Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([CH3:21])[CH2:18][O:17][C:16]=3[CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C)C=O>[C:33]([C:32]1[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:31]=1[N:20]1[CH:19]([CH3:21])[CH2:18][O:17][C:16]2[CH:22]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2)#[N:34]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(C)N3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(C)N3c2ccc(C(F)(F)F)cc2C#N)cc1
Temperature: 90 °C
Yield: 56 %

Procedure:
To a solution of N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (900 mg, 2.08 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (546 mg, 2.49 mmol, Alfa Aesar) in dimethylformamide (20 mL) was added Cs2CO3 (1.35 g, 4.16 mmol, GLR) and the mixture was heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature and water (200 mL) was added. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-3% methanol in dichloromethane) to obtain 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (700 mg, 56%) as off white solid. 1H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.35 (d, J=3.6 Hz, 1H), 7.30-7.12 (m, 4H), 6.85 (d, J=8.7 Hz, 2H), 6.55 (d, J=8.6 Hz, 1H), 5.02 (s, 2H), 4.23 (m, 2H), 4.19-4.06 (m, 1H), 3.70 (s, 3H), 1.21-1.09 (m, 3H); MS (ESI, positive ion) m/z 601.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][CH3:23]>C(#N)C>[CH3:23][O:22][CH2:21][CH2:20][N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 80 °C

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (190 mg, 1.13 mmol) in acetonitrile (10 mL) was added K2CO3 (311.9 mg, 2.26 mmol) and 1-bromo-2-methoxyethane (188.3 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 17 h under microwave irradiation. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 133a as a white solid (230 mg, 90%), which was used in the next step without further purification. MS-ESI: [M+H]+ 227.0
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]C)=[O:10])=[C:4]([CH3:13])[N:3]=1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[C:4]([CH3:13])[N:3]=1
Reactant: COC(=O)c1c(C)nc(C)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C)c(C(=O)O)c(C)n1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Methyl 2,4,6-trimethylpyrimidine-5-carboxylate (27 g), methanol (27 ml) and water (27 ml) were charged. 25% sodium hydroxide solution (25 ml) was charged and the batch warmed to 50° C. for 90 minutes. The batch was cooled to between −5 and 0° C. and concentrated hydrochloric acid was charged slowly, keeping the temperature within the range of −5 to +5° C. until a pH of 1.5 was reached (22.5 ml conc. HCl used). The batch was agitated for-about 1.5 hours at about 2.7° C. The solid product was recovered by filtration. The batch was dried under vacuum at 40–45° C. The 2,4,6-trimethylpyrimidine-5-carboxylic acid was recrystallized from ethyl acetate. m. p. 163–164° C., 1H NMR (CD3OD): δ2.43 (6H, s, CH3), δ2.52 (3H, s, CH3). 13H CMR (CD3OD): δ170.42, δ168.30, δ166.09, δ126.63, δ25.64, δ22.97. HR-MS; Calculated for C8H11N2O2, m/z=167.0821. Found 167.0816.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[N:28]1([C:32]([C:34]2[N:39]=[CH:38][C:37](Br)=[CH:36][N:35]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:37]2[CH:36]=[N:35][C:34]([C:32]([N:28]3[CH2:31][CH2:30][CH2:29]3)=[O:33])=[N:39][CH:38]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ncc(Br)cn1)N1CCC1
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from azetidin-1-yl-(5-bromo-pyrimidin-2-yl)-methanone (172a) (331 mg, 1.37 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (304 mg, 1.37 mmol) to give a white foam (136 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1 H) 8.53 (s, 2 H) 7.29 (s, 1 H) 4.64 (t, J=7.45 Hz, 2 H) 4.30 (t, J=7.58 Hz, 2 H) 3.88 (s, 3 H) 2.93 (s, 2 H) 2.36 (t, J=7.45 Hz, 2 H) 1.50 (s, 6 H); LCMS for C20H21 N3O5 m/z 384.00 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[O-]CC.[Na+].Cl>C(#N)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]1=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: Clc1nc2ccccc2s1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: N#CC(C#N)=C1Nc2ccccc2S1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.7 %

Procedure:
To a stirred solution of 2-chlorobenzothiazole (1.0 mL, 8.1 mmol) and malononitrile (534 mg; 8.1 mmol) in acetonitrile (4 mL) was added sodium ethoxide (3.0 mL of 21 wt % solution in ethanol, 8.0 mmol). The mixture was stirred at room temperature for 4 d, then acidified with 2M hydrochloric acid. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to give 2-(benzothiazol-2(3H)-ylidene)malononitrile (770 mg) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.O>COCCOC.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>[NH2:12][C:13]1[CH:18]=[C:17]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1ccn2c(Br)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2c(-c3cccc(N)c3)cnc2c1
Yield: 100.8 %

Procedure:
3-Bromo-7-methylimidazo[1,2-α]pyridine (4.2 g, 20.0 mmol) and 3-aminophenylboronic acid (4.0 g, 25.8 mmol) were suspended in 1,2-dimethoxyethane (80 ml) and sodium carbonate (40 ml of a 2M solution) and the resulting solution degassed for 25 minutes. Tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.2 mmol) was added and the mixture heated at reflux for 17 hours. The cooled reaction mixture was poured into water (150 ml), extracted with ethyl acetate (3×70 ml) and the combined organics dried over anhydrous magnesium sulphate. The solution was filtered and concentrated in vacuo to yield 3-(3-aminophenyl)-7-methylimidazo[1,2-α]pyridine as a colourless oil (4.5 g, 100%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δH 2.38 (3H, s), 3.58 (2H, br s), 6.60 (1H, d, J 7), 6.70 (1H, d, J 8), 6.81 (1H, s), 6.91 (1H, d, J8), 7.24-7.28 (1H, m), 7.39 (1H, s), 7.57 (1H, s), 8.23 (1H, d, J 7); m/z (ES+) 224 (M++H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1>>[CH3:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:14])=[CH:9][CH:8]=1
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
Racemic alanine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.Cl[P:16]([O:22][CH2:23][CH2:24][C:25]#[N:26])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:25]([CH2:24][CH2:23][O:22][P:16]([C:4]1[NH:3][C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=1)[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)#[N:26]
Reactant: Clc1nc[nH]c1Cl
Reactant: N#CCCOP(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCOP(c1nc(Cl)c(Cl)[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a stirred solution of 4,5-dichloroimidazole (1.59 g, 11.63 mmol) and triethylamine (1.95 mL, 1.41 g, 13.96 mmol) in CH2Cl2 (30 mL) was added dropwise Chloro(2-Cyanoethoxy) pyrrolidinophosphine (2.40 g, 11.63 mmol) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 4 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (2.93 g, 82%). 31P NMR (CDCl3) δ 123.2.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(#N)C>[N+:40]([C:39]1[C:34]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:35][CH:36]=[CH:37][CH:38]=1)([O-:42])=[O:41]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 107.8 %

Procedure:
To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (320 mg, 1.0 mmol) in acetonitrile (˜5 mL), was added Hunig's base (190 μL, 1.1 mmol, 1.1 eq.) and 2-chloro-3-nitropyridine (175 mg, 1.1 mmol, 1.1 eq.) and the mixture stirred at reflux for 4 hours. The reaction mixture was then concentrated in vacuo and partitioned between saturated NaHCO3 solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (475 mg, 100%) as a yellow oil. LRMS APCI+ m/z 441 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:27][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:20])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:27][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:20])=[CH:17][C:12]=3[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)c1ccccn1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Yield: 88.6 %

Procedure:
A solution of amide 21 (0.80 g, 0.222 mmol) in THF/MeOH (5 ml/5 ml) was stirred with Raney Nickel (0.150 ml) under H2 atmosphere at room temperature for 2 h. The amine was freed from catalyst by filtration through celite to give 22 (0.065 g, 88%) dried and used as is for the next step.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11]C1OCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:22].O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH:11]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: c1ccc(Cc2cccc(CC3OCCO3)c2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc(Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
A mixture of 2-(3-benzylbenzyl)-1,3-dioxolane (8.2 g), acetone (100 cm3), water (10 cm3) and concentrated sulphuric acid (20 drops) was stirred overnight, then added to diethyl ether. The resultant mixture was washed with sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzylbenzaldehyde (6.5 g), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30](Cl)=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([NH:16][C:30](=[O:31])[C:29]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:28]=1[CH3:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([I:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(I)cc2)C(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
1.5 g (4.32 mmol) of (1) and 2.9 ml (17.3 mmol) of DIPEA were dissolved in 15 ml of DCM and cooled to 0° C. 1.73 g (9.51 mmol) of 2,4,6-trimethylbenzoyl chloride were added and the solution was stirred at room temperature for 3 h. The solution was poured into saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate. The organic layer was extracted with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 1.83 g of (2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:17]=4[NH:16][C:15](=[O:18])[CH2:14]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Nc1cccc(Nc2cccc3c2NC(=O)C3)c1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 7-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (80 mg, 0.33 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (113 mg, 0.37 mmol), N,N-diisopropylethylamine (0.22 g, 1.67 mmol) and HATU (0.14 g, 0.37 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][C:3]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].[Cu][C:28]#[N:29]>CN(C)C=O.O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:6]1[CH:5]=[CH:4][C:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:2]([CH:7]=1)[C:28]#[N:29]
Reactant: N#C[Cu]
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: 130 °C
Yield: 43.7 %

Procedure:
2-Bromo-4-[(E)-2-(2,4-difluorophenyl)vinyl]-1-(phenylsulfonyl)benzene (Example 55, 130 mg, 0.3 mmol) and copper(I) cyanide (40 mg, 0.45 mmol) were combined in N,N-dimethylformamide (20 mL) and heated to 130° C. for 3 hours. Further copper(I) cyanide (40 mg, 0.45 mmol) was added and heating continued overnight. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20-30% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound (50 mg, 44%). δH (360 MHz, d6 DMSO): 8.41 (1H, d, J=1.6 Hz), 8.28 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.7, 8.4 Hz), 8.01-7.98 (2H, m), 7.86-7.64 (4H, m), 7.58 (1H, d, J=16.6 Hz), 7.37 (1H, d, J=16.8 Hz), 7.32-7.28 (1H, m), 7.17 (1H, td, J=2.4, 8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:19][CH2:20][CH2:21][CH2:22]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:39]4[CH2:38][CH:37]5[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]5[CH2:40]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a mixture of N-(4-bromo-2-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.25 g), K2CO3 (0.78 g) and a catalytic amount of KI in DMF (20 mL) was added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.78 g) at room temperature. The reaction mixture was heated to 80° C. and stirred for 8 h, then diluted with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (1.16 g, 66.50%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1CCCN.[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:19][CH:18]=1>CO>[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][NH:1][CH2:5][CH2:4][CH2:9][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)=[CH:19][CH:18]=1
Reactant: NCCCc1nc2ccccc2[nH]1
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CNCCCn2cnc3ccccc32)cc1

Procedure:
A mixture of 9.8 grams of 1H-benzimidazole-2-propanamine and 12.16 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 400 ml of 95% methanol was refluxed for 17 hours. The solvent was then evaporated under reduced pressure and the residue was chromatographed on a silica gel column packed in chloroform and eluted with solutions containing increasing percentages of methanol in chloroform. The fractions eluted with 30% methanol were combined and the solvent evaporated under reduced pressure. The solid residue was triturated with ether and then separated and dried at reduced pressure and room temperature to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-1H-benzimidazole-1-propanamine melting at about 92°-96° C. This compound has the following structural formula: ##STR12##
Reaction SMILES: [C@@H:1]12[CH2:8][N:7]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[CH2:34]([O:41][CH2:42][C:43](Cl)=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[F:26][C:10]1[CH:11]=[C:12]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:13]=[CH:14][C:9]=1[N:7]1[CH2:8][C@@H:1]2[C@@H:5]([CH2:4][N:3]([C:43](=[O:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:2]2)[CH2:6]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CNC[C@H]4C3)c(F)c2)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)COCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
(S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-ciazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (150 mg, 0.30 mmol), methylene chloride (5 mL), and methanol (10 mL) are combined with 10% palladium on carbon (30 mg) and placed under a hydrogen atmosphere (balloon) for 15 hours. The reaction is filtered through celite and concentrated in vacuo to give crude (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. The crude amine is taken up in methylene chloride (15 mL), cooled to 0° C., and triethylamine (0.09 mL, 0.67 mmol) and benzyloxyacetyl chloride (0.06 mL, 0.40 mmol) are added. The reaction is warmed to ambient temperature, stirred 15 hours, and diluted with methylene chloride (100 mL). The organic phase is washed with water (2×50 mL) and saline (150 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.41, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 138-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C

Procedure:
A mixture of 30.0 g 3-(1,1-dimethylethyl)-4-hydroxybenzoic acid methyl ester, 42.9 ml of 1-bromotetradecane, 47.8 g of potassium carbonate and 700 ml of acetone is refluxed for 48 hours. The cooled reaction is filtered, concentrated in vacuo and purified by column chromatography (silica gel:0-3% ethyl acetate/hexane) to give 38.8 g of the desired product as colorless prisms.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
14 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.86 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxybutyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 14 ml of ethanol, and the resulting mixture was heated under reflux for 10 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c) to afford 0.58 g of the title compound as an amorphous solid.