Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2[N:6]=[N:7][CH:8]=[CH:9][C:4]=2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1>CCO.[Pd]>[NH:14]1[CH2:15][CH2:16][CH:11]([N:3]2[C:4]3[CH:9]=[CH:8][N:7]=[N:6][C:5]=3[NH:10][C:2]2=[O:1])[CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3nnccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH]c2nnccc2n1C1CCNCC1
Yield: 119.8 %

Procedure:
A solution of benzyl 4-(6-oxo-6,7-dihydro-5H-imidazo[4,5-c]pyridazin-5-yl)piperidine-1-carboxylate (35 mg, 0.099 mmol) and 10% Pd/C (50 mg) in EtOH (5 mL), was hydrogenated under a balloon overnight. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (26 mg). MS 220.2 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[C:11]([C:18]([OH:20])=O)[N:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:42]12([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH2:43]1)[CH2:49]2>CN(C=O)C.C(OCC)(=O)C>[C:42]12([NH:52][C:18]([C:11]3[N:10]=[C:9]([CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=34)=[O:20])[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:45][CH:44]([CH2:50]3)[CH2:43]1)[CH2:51]2
Reactant: O=C(O)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1nc(CCN2CCOCC2)n2ccccc12
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a solution of 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carboxylic acid (150 mg, 0.54 mmol) in DMF (5 mL) was added EDC (161 mg, 0.84 mmol), HOBt, (90 mg, 0.67 mmol) and Et3N (0.23 mL, 1.68 mmol). The mixture was allowed to stir for 10 min. and adamantylamine (93 mg, 0.62 mmol) was added. The mixture was stirred for 15 h. then diluted with ethyl acetate (30 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (195 mg, 89%). 1H NMR (DMSO-d6) δ 8.32 (1H), 8.02 (1H), 7.05 (1H), 6.93 (1H), 6.82 (1H), 3.56 (4H), 3.16 (2H), 2.73 (2H), 2.46 (4H), 2.07 (9H), 1.67 (6H); m/z (M+H)=409.18.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:26])[C@H:10]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:11]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[C:1]1([CH2:7][O:8][C:9](=[O:26])[C@H:10]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 35.3 g (94.5 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine phenylmethyl ester in 100 mL of dichloromethane at 17° C. is added 100 mL of trifluoroacetic acid over 15 minutes during which time the reaction mixture temperature rises to 21° C. The reaction mixture is stirred overnight, then is concentrated in vacuo. The residue is azeotroped with dichloromethane, toluene and methyl tert-butyl ether. The resulting oil is subjected to high vacuum to afford 3-cyclohexyl-(L)-alanine phenylmethyl ester trifluoroacetate (32.6 g). MS (ion spray) m/z 262 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([NH:7][CH2:8][C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:39]([S:36]([N:33]1[CH2:32][CH2:31][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:12]4[S:13][C:9]([CH2:8][NH:7][C@@H:2]([CH3:1])[C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:10][CH:11]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:35][CH2:34]1)(=[O:38])=[O:37])[CH3:40]
Reactant: C[C@H](NCc1ccc(B(O)O)s1)C(C)(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN[C@@H](C)C(C)(C)C)s4)cc23)CC1
Yield: 12 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1S)-1,2,2-trimethylpropyl]amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 10.3 mg of the title compound (12%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (Example 1; 1.0 g, 0.00304 mol) and 5-formyl-2-furanylboronic acid (0.384 g, 0.00274 mol), sodium carbonate (0.806 g, 0.0076 mol), toluene (15 mL), EtOH (15 mL) and water (5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.105 g, 0.000152 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 2.5 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 75% ethyl acetate in hexane) to yield the desired product [0.65 g, 62%]. 1H NMR (300 MHz, CDCl3): δ 9.73 (s, 1H), 8.20 (s, 1H), 7.90 (s, 2H), 7.38 (d, J=3.6 Hz, 1H), 7.06 (d, J=3.6 Hz, 1H), 3.91 (s, 4H), 3.90 (s, 4H). LC-MS (ESI): Calculated mass: 343.0; Observed mass: 344.3 (RT: 1.21 min).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.[N:20]1([CH2:26][CH2:27][N:28]2[C:32]3[CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:31]=3[NH:30][C:29]2=[O:46])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:35]3[CH:34]=[CH:33][C:32]4[N:28]([CH2:27][CH2:26][N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:29](=[O:46])[NH:30][C:31]=4[CH:36]=3)[C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c(=O)n3CCN2CCOCC2)OC1(C)C
Reactant: Fc1ccc2c(c1)COc1cc(F)ccc1C2=CBr
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: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccc(F)cc4COc4cc(F)ccc43)ccc2n1CCN1CCOCC1
Yield: 76.6 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,8-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 40 mg, 0.12 mmol), 1-(2-morpholin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (44 mg, 0.12 mmol), Na2CO3 (2M in water, 155 μL, 0.310 mmol), dioxane (1 mL), and Pd(PPh3)4 (7 mg, 0.006 mmol). Purify on silica gel (12 g), eluting with 2% to 5% (2M NH3/MeOH)/CH2Cl2 to afford 45 mg (78%) of the title compound as a white foam. HPLC (ISO80-10) t=1.86 min, 99%; MS [ES] 488 (M−H), 490 (M+H); 1H-NMR (DMSO-d6) δ 10.70 (s, 1H), 7.59 (dd, 1H, J=8.5, 7.1 Hz), 7.51 (dd, 1H, J=8.8, 2.6 Hz), 7.08 (td, 1H, J12.5, 4.3 Hz), 7.01 (m, 2H), 6.96 (d, 1H, J=7.9 Hz), 6.80 (td, 1H, J=12.0, 4.2 Hz), 6.73 (d, 1H, J=7.9 Hz), 6.62 (dd, 1H, J=10.3, 2.4 Hz), 6.58 (s, 1H), 5.72-4.85 (br d, 2H), 3.81 (t, 2H, J=6.4 Hz), 3.47 (t, 4H, J=4.4 Hz), 2.48 (m, 2H), 2.38 (s, 4H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>ClCCl.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution (3R)-6-cyclohexyl-3-(3-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 82) (450 mg, 0.72 mmol) and N-methylmorpholine (284 μl, 2.53 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (112 μl, 0.87 mmol) and stirred under an argon atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (355 μl, 2.90 mmol) was added and the mixture was stirred for 3.5 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (2.5 ml) and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (20 ml), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of 97:3:0.3 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a gum (123 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8]Cl)(=[O:3])[CH3:2].[CH:11]([O-:13])=[O:12].[Na+].O>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:11]([O:13][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:12]
Reactant: CC(=O)OCC=C(C)CCl
Reactant: O=C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)COC=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Acetoxy-2-methyl-1-chloro-2-butene (8.13 g, 50 mmol) was dissolved in dimethylformamide (25 ml) and placed in a 100 ml four neck flask. To this were added sodium formate powder (6.80 g, 100 mmol, 2 equivalents) and tetra n-butylammonium bromide (0.81 g, 2.5 mmol, 5 mol %). The mixture was stirred at 40° C. for 24 hours under heating. After completion of the reaction, the reaction mixture was poured into ice-cooled water (about 30 ml) and extracted with ether (50 ml) three times. The extracted ether layer was dried over anhydrous sodium sulfate. Evaporation of the ether followed by purification by silica gel column chromatography (ethyl acetate-hexane (=1:3)) gave 4-acetoxy-2-methyl-2-buten-1-ol formate (8.18 g, 47.5 mmol; Yield: 95.0%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][CH:12]([CH3:23])[CH2:13][C:14]1([C:20]([CH3:22])=[CH2:21])[CH2:18][CH2:17][NH:16][C:15]1=[O:19].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH3:11][CH:12]([CH3:23])[CH2:13][C:14]1([C:20]([CH3:22])=[CH2:21])[CH2:18][CH2:17][N:16]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]1=[O:19]
Reactant: CCOC(=O)CBr
Reactant: C=C(C)C1(CC(C)C)CCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C1(CC(C)C)CCN(CC(=O)OCC)C1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 91 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide (0.5M in toluene, 16.4 mL, 8.19 mmol) is cooled to 0° C., and a solution of 3-(2-methylpropyl)-3-(propen-2-yl)-2-pyrrolidinone (1.24 g, 6.82 mmol) in THF (10 mL) is added dropwise over 2 minutes After stirring at 0° C. for 40 minutes, ethyl bromoacetate (0.91 mL, 8.2 mmol) is added. The reaction is stirred at 0° C. for 3 hours and for 1 hour at room temperature. After quenching with saturated aqueous ammonium chloride (10 mL), aqueous workup (EtOAc, MgSO4) and purification by column chromatography (1:9:10 v/v CH2Cl2 :EtOAc:hexane) provided 1.66 g (91%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([NH:30][C:31]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[NH:7][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:5]4)[CH2:17][CH2:16]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Product: O=C(Nc1ccccc1)N1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
(5-Chloro-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine prepared in Example 93 and phenylisocyanate were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][S:12][CH3:13])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:14]1([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)O)[CH2:16][CH2:15]1.ClC1C=C(F)C=CC=1C(C1CC1)C1C2C(=C(CSC)C(F)=CC=2)NC=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]([CH:14]2[CH2:15][CH2:16]2)[C:6]2[C:5]3[C:9](=[C:10]([CH2:11][S:12][CH3:13])[C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)=[CH:20][CH:21]=1
Reactant: CSCc1c(F)ccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1
Agent: CSCc1c(F)ccc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12
Product: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 9A and 468 mg (2.56 mmol) of the compound from Example 153A in analogy to the synthesis of the compound from Example 233. 411 mg (44% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:25][CH2:26][CH3:27])[C@@H:5]1[CH2:9][CH:8]([F:10])[CH2:7][N:6]1C(=O)C1C=C(OC)C(O)=CC=1[N+]([O-])=O)[CH3:2].BrCCCBr.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CCCCCC>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:25][CH2:26][CH3:27])[CH:5]1[CH2:9][CH:8]([F:10])[CH2:7][NH:6]1)[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CC(F)CN1C(=O)c1cc(OC)c(O)cc1[N+](=O)[O-]
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(SCC)C1CC(F)CN1

Procedure:
A solution of (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)-4-fluoro pyrrolidine 2-carboxaldehyde diethylthioacetal VI (418 mg, 1 mmol), 1,3-dibromopropane (101 mg, 0.5 mmol) and K2CO3 (414 mg, 3 mmol) in dry acetone (40 ml) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc-hexane (7:3), the reaction mixture was poured on to the water and then extracted with ethylacetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1) to give the pure 1,1′-{[(Propane-1,3 diyl)dioxy]bis[2-nitro-5-methoxy-1,4-phenylene)carbonyl]}bis[4-fluoro pyrrolidine-2-carboxaldehyde diethylthioacetal] VII. H1 NMR (CDCl3, 200 MHz): δ 1.2–1.39 (m, 12H), 2.4–2.68 (m, 6H), 2.7–2.9 (m, 8H), 3.41–3.62 (m, 4H), 3.99 (s, 6H), 4.29–4.4 (m, 4H), 4.52 (d, j=3.9 Hz, 2H), 4.69–4.79 (m, 2H), 5.05 (t, 1H), 6.85 (s, 2H), 7.63 (s, 2H). FAB MASS: 877 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=O)CC(C3C=CC(F)=CC=3[C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)CC=2N=1.N1C=CC=CC=1B(O)O>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:40]3[CH:39]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Agent: OB(O)c1ccccn1
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccn1)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 4/a stage 1) using 2-pyridyl boronic acid instead of 3-pyridyl boronic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Cl.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][CH:13]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1C=CC=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:1]2([CH2:18][C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]2=[O:10])=[CH:14][CH:13]=1
Reactant: ClCc1ccncc1
Reactant: O=C1Cc2ccccc2C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1Cc2ccccc2C1(Cc1ccncc1)Cc1ccncc1

Procedure:
To stirred mixture of 2-indanone (2.64 g, 0.02 mol), 4-picolyl chloride hydrochloride (7.22 g, 0.044 mol), and benzyltriethylammonium chloride (0.45 g, 0.002 mol) in 100 ml of benzene was added 1N sodium hydroxide (84 ml, 0.084 mol) dropwise over a period of 30 min. The mixture was stirred for an additional 2.5 h. at room temperature, then heated to 60° and maintained at this temperature for 1 h. Thin layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was cooled, the organic layer was separated, and diluted with an additional 80 ml of benzene. The benzene solution was extracted with 100 ml of 1N HCl. The acidic layer was basified with 10% sodium hydroxide, wherein the crude product separated as a gum. The crude material was crystallized from cyclohexane, and further purified by recrystallization from cyclohexane to give 1,1-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indene-2-one as a white solid, 0.300 g, m.p. 95°-96°. NMR (200 MHz, CDCl3) δ 2.66 (s, 2H); 3.07-3.34 (d, 4H); 6.73 (d, 4H); 6.82-7.47 (m, 4H). IR (nujol) 1714 cm-1. Analysis. Calcd. for C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.47; H, 5.76; N, 8.89.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])C=1.[CH:27](N(C(C)C)CC)(C)C.CC(N)C>C(#N)C>[CH:6]([NH:5][C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=1)=[O:9])([CH3:27])[CH3:7]
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Solvent: CC#N
Solvent: CC(C)N
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)NC(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.1 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (22 μL, 0.13 mmol) dissolved in acetonitrile (0.6 mL). Then to the solution was added propan-2-amine (6 mg, 0.11 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[F:17][C:18]([F:23])([F:22])[C:19](O)=O>Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:19]([C:18]([F:23])([F:22])[F:17])=[N:16][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1N
Agent: Cl
Product: Fc1ccc(-c2cc3[nH]c(C(F)(F)F)nc3cc2Cl)cc1
Yield: 38 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5 g, 16.75 mmol) in dioxane (200 ml) was added (4-fluorophenyl)boronic acid (4.7 g, 33.59 mmol), water (20 ml), K3PO4 (7 g, 32.98 mmol), Pd(PPh3)4 (924 mg, 0.80 mmol) with an inert atmosphere of nitrogen. The resulting solution was stirred for 8 h at 95° C. and then concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 20% ethyl acetate in petroleum ether to produce 5-chloro-4-(4-fluorophenyl)-2-nitroaniline as a yellow solid (4.1 g, 91%). Next, a solution of 5-chloro-4-(4-fluorophenyl)-2-nitroaniline (4.1 g, 15.38 mmol) in ethanol (100 ml) was added to hydrogen chloride (4 ml, 48 mmol, conc) and Zn (6 g, 460 mmol) at room temperature. The resulting solution was stirred for 3 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (200 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with dichloromethane (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine as a brown oil (2.5 g, 70%). Finally, a solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (100 mg, 0.42 mmol) in hydrogen chloride (1 ml) and trifluoroacetic acid (5 ml) was stirred overnight at 80° C. The reaction was quenched by the addition of water (50 ml) and the pH value of the solution adjusted to 7 with aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (50.7 mg, 38%).