Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[CH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:7][C:6]=2[CH:32]=1.CCCCCC.C([Li])CCC.[C:44](=[O:46])=[O:45]>C1COCC1>[C:44]([C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[CH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:7][C:6]=2[CH:32]=1)([OH:46])=[O:45]
Reactant: O=C=O
Reactant: Clc1ccc(C2CCN(CCC=C3Cc4cc(Br)ccc4Oc4ncccc43)CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine (Example 160) (130 mg) in THF (1.0 ml) was added 1.6M n-butyllithium hexane solution (0.17 ml) at −78° C. After stirring 10 minutes at the same temperature, CO2 (dry-ice) was added to the mixture. After being warmed to ambient temperature, the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluted with dichloromethane-methanol (5:1) to give the titled compound
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Brc1ccc2[nH]cnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A mixture of 78 (4.5 g, 23 mmol), 3,4-dihydro-2H-pyran (9 mL, 0.1 mol), p-TsOH.H2O (1.0 g, 3.4 mmol) in THF (200 mL) was stirred under nitrogen at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (100:1) to afford 6.0 g (100%) of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (80) as yellow oil: MS (ESI) m/z=281.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[CH:7]=1.[Cl:26]N1C(=O)CCC1=O>CC(O)=O>[Cl:26][C:7]1[C:8](=[O:20])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Solvent: CC(=O)O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g, 0.4 mmol) in AcOH (3 mL) was added N-chlorosuccinimide (70 mg, 0.5 mmol), and the reaction mixture was heated at reflux for 10 min. The reaction mixture was cooled room temperature and the solvent was removed under reduced pressure. 1H NMR (300, MHz, CDCl3) δ 7.60-7.50 (m, 1H), 7.45-7.20 (m, 2H), 7.10-6.80 (m, 5H), 6.16 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.15 (s, 2H). ESHRMS m/z 380.0641 (M+H C19H14ClF3NO2 requires 480.0660).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[I:13](O)(=O)=O.II>C(O)C>[I:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [O-][I+2]([O-])O
Reactant: COc1cc(OC)cc(OC)c1
Agent: II
Solvent: CCO
Product: COc1cc(OC)c(I)c(OC)c1
Temperature: 50 °C
Yield: 171.6 %

Procedure:
1,3,5-Trimethoxybenzene (14.5 g, 0.086 mol) was dissolved in 10 mL of ethanol at rt before warming to 50° C. in a waterbath after which, an aqueous solution of iodic acid (7.6 g, 0.043 mol) was added. Solid iodine (21.88 g, 0.086 mol) was dissolved in 20 mL of ethanol and the resultant solution was added portion-wise over 60 min to the reaction mixture. Stirring was continued at 50° C. until the color of I faded and a white precipitate appeared. The reaction mixture2 was stirred at room temperature for 18 h. The precipitate that formed was isolated via vacuum filtration, washed with ethanol and crystallized from methanol to yield 6 (21.7 g, 86%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:29]([C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)(=[O:31])=[O:30])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3cccc4ccccc34)c3c(F)cc(F)cc23)CC1

Procedure:
(9.2 mg, 52%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 1-naphthalenesulfonyl chloride (13.6 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].P(Br)(Br)([Br:17])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Br:17][C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([N:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=P(Br)(Br)Br
Reactant: CCn1c(=O)c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCn1c(=O)c(Br)nc2ccccc21
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To 2 g (10.5 mM) of 1-ethyl-1,4-dihydroquinoxaline-2,3-dione in 20 ml of dichloroethane were added dropwise 3.16 g (11.0 mM) of POBr3. The reaction mixture was refluxed under stirring for 2 h and then treated with ice cold and an aqueous sodium carbonate solution. The mixture was filtered and the filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated to give 1,4 g of 3-bromo-1-ethyl-quinoxalin-2(1H)-one as a yellow solid. Yield: 53%.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8](OC2C=CC=CC=2)=[CH:7][CH:6]=1)[OH:4].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:40](=[O:43])([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:43][C:40]2[CH:19]=[CH:18][CH:2]=[CH:3][CH:5]=2)[CH:10]=1)[CH:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (472 mg, 88%).
Reaction SMILES: [CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc(N(CC)C2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.45 g, 0.76 mmol) and 1-methylpiperidin-4-one (0.173 g, 1.53 mmol) in dichloroethane (10 mL), acetic acid (0.276 g, 4.6 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.488 g, 2.3 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by column chromatography to afford the title compound (0.215 g, 41%).
Reaction SMILES: C[NH+]1CCOCC1.[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=2)[C:12]([C:26]#[N:27])=[C:11]([SH:28])[N:10]=1.Br[CH2:30][C:31]([NH2:33])=[O:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[C:12]([C:26]#[N:27])=[C:11]([S:28][CH2:30][C:31]([NH2:33])=[O:32])[N:10]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(C(=O)[O-])cc1
Reactant: NC(=O)CBr
Agent: C[NH+]1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCC(N)=O)c(C#N)c1-c1ccc(C(=O)O)cc1

Procedure:
72 mg (0.18 mmol) of 2-[4-(2-amino-3,5-dicyano-6-sulfanyl-4-pyridinyl)benzoic acid N-methylmorpholinium salt together with 59.2 mg (0.27 mmol) of bromoacetamide and 60.9 mg (0.72 mmol) of NaHCO3 are stirred in 0.5 ml of DMF overnight. After filtration, the reaction solution is prepurified by preparative HPLC. The isolated fraction is reconcentrated under reduced pressure and the residue is purified by preparative thin-layer chromatography.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH2:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)(C)CNCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of neopentylamine (8.5 g, 98 mmol) in tetrahydrofuran (75 mL) was slowly added a solution of 1,3-propane sultone (11.5 g, 93 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×50 mL). The solid was suspended in EtOH (150 mL). The suspension was stirred at reflux for 15 minutes. The solid product was collected by filtration, washed with acetone (2×50 mL), and dried in vacuo, to afford compound DL (13.3 g, 69%). 1H NMR (D2O, 500 MHz) δ ppm 3.09 (t, 2H, J=7.3 Hz), 2.89 (t, 2H, J=7.3 Hz), 2.78 (s, 2H), 2.04 (m, 2H), 0.901 (s, 9H). 13C NMR (D2O, 125 MHz) δ ppm 59.44, 48.31, 47.83, 29.91, 26.42, 21.06. ES-MS 208 (M−1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[N+:13]([O-:21])=[N:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[N+:13]([O-:21])=[N:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:30]4[N:29]=[CH:28][C:27]5[O:26][CH2:25][CH2:24][O:23][C:32]=5[CH:31]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: O=c1n[n+]([O-])c2ccc(Cl)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (Intermediate 205, (0.25 g) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (0.14 g) and sodium acetoxyborohydride (0.34 g) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane gave 60 mg of the title compound as acetic acid salt (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]OC1C(Cl)=CC(C=O)=C(F)C=1>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: COc1cc(C=O)c(Cl)cc1O
Reactant: O=Cc1cc(Cl)c(OCc2nc3ccccc3[nH]2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(Cl)cc1OCc1nc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 2.30 g, 0.0123 mol) was dissolved in N,N-dimethylformamide (89.5 mL, 1.16 mol) and sodium hydride (60% dispersion in mineral oil, 541 mg, 0.0135 mol) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole (106, 2.05 g, 0.0123 mol) was added to the reaction. The reaction was stirred at 80° C. overnight. The reaction was concentrated in vacuo to an oil. Ethyl acetate was added and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%). MS (ESI) [M+H+]+=317.1, 319.1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=N[C:3]=1[C:8]([OH:10])=O.[CH3:11]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][C:43]1[N:48]=[C:47]([NH2:49])[CH:46]=[CH:45][CH:44]=1>CN(C)C=O>[CH3:42][C:43]1[N:48]=[C:47]([NH:49][C:8]([C:3]2[CH:11]=[C:5]([CH3:7])[S:6][C:2]=2[Br:1])=[O:10])[CH:46]=[CH:45][CH:44]=1
Reactant: Cc1cccc(N)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(C(=O)O)c(Br)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2cc(C)sc2Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid (prepared as described in example 119, steps A to B) (0.31 g, 1.39 mmol) in dimethylformamide (20.00 ml) was treated with DIPEA (0.27 g, 2.08 mmol), TBTU (0.47 g, 1.46 mmol) and 6-methyl-pyridin-2-ylamine (0.18 g, 1.66 mmol) and stirred at room temperature overnight. The volatiles were removed under vacuum and the residue purified by flash chromatography (heptane/ethyl acetate) to yield 2-bromo-5-methyl-thiophene-3-carboxylic acid (6-methyl-pyridin-2-yl)-amide (0.16 g, 38%) as a light yellow solid, MS (ISP): m/e=314.0, 312.0 (M+H+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[F:11][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,2-difluoro-4-nitro-benzene Compound 132a (1.3 g, 8.2 mmol), K2CO3 (1.2 g, 9.0 mmol) and phenol Compound 132b (0.84 g, 9.0 mmol.) were combined with 10 mL of NMP in a sealed pressure tube. The reaction was heated in a microwave at 140° C. for 50 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO4, then filtered and concentrated down to an oil. The crude oil in ethyl acetate (25 mL) was added to 10% Pd/C (1.3 g) and placed under 40 psi of hydrogen in a Parr apparatus for 1 hr. The solution was then filtered through Celite and concentrated to give 3-fluoro-4-phenoxy-phenylamine Compound 132c (1.9 g). MS 204 (MH+). An alternative procedure for making Compound 132c is described in U.S. Pat. No. 3,652,665. Using the procedure of Example 1, 3-fluoro-4-phenoxy-phenylamine Compound 132c was used in place of Compound 1e to prepare 4-chloro-6-(3-fluoro-4-phenoxy-phenylamino)-pyrimidine-5-carbonitrile Compound 132d. Using the procedure of Example 1, Compound 132d was carried forward in place of 4-chloro-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile Compound 1f to prepare 5-(3-fluoro-4-phenoxy-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 112. MS 423 (MH+). Compound 112 was carried forward in place of Compound 1 and 4-morpholin-4-ylmethyl-phenylamine Compound 3e was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 113. MS 597 (MH+).
Reaction SMILES: C(O[C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9])C=C.O.C(OCC)(=O)C.CN1C[CH2:28][CH2:27][C:26]1=O>>[CH2:28]([C:14]1[C:5]2[O:10][C:8]([CH3:9])=[N:7][C:6]=2[CH:11]=[CH:12][C:13]=1[O:15][CH3:16])[CH:27]=[CH2:26]
Reactant: C=CCOc1cc(OC)ccc1NC(C)=O
Reactant: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(OC)ccc2nc(C)oc12
Temperature: 190 °C

Procedure:
1.04 g of 2′-allyloxy-4′-methoxyacetanilide was dissolved in 20 ml of 1-methyl-2-pyrrolidone. The reaction solution was then stirred while heating at 190° C. under nitrogen atmosphere. Eight hours later, the reaction solution was stood to cool. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, so as to obtain a product (1.01 g). The obtained product was dissolved in 20 ml of acetic acid without purification, and the obtained solution was stirred while heating at 135° C. After completion of the reaction, the reaction solution was stood to cool. Thereafter, the solvent was concentrated under a reduced pressure. 5 N NaOH and ethyl acetate were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 371 mg of the subject compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:13]2[CH2:14][N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[CH2:12]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCCN1CC(Cc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCN1CC(Cc2ccc(Cl)cc2)C1
Reaction time: 1.25 h

Procedure:
A solution of {3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propyl}-carbamic acid tert-butyl ester (0.48 g, 1.43 mmol) in DCM (5 ml) is treated with trifluoroacetic acid (2 ml) and the reaction mixture stirred for 1.25 hours. The solvent is evaporated and the crude product partitioned between 1 M sodium hydroxide solution and 20% isopropanol in DCM. The organic phase is evaporated to afford 3-[3-(4-chloro-benzyl)-azetidin-1-yl]-propylamine. [M+H] 239.13.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.N#N>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([OH:18])[CH2:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Solvent: ClCCl
Product: O=C1CCC(O)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidine-2,5-dione (100 mg, 0.33 mmol) in anhydrous CH2Cl2 (1.5 mL) is cooled down to −78° C. in a dry ice bath. DIBAL-H (0.6 mL, 1 M solution in hexane, 0.66 mmol) is added into the solution dropwise under N2. After the addition, the mixture is stirred at the same temperature for 10 min and quenched by H2O (10 mL). The mixture is warmed up to room temperature and extracted with CH2Cl2 (3×10 mL). The combined organic layer is washed with brine and dried (MgSO4). After filtering the drying agent, the filtrate is concentrated and purified by flash column chromatography (silica gel, EtOAc) to provide the (±)-1-[4-(4-chloro-phenoxy)-phenyl]-5-hydroxy-pyrrolidin-2-one as off white solid (72 mg, 72%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([OH:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:8]1[C:9](=[O:18])[CH:10]2[CH:12]([CH:11]2[C:15]([O:17][CH2:20][CH3:21])=[O:16])[C:13]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1C2C(=O)N(Cc3ccccc3)C(=O)C12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1C2C(=O)N(Cc3ccccc3)C(=O)C12
Yield: 726.3 %

Procedure:
3-Benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1.50 g, 6.13 mmol) was suspended in ethanol (30 ml), followed by adding p-toluenesulfonic acid monohydrate (145 mg, 0.76 mmol), heating the mixture under reflux for 8 hours, adding sodium carbonate to the reaction solution for neutralization, concentrating the mixture under reduced pressure, adding a saturated aqueous sodium bicarbonate to the reaction residue, extracting it with ethyl acetate, washing the extraction solution successively with water and saturated aqueous NaCl solution, drying it over anhydrous magnesium sulfate, concentrating the resulting solution to obtain ethyl 3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (1.51 g, 5.52 mmol, 90%), and recrystallizing it from ethanol to obtain a pure product.