 3.10 mmole), Boc-L-4-fluorophenylalanine (970 mg, 3.41 mmole), EDC (710 mg, 3.72 mmole), and 10 ml of pyridine. The reaction was stirred at room temperature for 5.5 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 103.1.A (1.35 g, 99% yield) as colorless amorphous.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH2:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH:16][CH2:1][CH:3]2[O:5][CH2:4]2)([CH3:14])[CH3:15])=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NCC1CO1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Epichlorohydrin (8.05 ml) was added dropwise to a solution of 1-(4-chlorophenyl)-1-methylethylamine (17.38 g) in methanol (17.5 ml) at 0° C. with stirring. The solution was warmed to ambient temperature and stirred for 48 hours. Sodium hydroxide solution (50%) (17.5 ml) was added and the mixture stirred for 15 minutes. The product was extracted with ether to give an oil which was purified by flash column chromatography on silica using petroleum ether, b.p. 40-60° C./ethyl acetate/triethylamine (8:2:1) as the mobile phase with gradually increasing amounts of ethyl acetate to give N-[1-(4-chlorophenyl)-1-methylethyl]-2,3-epoxypropylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:7]2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnc2c(Cl)ccnc2c1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 56.3 %

Procedure:
A resealable pressure bottle was charged with 8-chloro-1,5-naphthyridin-3-ol (80 mg, 0.44 mmol), cesium carbonate (433 mg, 1.3 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (360 mg, 1.55 mmol), and DMF (0.9 ml). Vessel sealed and placed in a pre-heated at 50° C. oil bath. Reaction allowed to stir at this temperature for 45 minutes. LC/MS shows complete conversion. Quench with water, dilute with aqueous sodium bicarbonate solution and dichloromethane. Layers separated, organic layer collected and dried over sodium sulfate. This was concentrated to afford yellow oil; which was purified by ISCO silica gel chromatography (20-40% EtOAc/Hexanes) to afford 8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine (65 mg, 56% yield). MS [M+H]=263.0@1.89 minutes. Calc'd for C10H6ClF3N2O=262.6.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: Cn1cc(Br)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)C(=O)Cn1c(=O)c(Br)cn(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-1-methylpyrimidine-2,4(1H,3H)-dione (80 mg, 0.390 mmol), 2-chloro-N,N-dimethylacetamide (47.4 mg, 0.390 mmol), and potassium carbonate (64.7 mg, 0.468 mmol) in DMSO (3 mL) was stirred at room temperature 2 hours. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 5-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].[C:8]([C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:10])[CH3:9]>C1COCC1>[Cl:16][C:13]1[S:12][C:11]([C:8]([OH:10])([CH3:9])[CH2:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: CCOS(C)(=O)=O
Solvent: C1CCOC1
Product: CCOS(=O)(=O)CC(C)(O)c1ccc(Cl)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A solution of ethyl methanesulphonate (4.97 g) in THF (20 ml) was added dropwise to a solution of lithium hexamethyldisilylamide (42.0 ml of 1M solution in THF plus 20 ml of THF) at −78° C. under nitrogen, and the solution was stirred for 30 min. A solution of 2-acetyl-5-chlorothiophene (6.75 g) in THF (70 ml) was added to this over 15 min and the temperature maintained at −78° C. for 90 min. The reaction was quenched with saturated aqueous ammonium chloride and the mixture extracted with ethyl acetate. The combined organic fractions were washed with brine; dried (over magnesium sulphate) and concentrated under reduced pressure to afford a crude oil that was purified by Biotage™ chromatography (silica, eluting with ether-cyclohexane 1:3) to give the title compound (10.9 g) as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>CO>[OH:1][CH2:2][CH2:3][N:4]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:5]1
Reactant: NNCCO
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CO
Product: O=C1CCCc2c1cnn2CCO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-hydroxyethyl hydrazine (1.36 mL, 20 mmol) was slowly added to an ice-cooled solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (3.34 g) in methanol (50 mL). After stirring at room temperature for 20 min, the solvent was evaporated. Flash chromatography (SiO2, EtOAc/MeOH=100:5 to 100:7 to 100:10) gave the title compound as a white solid. B. Preparation of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-1H-indazol-4(5H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].C([Sn](CCCC)(CCCC)[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC.O.Cl>CN(C=O)C.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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]=2)=[O:4]
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2cc(C#Cc3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 104.3 %

Procedure:
A mixture of 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (500 mg, 1.77 mmol), tributyl(phenylethynyl)tin (0.8 mL, 2.13 mmol), and PdCl2(PPh3)2 (249 mg, 0.35 mmol) in DMF (18 mL) was heated at 120° C. for 2 h under N2 atmosphere. After cooling the mixture to r.t., water and EtOAc were added. 1 M HCl was added with stirring until pH was ˜2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by column chromatography (0-40% EtOAc/hexanes) to give 560 mg of the title compound as a yellow solid. MS: (+) m/z 304.10 (M+1).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)(Cl)(Cl)[Cl:16]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: ClC#Cc1ccccc1
Yield: 96 %

Procedure:
Phenylacetylene (1.02 g, 10 mmol), 1.92 g of cesium carbonate (10 mmol), and 0.15 g tetra-n-butylammonium chloride hydrate and 5 mL carbon tetrachloride were mixed at 70° C. for 5 h. Gas chromatographic analysis of the mixture showed that it contained 1.32 g of 1-chloro-2-phenylacetylene (96% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]([F:28])([F:27])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC#N>CCCCO>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([F:17])([F:27])[F:28])[N:7]=1)([CH3:15])[CH3:14]
Reactant: NC(c1ccccc1)C(F)(F)F
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Solvent: CC#N
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(NC(c2ccccc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 25.4 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (163 mg, 0.674 mmol), 2,2,2-trifluoro-1-phenylethanamine (624 mg, 3.56 mmol, 5.3 equiv) and p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110° C. for 2 h and treated with additional p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv), then heated at 110° C. for 1½ h. After cooling, the solid reaction mixture was treated with MeCN, sonicated and filtered. The filtrated was concentrated and purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%) to give (4S)-4-isopropyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one (65 mg) in 25% yield. HRMS(B) m/z 381.1545 (M+H)+. Anal. RP-HPLC tR=4.31//4.46 min (1.0 mL/min flow rate with gradient from 5% to 15% acetonitrile with 0.05% formic acid in 5.00 min and then 15% to 95% acetonitrile with 0.05% formic acid from 5.00 min to 9.50 min, aqueous phase modified with 0.1% formic acid. Silica gel column chromatography separated the two diastereomers (S)-4-isopropyl-3-(2-((R)-2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][CH:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:32]=1)[C:39]([O:41][CH3:42])=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C)cc1C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
To a suspension of 1.05 g (9.15 mmol) of a 35% oil dispersion of KH in 15 mL of DMF was added 1.50 g (9.15 mmol) of 2-tert-butyl-4-methylphenol and the mixture was stirred under N2 at room temperature. After 10 minutes, 2.41 g (91.5 mmol) of 18-crown-6 and then a solution of 2.30 g (10.1 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF were added. The reaction mixture was stirred 17 hours, then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.750 g (26%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.C1(C)C=CC=CC=1>C(OCC)(=O)C.Cl[Pd]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]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(C)(=O)=O)cn2)c1C
Temperature: 80 °C
Yield: 10 %

Procedure:
A mixture of [6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.130 g, 0.36 mmol), 2-bromo-5-methanesulfonylpyridine (0.086 g, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.005 g, 0.0068 mmol), and 1.0 M aqueous sodium carbonate (0.4 mL, 0.4 mmol) in 1:1 THF-toluene (4 mL) was heated at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The resulting mixture was washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated to give an oily yellow solid. Flash chromatography (40 g Analogix column, 5-60% ethyl acetate in hexanes) gave [6-fluoro-4-(5-methanesulfonyl-pyridin-2-yl)-3-methyl-naphthalen-2-yl]acetic acid methyl ester (0.014 g, 10%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.27 (d, J=3.00 Hz, 1 H), 8.49 (dd, J=8.00, 3.00 Hz, 1 H), 8.04 (dd, J=8.80, 6.60 Hz, 1 H), 7.97 (s, 1 H), 7.73 (d, J=9.00 Hz, 1 H), 7.41 (td, J=8.00, 3.20 Hz, 1 H), 6.72-6.78 (m, 1 H), 3.97-3.99 (m, 2 H), 3.65 (s, 3 H), 3.46 (s, 3 H), 2.05 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:22]([N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1.O.NN.Cl>CCO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:22]([NH2:24])[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1
Reactant: CC(c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethyl) isoindoline-1,3-dione (1.2 g, 2.52 mmol in EtOH (40 mL) was added hydrazine hydrate (0.8 mL, 16.4 mmol) at 25° C. The reaction mixture was stirred for overnight at 25° C. The reaction mixture was acidified with 5 N hydrochloric acid and concentrated in vacuo. Water was added to residue and extracted with EtOAc. Aq. layer was basified with aq. NaOH solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanamine: LC-MS (ESI) m/z 345.96 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)=O.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]([C:5]1[N:10]=[CH:9][N:8]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:22])[N:11]=[C:7]2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)ncn1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2nc(-c3ccccc3N)cn2cn1
Temperature: 0 °C

Procedure:
A solution of 15.1 g (100 mmol) of 6-tert-butylpyrimidin-4-ylamine [3435-27-6] and 24.4 g (100 mmol) of 2-bromo-1-(2-nitrophenyl)ethanone [6851-99-6] in 300 ml of ethanol is heated under reflux for 8 h. The solvent is removed in vacuo, the residue is taken up in 200 ml of water, the mixture is rendered alkaline by addition of 2 N NaOH, the aqueous phase is extracted three times with 100 ml of dichloromethane each time, the organic phase is washed once with 100 ml of saturated sodium chloride solution, and the dichloromethane is removed in vacuo. The oily residue is dissolved in 500 ml of ethanol, 112.8 g (500 mmol) of tin(II) chloride dihydrate are added, and the mixture is heated under reflux for 2 h. After cooling, the reaction mixture is poured into 1000 ml of ice-water, the mixture is rendered weakly alkaline by addition of saturated sodium hydrogencarbonate solution, 500 ml of ethyl acetate are added, the mixture is filtered through a short Celite bed, the organic phase is separated off, washed once with 300 ml of water and once with 300 ml of saturated sodium chloride solution, and the solvent is then removed in vacuo. The 2-(7-tert-butylimidazo[1,2-c]pyrimidin-2-yl)phenylamine obtained in this way is reacted further as described in Example 1 with 42.1 g (500 mmol) of 2,2-dimethylpropanal [630-19-3] and 1.9 g (10 mmol) of p-toluenesulfonic acid hydrate. Yield: 9.0 g (27 mmol), 27%, purity: about 99.5% (NMR).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH:22]1[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=S1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCS(=O)CC1
Yield: 37 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and thiomorpholine 1-oxide and purified by flash chromatography (ethyl acetate), yield 37%. White crystals, m.p. 156–157° C.; 1H NMR (CDCl3) δ 8.47–8.40 (s-like, 1H), 7.94–7.87 (dd-like, 1H), 7.24–7.13 (m, 4H), 7.06–6.99 (d-like), 4.31–3.91 (m, 4H), 2.97–2.87–2.75 (m, 2H+2H); IR (KBr): ν 1710 (C═O) cm−1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(Cl)nn1

Procedure:
As shown in FIG. 5, a mixture of 40 g (0.27 mole) of 3,6-dichloropyridazine and 40 mL of 80% hydrazine hydrate in 80 mL of ethanol was refluxed for one hour. The reaction mixture was evaporated to dryness and the residue was recrystallized from benzene to give 39 g of 1-(6-chloropyridazin-3-yl)hydrazine (compound 1003) (see Takahayashi, J. Pharm. Soc. Japan 75:778-781, 1955).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[CH:12]1(O)[CH2:16][CH:15]=[CH:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH:15]2[CH2:14][CH:13]=[CH:12][CH2:16]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: OC1CC=CC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)ccc1OC1CC=CC1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 2-nitro-4-chlorophenol (3.46 g, 20 mmol), 3-cyclopenten-1-ol (2.1 g, 24 mmol), triphenylphosphine on polystyrene (3.0 mmol per gram, 10 g, 30 mmol) and di-tert-butyl azadicarboxylate (6.9 g, 30 mmol) in THF (200 mL ) was shaken for 1 hour and filtered. The resin was washed with dichloromethane (4×50 mL). The combined organic solutions were mixed with 20 g of silica gel and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 4.08 g (85%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.8, 2.7 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.75 (br s, 2H), 5.03–5.13 (m, 1H), 2.87 (d, J=6.8 Hz, 1H), 2.82 (d, J=6.8 Hz, 1H), 2.65 (br s, 1H), 2.59 (br s, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH2:40][C@H:41]([OH:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)C(=O)OC(C)(C)C)=[CH:26][CH:25]=2)=[CH:20][C:19]=1[O:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)(=[O:17])=[O:16])=[O:13])=O)(C)(C)C.[ClH:56]>C(OCC)(=O)C>[ClH:56].[ClH:56].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][CH2:40][C@H:41]([OH:48])[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:26][CH:25]=2)=[CH:20][C:19]=1[O:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)(=[O:17])=[O:16])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NS(=O)(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCC(=O)NS(=O)(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)cc1OC1CCCCC1
Reaction time: 6 h

Procedure:
To a solution of tert-butyl [2-[4′-[[[4-[(tert-butoxycarbonyl)amino]butanoyl]amino]sulfonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (110 mg) in ethyl acetate (1 ml) was added hydrogen chloride in ethyl acetate (4N, 1 ml) at room temperature and the mixture was stirred at the same temperature for 6 hours. The mixture was filtered to collect the precipitate and the precipitate was washed with ethyl acetate/hexane (1:1). The precipitate was dried under reduced pressure to give 4-amino-N-[[3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]-amino]ethyl]-4-biphenylyl]sulfonyl]butanamide dihydrochloride (85 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[C:20]([Cl:22])[CH:21]=[C:14]3[CH2:13][C:12]2=[O:23])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[C:20]([Cl:22])[CH:21]=[C:14]3[CH2:13][C:12]2=[O:23])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)Cc2cc(Cl)ccc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)Cc2cc(Cl)ccc2C1=O

Procedure:
The mixture of 1.7 g of N-(4-nitro-o-tolyl)-5-chlorohomophthalimide, 0.8 g of Raney nickel and 250 ml of ethyl acetate is hydrogenated at 2.4 atm. and room temperature until the hydrogen uptake has ceased. It is filtered, the filtrate evaporated and the residue recrystallized from acetonitrile to yield the N-(4-amino-o-tolyl)-5-chlorohomophthalimide of the formula ##STR7## melting at 250°-252° with decomposition.