Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1.C1COCC1.[Si:28](Cl)([Cl:31])([Cl:30])[Cl:29]>C1COCC1.CCOCC>[Cl:29][Si:28]([Cl:31])([Cl:30])[C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cl[Si](Cl)(Cl)c1ccc2ccc3cccc4ccc1c2c34
Temperature: -60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Under a dry nitrogen atmosphere, n-BuLi (10.6 mL, 1.6 M) in hexanes was added drop-wise to a cooled (−60° C.) solution of 1-bromopyrene (5.01 g, 0.018 mol) in THF/Et2O (1:1) (80 mL) and stirred for 2 hours at −60° C. The solution was cooled to −90° C. and a THF solution of SiCl4 (8.66 g, 0.051 mol) (10 mL) was added slowly and stirred for 24 hours at room temperature. The reaction mixture was evaporated to dryness, washed in Et2O (100 mL), and filtered to remove any unreacted 1-bromopyrene and LiBr. The filtrate was collected and evaporated to dryness to give a 48% yield of 1-trichlorosilylpyrene, a yellow powder. 1HNMR (CDCl3, ppm) 8.66 (d, J=9.3 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.30 (m, 5H), 8.11 (m, 2H). 13C {1H}NMR (CDCl3, ppm) 136.18 (C), 135.85 (C), 133.13 (CH), 132.06 (C), 131.30 (C), 131.22 CH), 130.31 (CH), 127.96 (CH), 127.67 (CH), 127.61 (CH), 126.65 (CH), 125.61 (C), 125.01 (CH), and 124.39 (C). 29Si{1H} (CDCl3, ppm) −1.64 (s).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[CH:19]=1)=[O:13]>C(#N)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([I:1])=[CH:21][N:22]=2)[CH:19]=1)=[O:13]
Reactant: NC(=O)CCC(=O)NI
Reactant: COC(=O)c1ccc2nccn2c1
Solvent: CC#N
Product: COC(=O)c1ccc2ncc(I)n2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N-iodosuccinamide (1.55 g, 6.89 mmol) was added to a solution of imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (1.1 g, 6.24 mmol) in acetonitrile (50 mL) which had been cooled to 0° C. under a nitrogen atmosphere. The reaction stirred for 1 hr, then concentrated in vaccuo to a residue. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% sodium bisulfate (2×10 ml) and brine (1×20 mL), then the organic layers were dried over MgSO4 and evaporated to give 3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a pale yellow solid (1.79 g, 95%). 1H NMR (250 MHz, CDCl3): δ 8.91 (s, 1H), 7.85 (dd, 1H, J=2.5, J=10), 7.80 (s, 1H), 7.69 (d, 1H, J=10), 4.01 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:15]1[CH2:19][C:18]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:17][C:16]1=[O:29])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[O:20][C:18]1[CH2:19][N:15]([CH:5]([CH2:6][C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])[C:4]([OH:30])=[O:3])[C:16](=[O:29])[CH:17]=1
Reactant: CCOC(=O)C(Cc1c(F)cccc1F)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1c(F)cccc1F)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution containing 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid ethyl ester (96 mg, 0.23 mmol) in tetrahydrofuran (1 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (12 mg, 0.27 mmol) in water (2 mL). The mixture was stirred at 25° C. for 3 h, then acidified with 2N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over magnesium sulfate and concentrated to afford 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (90 mg, 100%) as an off-white solid. LR-ES-MS m/z calculated for C19H13F4NO4 [M]+ 395, observed [M+H]+ 396.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([NH:13][CH2:14][C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=3C)[C:7]2=[N:6][C:5]=1[CH3:23])(=[O:3])[CH3:2].[CH3:24]O.[BH4-].[Na+]>O1CCCC1>[CH3:21][C:20]1[C:19]([CH3:24])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][NH:13][C:12]1[C:7]2[N:8]([C:4]([CH:1]([OH:3])[CH3:2])=[C:5]([CH3:23])[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: CC(=O)c1c(C)nc2c(NCc3c(C)cccc3C)cccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CNc2cccn3c(C(C)O)c(C)nc23)c1C
Reaction time: 1 h

Procedure:
To a mixture of 3-acetyl-8-(2,6-dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine (500 mg, 1.63 mmol) and methanol (20 ml) was sodium borohydride (62 mg, 1.63 mmol) added in portions. Tetrahydrofurane was added and the mixture stirred for 1 hour. TLC showed starting material and sodium borohydride (62 mg, 1.63 mmol) was added and the mixture stirred for 1.5 hour. The solvent was removed under reduced pressure and to the residue, methylene chloride and water was added. pH was adjusted to pH=3 with hydrogen chloride (conc.) and thereafter alkaline with sodium bicarbonate. The methylene chloride layer was separated washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was treated with ethanol/ethyl acetate and after filtration (410 mg, 81%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.Br[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:21]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
U1 was prepared from 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate following the general procedure reported in Preparative Example 54 Step 1-2. 1H NMR (400 MHz, CDCl3, 300K) δ 1.22 (m, 2H), 1.40 (s, 9H), 1.82 (d, J=12.7 Hz, 2H), 2.10 (m, 1H), 2.69 (t, J=12.3 Hz, 2H), 3.77 (m, 2H), 3.96 (s, 3H), 3.97 (m, 2H), 4.10 (m, 2H), 6.31 (d, J=5.2 Hz, 1H), 6.46 (m, 2H), 6.96 (t, J=8.7 Hz, 1H), 7.31 (s, 1H), 7.51 (s, 1H), 8.40 (d, J=5.2 Hz, 1H). MS (ES) C27H32FN3O5 requires: 497. Found: 498 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Nc1ccc(OCc2ccccc2)cc1)c1cccc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(COc2ccc(NCc3cccc(OC4CCCCO4)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4-benzyloxy-phenyl)-[3-(tetrahydro-pyran-2-yloxy)-benzylidene]-amine (21.0 g, 54.2 mmol) in 350 mL methanol and 150 mL methylene chloride at 0° C. was added sodium borohydride (3.3 g, 86.7 mmol) in portions over 20 minutes. The reaction mixture was stirred at 0° C. for 1 hr. and at room temperature for 3 days. Saturated aqueous sodium bicarbonate (250 mL) was added and the aqueous solution was washed with methylene chloride (3×500 mL). The combined organic layers were washed with 500 mL saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated to afford 20.6 of the title compound of Step B.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C[Si](C)(C)[O:40][NH2:41]>C1COCC1>[OH:40][NH:41][C:13](=[O:15])[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=CCCCCc1ccccc1
Reactant: C[Si](C)(C)ON
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=CCCCCc1ccccc1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
7-Phenylhept-2-enoic acid (7 g; 34 mmol) is dissolved in dry THF and cooled to 0° C. Diphenylphosphinic chloride (ClP(O)Ph2) (7.1 mL; 37 mmol) is added followed by dropwise addition of triethylamine (4.7 mL; 34 mmol). After 45 min at 0° C., a mixture of O-(trimethylsilyl)hydroxylamine (TMSONH2) (4.3 g; 37 mmol) and triethylamine (4.7 mL; 34 mmol) is added dropwise at 0° C. The bath is removed and the reaction is allowed to stir at 20° C. for 2 hours. The reaction is then filtered and the solid is extracted with EtOAc (500 mL). The EtOAc is washed with 60 mL 1 N HCl, 50 mL brine and dried (MgSO4). The resulting solution is concentrated in vacuo to yield a white solid which is purified by tituration with Et2O to obtain 7-phenylhept-2-enoic acid hydroxyamide (3.9 g; 18 mmol). MS (EI) m/e 219 (M+). Anal. (C13H17NO2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:4]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH:3]=1.CC1(C)C(C)(C)OB([C:53]2[CH:54]=[C:55]([P:59](=[O:64])([O:62][CH3:63])[O:60][CH3:61])[CH:56]=[CH:57][CH:58]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[Si:38]([O:37][C:4]1[CH:3]=[C:2]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([P:59](=[O:64])([O:62][CH3:63])[O:60][CH3:61])[CH:54]=2)[CH:7]=[CH:6][C:5]=1[C@@H:8]1[C@@H:9]([CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10](=[O:18])[N:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: COP(=O)(OC)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.080 g, 0.11 mmol), crude dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate (0.054 g total, 0.030 g calculated, 0.096 mmol) and aqueous 2 M potassium carbonate (0.12 mL, 0.24 mmol) were mixed in ethanol (1.0 mL) and toluene (3.0 mL). The solution was deoxygenated by bubbling nitrogen through the mixture for 5 min while stirring. Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added and the reaction was heated for 3 h at 70° C. under an atmosphere of nitrogen. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation under reduced pressure. The product was purified by chromatography over silica gel using ethyl acetate-hexane (gradient: 10% ethyl acetate to 80%) to afford dimethyl (3′-{[tert-butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate as a colorless syrup (0.065 g, 84%). 1H NMR (300 MHz, CDCl3) δ 6.9-8.0 (m, 16H), 5.09 (d, J=2.2 Hz, 1H), 4.64 (d, J=6.1 Hz, 1H), 3.79 (d, J=2.4 Hz, 3H), 3.76 (d, J=2.4 Hz, 3H), 3.05-3.15 (m, 1H), 1.8-2.0 (m, 4H), 1.06 (s, 9H), 0.85 (s, 9H), 0.36 (s, 3H), 0.33 (s, 3H), 0.00 (s, 3H), −0.20 (s, 3H) ppm
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[N:15][CH:16]=[C:11]([F:10])[CH:12]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1cc(Br)ccc1I
Product: Cc1cc(Br)ccc1-c1cncc(F)c1

Procedure:
The title compound was prepared from 5-bromo-2-iodotoluene and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 265.8 and 267.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH:10]([C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[OH:11])[CH2:9][CH2:8]2)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+]>C(Cl)Cl.CO>[OH:11][CH:10]([C:7]1([C:2](=[O:3])[CH3:1])[CH2:9][CH2:8]1)[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC1(C2(C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)C1(C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
3.2 g of 98 in 50 ml of methylene chloride/methanol 1:1 is dissolved, and 750 mg of p-toluenesulfonic acid is added. It is stirred under argon for 2 hours at room temperature. Sodium chloride solution is added, extracted with methylene chloride, the organic phase is washed with sodium bicarbonate solution and sodium chloride-solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 2.7 g of 1-[1-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)cyclopropyl]ethanone 99 is obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:33][CH2:34][CH3:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCBr
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(OCCC)cc12
Yield: 87.8 %

Procedure:
A solution of tert-butyl(4-butoxy-6-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.52 g, 1.2 mmol), 1-bromopropane (0.16 ml, 1.2 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-2-neopentyl-1-oxo-6-propoxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.50 g, 89.3%) as an amorphous.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:14]=[C:15]([C:25]([F:28])([F:27])[F:26])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:5]([O:4][C:2]([N:22]1[CH2:23][CH2:24][N:19]([C:16]2[C:15]([C:25]([F:28])([F:26])[F:27])=[CH:14][C:13]([Br:12])=[CH:18][N:17]=2)[CH2:20][CH2:21]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1cc(Br)cnc1N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 0 °C

Procedure:
Benzyl chloroformate (806 μL, 5.7 mmol, Aldrich) was added dropwise to a mixture of 1-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine (1.6 g, 5.2 mmol, Example 112a) and diisopropylethylamine (1.1 mL, 6.24 mmol, Aldrich) in dichloromethane (35 mL) with stirring at 0° C. The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (2%-100% EtOAc/hexane) to give the title compound as an orange oil. MS (ESI, positive ion) m/z: 444 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Product: CN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 51 %

Procedure:
Using the procedure of Example 2, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 1-methyl-piperazine were reacted to obtain a 51% yield of 5,11-dihydro-11-[3-(4-methyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 232°-233° C. after crystallization from an ethyl acetate-ethanol mixture. The dihydrochloride thereof melted at 235° C. after crystallization from ethanol.
Reaction SMILES: [N:1]1([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[N:1]1([CH:5]([C:7]2[N:8]=[C:9]([NH:14][C:15]3[S:16][C:17]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][C:19]=3[C:20]([NH2:22])=[O:21])[CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(c1cccc(Br)n1)N1CCC1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Product: CC(c1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)N1CCC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(1-azetidin-1-ylethyl)-6-bromopyridine (200 mg, 0.83 mmol) and 2-amino-5-(4-fluorophenyl)thiophene-3-carboxamide (216 mg, 0.91 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>C1COCC1>[Cl:30][CH2:31][CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])=[O:35]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCl)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-chlorobutryl chloride (21.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (58.8 mg, 84%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OC(=O)[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=1)(C)C>C(#N)C.Cl.O>[ClH:30].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: NCCCNc1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Br
Yield: 74.3 %

Procedure:
To a solution of 4-aminobenzenesulfonamide (190 mg) in acetonitrile (20 mL), hydrochloric acid solution (4M in dioxane, 0.3 mL) and water (0.3 mL) was added (3-((5-bromo-2-chloro-4-pyrimidinyl)amino)propyl)-carbamic acid-1,1-dimethylethyl ester (360 mg). The resulting mixture was refluxed overnight. The precipitate was collected and washed with acetonitrile and methanol to afford the title compound (320 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH:17]=[N:18]O)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C(O)(=O)C>[Pd]>[NH2:18][CH2:17][CH2:16][CH2:15][C:11]1[N:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCC=NO)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(CCCN)n1
Reaction time: 18 h

Procedure:
To a solution of (tert-butoxy)-N-[6-(3-(hydroxyimino)propyl)(2-pyridyl)]carboxamide in ethanol/acetic acid (4 eq/1 eq, 0.1M) under nitrogen was added 5% palladium on carbon. The reaction was stirred under hydrogen at 60 psi for 18 hr. The reaction was filtered thru celite and concentrated in vacuo to yield the product. EI-MS m/z 252(M+H)+
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C.CN(C)C=O>[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]4)[CH2:19][CH2:20]2)=[CH:36][CH:35]=1
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCC(Oc3ccc4c(=O)[nH]ccc4c3)CC2)cc1
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (100 mg, 3.9 mol eq) was added to a solution of 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol), acetic acid (2 drops) and 4-methylbenzaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (700 μl) and shaken for 17 hours. The reaction was quenched with water and methanol and the product semi-purified using an SCX cartridge. The product was further purified by prep-HPLC to afford 6-[1-(4-Methylbenzyl)piperidin4-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=349.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13](I)[CH3:14]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH3:14]
Reactant: CCI
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Product: CCOc1ccc(C(F)(F)F)cc1Br

Procedure:
Starting from commercially available 2-bromo-4-trifluoromethyl-phenol and ethyliodide the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:2]1([C:10]2[CH:9]=[CH:8][C:7]([Br:6])=[CH:12][N:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc(N2CCC2)nc1
Temperature: 95 °C
Yield: 85.7 %

Procedure:
A mixture of azetidine HCl salt (590 mg, 6.3 mmol), 5-bromo-2-fluoropyridine (1.11 g, 6.3 mmol), Cs2CO3 (4.1 g, 12.6 mmol) and dry DMSO (7 mL) was stirred and heated at 95° C. for 20 h. The reaction mixture was cooled and filtered. The solid was treated with H2O, extracted with CH2Cl2×3. The combined organic layers were dried, filtered to provide 1.15 grams (86%) of desired product as a light yellow solid. MS (M+H)=213.0/215.0. 1H NMR (CDCl3) δ 8.18 (d, 1H), 7.50 (dd, 1H), 6.18 (d, 1H), 4.03 (t, 4H), 2.40 (q, 2H).