Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N(CC)CC)C>C(O)CCC>[S:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:2][CH2:3]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: N#Cc1ccc(N2CCSCC2)nc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a round bottom flask was added thiomorpholine 8-1 (3.6 g, 34.8 mmol), 6-chloronicotinonitrile 8-2 (4.0 g, 29 mmol), triethylamine (8 mL, 58 mmol) and butanol (10 mL). The reaction was stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction formed a solid cake. The cake was triturated in 50 mL H2O at 100° C. After cooling, the solid was collected by filtration to give 6-thiomorpholinonicotinonitrile 8-3 as an off-white solid. MS m/z 206.1 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Reactant: OCCN1CCNCC1
Product: CCOC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Yield: 80.6 %

Procedure:
Prepared from ethyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate and Compound 3: ethyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 80.6%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.COC[C@H]1[C@@H](C=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@H](COC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 66 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 13a as the starting material afforded the title compound (53 mg, 66% yield) as a white solid:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9].[H-].[Na+].[N:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[CH:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1)=[C:15]=[S:16]>O1CCCC1>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH:26]=[N:27][C:23]([C:20]3[CH:21]=[CH:22][C:17]([NH:14][C:15]([NH:9][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:10])[F:11])=[S:16])=[CH:18][CH:19]=3)=[N:24]2)=[CH:33][CH:32]=1
Reactant: Nc1cnccc1C(F)(F)F
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC(=S)Nc4cnccc4C(F)(F)F)cc3)n2)cc1
Reaction time: 48 h
Yield: 16.3 %

Procedure:
To 4-(trifluoromethyl)pyridin-3-amine (0.091 g, 0.56 mmol) in tetrahydrofuran and under an atmosphere of nitrogen was added sodium hydride (60% in mineral oil, 0.022 g, 0.56 mmol). 3-(4-Isothiocyanatophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (WO 2011/017513) (0.10 g, 0.28 mmol) was added and the reaction was allowed to stir for 48 hours. The reaction mixture was concentrated. Purification by silica gel chromatography provided the title compound (0.024 g, 16%).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (20 mL) was added a solution of 4-(trifluoromethyl)phenyl isocyanate (0.41 g, 2.2 mmole) in dry dichloromethane (3 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. The resulting mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and 2N aqueous HCl. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield the title compound as an orange solid (0.36 g, 49% yield), mp=81–83° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−25.6° (c=1, EtOH).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>>[Si:21]([O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Product: COC(=O)[C@@H]1Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2CN1
Yield: 87 %

Procedure:
Prepared as in Example 12-1c from (S)-methyl 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (Example 13-1c) and tert-butylchlorodimethylsilane. Yield 87%, yellow oil. MS 322 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]([CH3:10])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:11]([O:1][N:2]=[C:3]([C:8]([CH3:10])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(=NOCc1ccccc1)C(C)=O
Yield: 77.2 %

Procedure:
To a solution of 15.0 g (103 mmol) of methyl 2-hydroxyiminoacetoacetate in 200 ml of acetone, 14.4 g (113 mmol) of benzyl chloride and 21.4 g (155 mmol) of potassium carbonate were added and the mixture was heated under reflux for 15 hours. The reaction mixture was combined with 200 ml of water and extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off. The residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 18.7 g (yield: 77%) of methyl 2-benzyloxyiminoacetoacetate as a colorless crystal.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[N:14]=[C:13]2[CH:23]([CH3:25])[CH3:24])[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[CH:17]([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[N:14]=[C:13]2[CH:23]([CH3:25])[CH3:24])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCCC2
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Sodium borohydride (204 mg) was added to a stirred solution of Intermediate 7 (630 mg) in dichloromethane (2 mL) and methanol (2 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated; the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (600 mg). LC/MS MH+ 353/355, Rt 1.13 min (2 minute run).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([N:13]([CH2:29][CH3:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15])[CH3:12].C1N2CCN(CC2)C1>C(#N)C>[CH2:29]([N:13]([CH2:11][CH3:12])[S:14]([C:17]1[C:18]([S:23]([NH:26][C:27]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:28])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH3:30]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Yield: 34.2 %

Procedure:
A mixture of 0.8 g of 2-amino-4-methoxy-6-methylpyrimidine, 2.8 g of the crude sulfonyl isocyanate from Example 4 and a few crystals of DABCO in 25 ml of acetonitrile was stirred at room temperature for 16 hours. A small amount of unreacted aminopyrimidine was filtered off and the filtrate concentrated in-vacuo to give a hard glass. Crystallization from methanol gave 0.9 g of N,N-diethyl-N'[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-1,2-benzenedisulfonamide as a white solid, m.p. 170°-2°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (Aldrich, 3.0 g, 17.2 mmol) in sulfuric acid (18 mL) was added nitric acid (60-61%, Wako Pure Chemical Industries, Ltd., 6 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was poured into ice water and obtained precipitate was collected by filtration. The solid was washed with water and dried in vacuo to afford the title compound (2.5 g, 68%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:32])[CH2:30]Cl)=[C:23]([CH2:33][CH3:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:35])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH2:41])[CH3:40].CCOC(C)=O.CO>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:32])[CH2:30][NH:41][CH2:39][CH3:40])=[C:23]([CH2:33][CH3:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1NC(=O)CCl
Reactant: CCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNCC(=O)Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1CC
Reaction time: 48 h

Procedure:
To a solution of N-{4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-ethyl-6-fluoro-phenyl}-2-chloro-acetamide 0.087 g, 0.15 mmol) in DMF (2 mL) was added a 4M solution of ethylamine in DMF (0.1 mL, 0.4 mmol) and the reaction mixture was kept for 2 days at 25° C. After evaporation, the product was dissolved in water and extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to provide a yellow foam: TLC (EtOAc-MeOH 9:1) Rf=0.25; UPLC RtD=1.443 min; ESIMS [M+NH4]+=574.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3>C1C=C2C3N=C(C2=CC=1)N=C1C2C(C(=N1)N=C1C4C(C(=N1)N=C1C5C(C(=N1)N=3)=CC=CC=5)=CC=CC=4)=CC=CC=2.[Cu]>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Agent: [Cu]
Agent: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
A surface-modified quinacridon colorant was prepared following the procedure of Preparation Example 6, except that hostaperm pink E colorant (colorant red 122) was used instead of phthalocyanine blue. As in Preparation Example 6, the resulting surface-modified coloring colorant was readily dissolved in an aqueous medium by stirring.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:27]OS([O-])=O.[K+].O>C(Cl)Cl.CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][SH2:24](=[O:27])[CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCSCC2)no1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CC[SH2](=O)CC2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(Thiomorpholine-4-carbonyl)-piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (150 mg; 0.394 mmol) in 50% methylene chloride in methanol (4 mL) is added oxone (122.8 mg; 0.2 mmol) and water (0.1 mL). The reaction mixture is stirred at room temperature for 2 hours. The mixture is quenched with water and extracted with dichloromethane 3 times. The organics are combined and dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 397 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7](I)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:16]=1[C:22]([CH3:27])([CH3:26])[C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C(C)(C)C)(=O)C(C)(C)C>[Cu]Cl.CN1CCCC1=O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([O:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[C:16]=3[C:22]([CH3:27])([CH3:26])[C:23](=[O:25])[CH3:24])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc(I)cnc2c1F
Reactant: CC(=O)C(C)(C)c1c(O)cccc1F
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(=O)C(C)(C)c1c(F)cccc1Oc1cnc2c(F)c(F)ccc2c1
Temperature: 130 °C
Reaction time: 48 h
Yield: 10.5 %

Procedure:
3 ml of N-methylpyrrolidone was added to 0.78 g of 7,8-difluoro-3-iodoquinoline, 0.26 g of 3-(2-fluoro-6-hydroxyphenyl)-3-methyl-butan-2-one, 1.05 g of cesium carbonate, 53 mg of dipivaloylmethane, and 0.27 g of copper (I) chloride. After 48 hours of stirring at 130° C., the reaction solution was filtered with CELITE and the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 0.05 g of 3-[2-(7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl]-3-methyl-butan-2-one (Compound Number 267).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[CH3:14]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C(OCC)(=O)C>CC(C)=O>[C:12]([CH:9]1[CH2:10][CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:8]1)(=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: C=CCOC(=O)N1CCC(CO)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC(C(C)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 1-allyloxycarbonyl-3-hydroxymethylpyrrolidine (2.6 g) in acetone was added Jones reagent (1.25N, 20 ml) at ambient temperature. After stirring for 1 hour, isopropyl alcohol (10 ml) was added thereto. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane, dicyclohexylcarbodiimide (0.79 g), Meldrum's acid (0.55 g), 4-methylaminopyridine (0.47 g) to the solution at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid and evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (10 ml) and water (7 ml), and the mixture was refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give 3-acetyl-1-allyloxycarbonylpyrrolidine (2.01 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1([NH2:22])[CH2:13][CH2:12][CH2:11][C:10]2[N:9]=[C:8]([O:14]CC3C=CC=CC=3)[CH:7]=[CH:6][C:5]1=2.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:22][C:4]1([CH3:3])[CH2:13][CH2:12][CH2:11][C:10]2[NH:9][C:8](=[O:14])[CH:7]=[CH:6][C:5]1=2
Reactant: [H][H]
Reactant: CC1(N)CCCc2nc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(N)CCCc2[nH]c(=O)ccc21
Yield: 56.2 %

Procedure:
5,6,7,8-Tetrahydro-5-methyl-2-(phenylmethoxy)-5-quinolinamine dihydrochloride (9.5 g) and 10% palladium-on-carbon (730 mg) in absolute ethanol (500 ml) were shaken on a Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was removed by filtration, and the filtrate was neutralized with 4-polyvinylpyridine and concentrated. The residue was suspended in hot methanol and the solid was collected. The solid was combined with the material that crystallized from the methanol to afford 3.36 g (56%) of product, mp 214°-216° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH3:14]>CO>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH2:14])=[O:8]
Reactant: COC(=O)c1cc(Br)c(Cl)cc1O
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Br)c(Cl)cc1O
Temperature: 65 °C

Procedure:
A mixture of methyl 5-bromo-4-chloro-2-hydroxybenzoate (2.655 g, 10.00 mmol) in a solution of ammonia (50.0 ml, 100 mmol) in MeOH was heated at 65° C. for 72 hr. After concentration, the title product was obtained as solid (2.53 g). ESI-MS m/z: 252.1 [M+1]+, Retention time 1.19 min; 1HNMR (CDCl3, 400.342 MHz) δ 7.15 (s, 1H), 7.61 (s, 1H), 12.2 (brs, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH:13]1([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C2CC2)ncc1[N+](=O)[O-]
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-4-methoxy-5-nitropyridine (1.6 g, 8.48 mmol), cyclopropylboronic acid (1.458 g, 16.97 mmol), PdCl2(dppf)-CH2Cl2 adduct (1.386 g, 1.697 mmol), cesium carbonate (8.29 g, 25.5 mmol), and 1,4-Dioxane (15 mL) were heated using the microwave at 140° C. for 10 minutes. The reaction mixture was purified by normal phase chromatography (ISCO, 120 g silica, 0-3% methanol/DCM) to afford 2-cyclopropyl-4-methoxy-5-nitropyridine as a red solid (492 mg, 28%). MS (m/z) 195.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.Cl>C(O)C.C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][NH2:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnnn1Cc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CCOCC
Product: NCc1nnnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of the solid isolated in Step B (7.88 g, 24.7 mmol) in ethanol (300 mL), hydrazine (1.58 g, 49.3 mmol) was added. The reaction mixture was then refluxed four hours. After cooling down to room temperature, the white solid from the solution was removed by filtration. The filtrate was concentrated. Acetonitrile (50 mL) was added to the residue. The precipitate from the solution was removed by filtration. The filtrate was concentrated to yield a colorless oil which was treated with 1 N HCl in diethyl ether to yield C-(1-benzyl-1H-tetrazol-5-yl)-methylamine as a white solid, as its corresponding HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:5]([O:4][C:3]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:2]=2[F:1])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1c(F)cccc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1Oc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
A suspension of methyl 2-(2,6-difluorophenoxy)-5-nitrobenzoate (step 1, 365 mg, 1.18 mmol) and 5% Pd/C (37 mg) in methanol (10 mL) was stirred under hydrogen atmosphere for 16 h at room temperature. After filtration through a pad of Celite®, the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1 to 1/2) to afford 325 mg of the title compound: 1H-NMR (CDCl3) δ 7.21 (1H, d, J=2.9 Hz), 7.12–6.88 (3H, m), 6.77 (1H, dd, J=8.8, 2.9 Hz), 6.64–6.58 (1H, m), 3.87 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([CH:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C:8]([OH:10])=[O:9])[O:4][N:3]=1.O.NN.C(O)(=O)C>O>[NH2:11][C@@H:7]([C@H:5]1[O:4][N:3]=[C:2]([Br:1])[CH2:6]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(C1CC(Br)=NO1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@H](C(=O)O)[C@@H]1CC(Br)=NO1
Reaction time: 7 h
Yield: 46.8 %

Procedure:
To 710 mg (2.3 mmole) of 3-bromo-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid in 15 ml of water is added 260 μl of hydrazine hydrate and the solution stirred at 50° for 7 hours. After cooling, the solution is adjusted to pH 5.5 with acetic acid (80 μl), filtered, and the precipitate washed with 13 ml water. The filtrate is diluted with 200 ml of 2-butanol and allowed to crystallized in the refrigerator for 18 hours. Filtration yielded 240 mg of (αS,5S)-α-amino-3-bromo-4,5-dihydro-5-isoxazole acetic acid; concentrating the mother liquors approximately 15% afforded 50 mg of a second crop of (αS,5S)-α-amino-3-bromo-4,5-dihydro-5-isoxazole acetic acid (71%).