Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CS(C)=O>[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])=[CH:35][CH:34]=1
Reactant: Cc1ccc(O)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OCCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40 mg, 0.087 mmol) in DMSO (1.0 mL), were added 4-methylphenol (108 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg). The reaction solution was heated to 80° C. overnight. After which time the reaction mixture was filtered and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (6.3 mg, 14%).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.C([N:21]([CH2:34][CH3:35])[C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]C)[C:24]=1[CH2:31]C)C.[CH2:36]([N:43]1[CH2:47]C[CH:45](C#N)[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([N:43]1[CH2:44][CH2:45][CH:35]([C:34]2[NH:21][C:22](=[O:33])[C:23]3[C:24]([CH:31]=2)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[CH2:47]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCc1cccc(C(=O)N(CC)CC)c1CC
Reactant: N#CC1CCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(C3CCN(Cc4ccccc4)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
A solution (400 mL) of diisopropylamine (26.9 g) in tetrahydrofuran was cooled to −5° C. and 1.57 M n-butyllithium hexane solution (154 ml) was added dropwise to the solution. After stirring at 0° C. for 30 min, the mixture was cooled to −78° C. and a solution (50 mL) of N,N-diethyl-2,3-diethylbenzamide (45.1 g) in tetrahydrofuran was added dropwise. After stirring at −78° C. for 1 hr, a solution (50 mL) of 1-benzyl-3-cyanopyrrolidine (37.18 g) in tetrahydrofuran was added dropwise. After Completion of the dropwise addition, the reaction mixture was heated to room temperature and the mixture was stirred overnight at room temperature. The mixture was further stirred under reflux for 1 hr and the reaction mixture was concentrated to about half. Water and methylene chloride were added and the organic layer was partitioned washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (ethyl acetate) to give (±)-3-(1-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (66.38 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]1)=S)[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].CCN(CC)CC>CN(C=O)C.Cl[Hg]Cl>[CH2:1]([N:3]1[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]2)=[N:17][N:16]=[N:15]1)[CH3:2]
Reactant: CCNC(=S)N1CCC(CCO)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Hg]Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1nnnc1N1CCC(CCO)CC1
Reaction time: 10 h
Yield: 40.6 %

Procedure:
To a mixture of N-Ethyl-4-(2-hydroxyethyl)piperidine-1-carbothioamide (200 mg, 0.93 mmol), HgCl2 (277 mg, 1.02 mmol), and NaN3 (181 mg, 2.78 mmol) in DMF (2.5 mL) was added NEt3 (388 μL, 2.78 mmol) at rt. After stirring for 10 h, the reaction mixture was filtered, and the filter cake was washed with CH2Cl2. The combined filtrates and washings were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo, and the residue was purified by SiO2 chromatograph (60% EtOAc/hexane) to afford the titled compound (85 mg, 41%): 1H NMR (CDCl3) δ 4.18 (q, J=7.2 Hz, 2H), 3.75 (td, J=6.8, 5.2 Hz, 2H), 3.51 (brd, J=12.4, 2H), 3.03 (td, J=12.4, 2.8 Hz, 2H), 1.84 (brd, J=14.4 Hz, 2H), 1.71 (m, 1H), 1.59 (q, J=6.8 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H), 1.48-1.38 (m, 2H)
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([CH3:29])([C:27]#[CH:28])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[C:21]([OH:20])([CH3:29])[C:27]#[C:28][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(O)C(=O)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CN(C)C(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 13 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-hydroxy-N,N,2-trimethylbut-3-ynamide to give 24.2 mg of the titled compound (13%),
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7]1
Reactant: Brc1nccs1
Reactant: C[C@@H]1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CC1CN(c2nccs2)CCN1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A mixture of 2(R)-methyl piperazine (300 mg, 3 mmol), 2-bromo thiazole (0.27 ml, 3 mmol), (2-biphenylyldi-tert-butylphosphine (134 mg, 0.449 mmol), palladium acetate (101 mg, 0.45 mmol), and cesium carbonate (1.46 g, 4.49 mmol) in dioxane 25 ml (v/v 5/1) was kept at reflux temperature for 2 hours, then cooled to room temperature, then filtered through celite, then concentrated and then purified by chromatography eluting with 12% MeOH/MeCl2/NH4OH to yield the product as a white solid (145 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Br[CH2:18][CH2:19][Cl:20]>CS(C)=O>[Cl:20][CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
A mixture of (3,4-dichlorophenyl)piperazine (500 mg) and powdered sodium hydroxide (87 mg) in DMSO (5 mL) was treated with 2-bromo-1-chloroethane (387 mg) and stirred at ambient temperature for 16 hours. The reaction was poured into ice cold water (15 mL) and stirred for 0.5 hours. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (5 mL). The solid mass was dissolved with dichloromethane (5 mL) and the combined organics were dried with sodium sulfate, filtered and the solvent removed under vacuum. Flash chromatography (dichloromethane:methanol 1:0 to 10:1) yielded an oil (230 mg) as the titled compound.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][NH:22]3)=[CH:18][CH:17]=2)=[O:15])=[CH:9][C:8]=1[C:25]([F:28])([F:27])[F:26])#[N:6].[OH-].[NH4+]>C(O)(=O)C.O.ClCCl>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][NH:22]3)=[CH:18][CH:17]=2)=[O:15])=[CH:9][C:8]=1[C:25]([F:28])([F:26])[F:27])#[N:6]
Reactant: N#Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Sodium cyanoborohydride (4.6 g, 73.8 mmol, 3 equiv.) was carefully added to a stirred solution of 1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (2.4 g, 7.38 mmol, 1 equiv.) in acetic acid (25 mL) over 5 minutes at room temperature. The reaction mixture was stirred for 30 minutes then cooled down to 0° C. and slowly poured onto concentrated ammonium hydroxide (78 mL, d=0.880) at 0° C. The mixture was diluted with water (25 mL) and dichloromethane (25 mL), the organic layer was separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed under vacuum to afford crude 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 1.8 g (73% yield), this material was taken onto the next step without further purification. LC @215 nm; Rt 1.13: 80%, m/z (ES+): 372 (M+H+MeCN).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][CH:13]=2)[C:10]=1[Cl:11])=[O:5])C.[CH2:23]([NH2:25])[CH3:24]>O1CCCC1.O>[CH2:23]([NH:25][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:16][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][CH:13]=2)[C:10]=1[Cl:11])=[O:5])[CH3:24]
Reactant: CCOC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1Cl
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To 15 mg (0.045 mmol) of the above-prepared 4-chloro-5-(2-phenyl-thiazol-5-yl)-2H-pyrazole-3-carboxylic acid ethyl ester was added 45 mg (1.0 mmol) of 2M ethylamine in tetrahydrofuran followed by the addition of 2 drops of water. The mixture was heated to 60° C. in a sealed tube and allowed to stir overnight. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 2:5 ethyl acetate:hexanes as eluant to give 5 mg of the title compound (33%). 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H) 8.00 (d, 2H) 7.47 (m, 3H) 6.78 (m, 1H) 3.58 (m, 2H) 1.32 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[NH2:8][C:6]1[CH:5]=[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: CC(=O)N(C)c1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
4.5 g (0.0165 mol) of N-(3-bromo-5-nitrophenyl)-N-methylacetamide were dissolved in 75 ml of ethanol, treated while cooling with a solution of 15.0 g (0.0665 mol) of SnCl2.2H2O in 30 ml of HCl (37%) and stirred at room temperature for 18 hrs. Then, the solvent was removed, the residue was adjusted to pH 8 with sat. NaHCO3 solution, extracted with ethyl acetate and sat. sodium chloride solution and the organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:2, 1:1 and finally 2:1. There were obtained 2.35 g (59%) of N-(3-amino-5-bromophenyl)-N-methylacetamide as light brown crystals. MS (EI): me/e=244,242 (C9H11BrN2O+).
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: COc1ccc2c(c1)CCC(I)C(=O)N2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(N=[N+]=[N-])C(=O)N2
Reaction time: 2 h
Yield: 85.1 %

Procedure:
3-Iodo-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4.074 g, 12.85 mmol) and sodium azide (4.178 g, 64.3 mmol, 5 eq.) were dissolved in 50 mL of dimethylformamide and heated with stirring at 60° for 2 hours. The solvent was evaporated under vacuum at room temperature and the residue redissolved in 150 mL of ethyl acetate and washed with water (3×50 mL) and brine (1×50 mL). The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness under vacuum to yield 2.538 g (10.94 mmol, 85%) of product. 1H NMR (200 MHz, CDCl3): 2.2-2.7 (m,3H), 2.90 (m,1H), 3.75 (s,3H), 3.80 (m,1H), 6.75 (m,2H), 6.95 (d,8 Hz, 2H), 8.22 (br s,1H). FAB-MS: calculated for C11H12N4O2 232; found 233 (M+H,30%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([CH:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[NH:4][C:5](=[O:8])[NH:6][N:7]=2)[CH2:24][CH2:25]1)=[O:19]
Reactant: O=C(Cc1ccccc1F)C1CCNCC1
Reactant: O=c1[nH]nc(CCl)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1ccccc1F)C1CCN(Cc2n[nH]c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
After adding 150 mg of 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one, 335 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride and 180 mg of anhydrous potassium carbonate to acetonitrile, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (23 mg, 7% yield).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C@@H:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>CN(C=O)C>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH2:15][O:14][CH2:13][C@@H:12]([NH:11][CH2:2][C:3]#[N:4])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=1
Reactant: N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 1.5 h

Procedure:
Bromoacetonitrile (570 μl) was stirred in a 0.5M solution of anhydrous DMF (15ml) at 60° C. with potassium carbonate (2.07g) for 5 minutes before (S)-2-amino-1-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylethane (2.7g, Example 2b, liberated from the salt by extraction into ethyl acetate from aqueous Na2CO3 solution) was added. After 1.5 hours, the solution was cooled and the reaction quenched with water (100ml) and diluted with Ethyl acetate (60ml). The mixture was separated and the aqueous layer further extracted with ethyl acetate (4×30ml). The combined organic extracts were washed with brine (1×30ml), dried (MgSO4) and evaporated to a dark oil (4.1g). The crude oil was purified by flash silica gel chromatography in Ethyl acetate/hexane (1:1) to yield (S)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-cyanomethylamino-2-phenylethane as a viscous oil 2.5g. 1H NMR (250MHz, CDCl3) δ 7.82 (1H, s, Ar), 7.79 (2H, s, ArH), 7.36 (5H, m, Ph), 4.67 (2H, s, OCH2Ar), 4.27 (1H, t, J=6.5Hz, PhCHN), 3.68 (1H, d, J=17Hz) and 3.31 (1H, d, J=17Hz, CH2CN). m/z (CI+) 403 (M+1, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:12]2[C:13](=[O:19])[NH:14][C:15]3=[CH:16][CH:17]=[CH:18][C:10](=[C:11]23)[O:9][CH2:8]1.Cl.O>CO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[N:12]2[C:13](=[O:19])[NH:14][C:15]3=[CH:16][CH:17]=[CH:18][C:10](=[C:11]23)[O:9][CH2:8]1
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccn1)CO3
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]c2cccc3c2n1C(C1CCCCN1)CO3
Reaction time: 144 h
Yield: 82.6 %

Procedure:
The tricycle intermediate, 4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.25 g, 0.98 mmol) from Example 13, was partially dissolved in methanol (50.0 mL) and 12.0 M hydrogen chloride in water (1.0 mL, 12 mmol) in a Parr bottle. The reaction was degassed with nitrogen, followed by addition of palladium (10% on carbon), and the reaction was charged to 55 PSI hydrogen and shaken for 6 days. The reaction was filtered to remove the catalyst and concentrated in vacuo to give 4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a dark oil (0.21 g, 82%). LCMS calculated for C14H18N3O2 (M+H)+: m/z=260.1. found: 260.1.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][OH:12])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]=O>FC(F)(F)C(O)=O>[OH:12][CH2:11][CH2:10][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][O:9][CH2:8]1
Reactant: C=O
Reactant: OCCC(CO)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: OCCC1(c2ccccc2)COCc2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In trifluoroacetic acid (50 ml) was dissolved 2,2-diphenyl-1,4-butanediol (5 g) followed by addition of paraformaldehyde (1.7 g) and the mixture was heated and stirred at 50° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) followed by addition of sodium hydroxide (4 g) and water (50 ml) and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using isopropyl ether/ethyl acetate as the eluent to provide 4-(2-hydroxyethyl)-4-phenylisochroman (4.5 g).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:13][C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:19]([NH2:21])=[O:20])=[C:9]([F:10])[C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(F)c(F)c1F
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1ccc(C#N)c(F)c1F)C(N)=O
Temperature: 25 °C
Reaction time: 68 h
Yield: 25.2 %

Procedure:
To 2,3,4-trifluorobenzonitrile (265 mg, 1.68 mmol) in a flask, a solution of D-leucine amide hydrochloride (282 mg, 1.68 mmol) and DIEA (0.880 mL, 5.06 mmol) in DMSO (5 mL) was added. After being stirred at room temperature for 68 h, water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 0-70% EtOAc in hexane to give (R)-2-(4-cyano-2,3-difluorophenylamino)-4-methylpentanamide (113 mg).
Reaction SMILES: N=C=N.[CH3:4][O:5][C:6]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]([C:15]([NH2:17])=[O:16])=[CH:8][CH:7]=1.O.N1(O)C2C=CC=CC=2N=N1.[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([F:37])[CH:31]=1.C([NH+](CC)CC)C.C(=O)([O-])[O-]>CN(C)C=O>[Br:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:12](=[O:14])[C:11]2[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=2[O:5][CH3:4])[C:15]([NH2:17])=[O:16])=[C:32]([F:37])[CH:31]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Agent: CC[NH+](CC)CC
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To 202 mg (1.24 mmols/g) of N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), there were added 0.5 mL (0.25 mol) of an N,N-dimethylformamide solution of 6-methoxyisophthalamic acid prepared in step B, 0.75 mL (0.25M) of an N,N-dimethylformamide solution of benzotriazol-1-ol monohydrate, and 20 mg of 4-bromo-2-fluoroaniline. This mixture was agitated for 16 hours at room temperature, and then agitated for 24 hours at 60° C. To the mixture, 213 mg (2.64 mmols/g) of macroporous triethylammonium methylpolystyrene carbonate (MP-carbonate) and 0.5 mL of N,N-dimethylformamide were added, followed by agitating the mixture for 12 hours at room temperature. The polystyrene solid phase-carried reagent was separated by filtration, and washed with N,N-dimethylformamide, tetrahydrofuran, and dichloromethane in this order. Then, the filtrate and the washings were combined, and concentrated. The resulting residue was purified using a micromass spectrometer (ZMD produced by Micromass) equipped with a gradient high-performance liquid chromatograph 996-600E produced by Waters, thereby obtaining 9 mg (22%) of 3-N-(4-bromo-2-fluorophenyl)-4-methoxyisophthalamide.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]3=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH2:7][CH2:6]1
Reactant: O=c1ccccn1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(n2ccccc2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(1,4-dioxaspiro[4.5]decan-8-yl)pyridin-2(1H)-one (150 mg, 0.64 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
22.4 g (160 mmol) of 4-fluoro-benzeneboronic acid, 34 g (153.5 mmol) of 2,5-dibromopyridine and 1.24 g of tetrakis(triphenylphosphine)palladium were dissolved in 240 ml of ethanol and 480 ml of toluene. 480 ml of a 2 N sodium carbonate solution were added and the resulting mixture was heated to 50° C. with stirring for 2 h. After addition of 400 ml of ethyl acetate the mixture was filtered, the phases were separated and the organic phase was washed with a saturated sodium chloride solution, dried and evaporated. The obtained product was purified by column chromatography (silica gel, dichloromethane/heptane 1:1) and preparative HPLC (RP 18). Yield: 12 g.