Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][Br:18]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a cooled (0° C.) solution of (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester (28.7 g, 123 mmol) in dichloromethane (500 mL) was added CBr4 (51.0 g, 154 mmol). The mixture was stirred for 5 minutes before the portion-wise addition of triphenylphosphine (48.41 g, 185 mmol). The mixture continued to stir at 0° C. for 1 hour and was then allowed to warm to room temperature. The solvent was removed under reduced pressure and was then diluted with ether (500 mL) and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed eluting with ether/hexanes (1:2) to afford 27.5 g of white solid (76% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCc1ccc(O)cc1
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccc(O)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and tyramine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]3[O:23][CH2:22]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1>C(O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][N:34]3[CH2:33][CH2:32][N:31]([CH2:30][C:29]4[CH:37]=[CH:38][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:36][CH2:35]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(OCC3CO3)cc2o1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: O=c1cc(OCc2ccccc2)c2ccc(OCC(O)CN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Yield: 62.3 %

Procedure:
A mixture of 4-benzyloxy-7-(2,3-epoxypropyloxy)coumarin (8.48 g; 0.026 mole), 1-(4-chlorobenzyl)piperazine (6.20 g; 0.0295 mole) and ethanol (50 ml) were refluxed together for 90 mins and allowed to cool. Evaporation of the solvent in vacuo gave an oily residue which crystallized on trituration with petrol ether. Recrystallization from methanol gave 8.67 g (62%) of title compound of m.p. 130°-133° C., νmax (mull) 1720, 1615 cm-1 ; δ (CDCl3) 2.55 (10H, m); 3.20 (1H, m); 3.48 (2H, s); 4.07 (3H broad s); 5.20 (2H, s); 5.68 (1H, s); 6.89 (2H, m); 7.30 (4H, s); 7.45 (5H, s); 7.77 (1H, d, J 10 Hz). (Found: C, 67.72; H, 6.00; N, 5.29; Cl, 7.21; C30H31N2ClO5 requires; C, 67.34; H, 5.84; N, 5.24; Cl, 6.63%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C)C=O.O>[C:17]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1)#[N:18]
Reactant: CCc1cc(Br)cc(C)c1CC(=O)OC
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C#N)cc(C)c1CC(=O)OC
Temperature: 130 °C

Procedure:
7.5 g of methyl 4-bromo-2-ethyl-6-methylphenylacetate were dissolved in 140 ml of dimethylformamide, 5.5 g of copper cyanide were added, and the mixture was heated for 18 hours at 130° C., until the reaction was complete. The mixture was then cooled to room temperature and diluted with water, and the product was extracted repeatedly using tert-butyl methyl ether. The combined organic phases were dried over magnesium sulphate, concentrated and distilled. This gave 3.4 g (52% of theory) of methyl 4-cyano-2-ethyl-6-methylphenylacetate of a boiling point of 123-130° C. and a melting point of 65-72° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[N:9]=2)[CH2:3][CH2:2]1.Cl[CH2:29][C:30]#[N:31].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C.O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH2:13][N:12]2[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[N:9]=[C:8]2[NH:7][CH:4]2[CH2:3][CH2:2][N:1]([CH2:29][C:30]#[N:31])[CH2:6][CH2:5]2)=[CH:15][CH:16]=1
Reactant: c1ccc2c(Cn3c(NC4CCNCC4)nc4ccccc43)ccnc2c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: N#CCN1CCC(Nc2nc3ccccc3n2Cc2ccnc3ccccc23)CC1
Yield: 18.4 %

Procedure:
A mixture of N-(4-piperidinyl)-1-(4-quinolinylmethyl)-1H-benzimidazol-2-amine (comp. 23) (0.0129 mol), chloroacetonitrile (0.0155 mol), potassium iodide (0.00129 mol) and potassium carbonate (0.0258 mol) in 4-methyl-2-pentanone (80 ml) was stirred and refluxed for 5 hours. H2O was added. The solvent was evaporated. H2O and CH2Cl2 were added. The precipitate was filtered off. The filtrate was separated into its layers. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue (3.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/N OH 95/5/0.3; 1540 em). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.94 g 4-[[1-(4-quinolinylmethyl)1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile; mp. 190° C. (interm. 41).
Reaction SMILES: [C:1]([CH2:8][CH2:9][CH:10]([NH2:31])[C:11]([O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:17]([O:19][CH2:20]C)=[O:18])[C:12]([O:14][CH2:15]C)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO>[C:23]([O:22][CH3:11])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:1]([CH2:8][CH2:9][CH:10]([NH2:31])[C:11]([OH:22])([C:12]([O:14][CH3:15])=[O:13])[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC(=O)C(OC(=O)c1ccccc1)(C(=O)OCC)C(N)CCC(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)C(O)(C(=O)OC)C(N)CCC(=O)OC(C)(C)C
Product: COC(=O)c1ccccc1
Reaction time: 1 h
Yield: 129 %

Procedure:
A mixture of 4 g of ethyl 5-BOC-amino-2-benzoyloxy-2-ethoxycarbonyl-pentanoate and 2 g of K2 CO3 in 40 ml of anhydrous methanol, cooled to 0°-5° C., is stirred for 1 h. After filtration of the potassium carbonate excess, the solution is acidified to pH 6 with 2N HCl and filtered from the salts which separate. Solvent is evaporated off under vacuum and the residue is partitioned between cold water and ethyl acetate. The organic phase is washed repeatedly with a 5% K2CO3 cold solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue (3 g) is eluted, purified on 30 g of silica gel, eluent hexane-ethyl acetate from 95:5 to 80:20, to give methyl benzoate and 1.8 g of methyl 5-BOC-amino-2-hydroxy-2-methoxycarbonyl-pentanoate (oil). TLC (4:6 AcOEt-hexane) Rf=0.19 I.R.: (--OH and --NH--3400 cm-1 broad peak) (C=O 1730 cm-1 broad peak) NMR (CDCl3 /TMS): (δ) 1.45 s; 1.45-1.6 m; 2.0-2.1 m; 3.05-3.2 q; 3.8 s; 4.6 s. By acidification of the basic extracts with 20% KHSO4 and subsequent extraction with ethyl acetate, 0.17 g of 5-BOC-amino-2-hydroxy-2-methoxycarbonyl-pentanoic acid are obtained (oil) TLC (3:1:1 nBuOH-AcOH-H2O) Rf=0.54
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:20][C:21]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.CO>Cl.O>[CH2:27]([N:24]1[CH2:23][CH2:22][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([O:20][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][C:16]=2[Cl:19])[C:9](=[O:8])[NH:10][CH:11]=[CH:12]3)[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1cc2c(OCc3ccccc3)nccc2cc1OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ccc2cc(OC3(c4ccccc4)CCN(Cc4ccccc4)CC3)c(Cl)cc12
Reaction time: 8 h
Yield: 12.8 %

Procedure:
920 mg of 1-Benzyloxy-6-(1-benzyl-4-phenyl-piperidin-4-yloxy)-7-chloro-isoquinoline (68) were suspended in 1M HCl and dissolved by addition of methanol. After stirring overnight, the solution was diluted with water, extracted with methyl tert. butyl ether and the aqueous layer was lyophilized. The product was purified by crystallization to give 98 mg of the desired product as a white solid as the hydrochloride. Rt=1.46 min (Method A). Detected mass: 445.3 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.CC(C)=O.[CH3:12][O:13][C:14]([C:16]1[C:25]([CH3:26])=[C:24]([O:27]C(=O)C)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:31])[CH:22]=2)[CH:17]=1)=[O:15]>CO>[CH3:12][O:13][C:14]([C:16]1[C:25]([CH3:26])=[C:24]([OH:27])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:31])[CH:22]=2)[CH:17]=1)=[O:15]
Reactant: COC(=O)c1cc2ccc(F)cc2c(OC(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
A heterogeneous mixture of potassium carbonate (46 g, 0.33 mol), water (260 mL), and acetone (260 mL) was added in three portions to a 0° C. solution of 4-acetoxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (18.4 g, 0.066 mol) in methanol (1 L). The resulting mixture was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The remaining oily suspension was diluted with ethyl acetate and washed with 1 N aqueous HCl. The organic phase was dried (MgSO4), filtered, and concentrated to yield 9.64 g (62%) of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester as a yellowish tan solid. HRMS (ES−) cald. for C13H11FO3 [(M−H)−] 233.0619, obsd. 233.0619.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[CH3:11])[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2C)c1

Procedure:
4-Bromo-2-methylbenzoic acid (120 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].C(O)(=O)C.[I-].[Na+].ClC(C)[C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:23][CH3:24])=[C:18]([F:25])[CH:17]=1)=[O:15]>CC(C)=O.O>[F:22][C:20]1[CH:21]=[C:16]([CH:14]([OH:15])[CH:1]([OH:4])[CH3:2])[CH:17]=[C:18]([F:25])[C:19]=1[O:23][CH3:24]
Reactant: COc1c(F)cc(C(=O)C(C)Cl)cc1F
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1c(F)cc(C(O)C(C)O)cc1F

Procedure:
Potassium acetate (3.0 g) then glacial acetic acid (5 ml) and then sodium iodide (1.0 g) were added to a solution of 2-chloro-1-(3,5-difluoro-4-methoxyphenyl) propan-1-one (6.5 g) in acetone (50 ml). The mixture was stirred and heated under reflux for 4 hours, cooled and treated with water (150 ml) the acetone was evaporated and the aqueous residue was extracted into dichloromethane. The organic phase was washed with sodium bicarbonate solution, dried (magnesium sulphate), and concentrated under reduced pressure, the residual oil was dissolved in ethanol (150 ml) cooled in ice and treated with excess sodium borohydride (1.5 g). The solution was stirred for 2 hours at ambient temperature, the ethanol and the residue partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate layer was dried (magnesium sulphate) and evaporated to give 1-(3,5-difluoro-4-methoxy-phenyl)propane 1,2-diol as an oil which was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21]CC)=[O:20].[OH-].[Na+].[ClH:26]>CCO.O>[Cl-:26].[NH3+:17][C:14]([CH3:16])([CH3:15])[CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH3+:1])=[C:3]([C:19]([OH:21])=[O:20])[C:4]([CH3:18])=[N:5]2.[Cl-:26]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc(OCC(C)(C)[NH3+])c2c([NH3+])c1C(=O)O
Product: [Cl-]
Temperature: 80 °C
Yield: 54 %

Procedure:
To a solution of ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) (0.65 g, 2.05 mmol) in EtOH (35 mL) was added a solution of NaOH in H2O (2.0 M, 5.2 mL) at room temperature under a nitrogen atmosphere. The obtained reaction mixture was heated at 80° C. over 3 h and cooled to room temperature. The pH of the cold mixture was adjusted to 1 with a solution of HCl (1.5 M) and the acidified solution was evaporated to dryness. The residue was dissolved in a mixture of EtOH and H2O (30 mL, 1:1) and the product was isolated by preparative HPLC (RPC18, H2O→CH3CN gradient). The appropriate fractions were collected and evaporated under reduced pressure. The residue was dried in a dessicator over phosphorus pentoxide to give 0.41 g (54%) 5-(2-ammonio-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminium chloride as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.05-9.90 (m, 1H), 9.15-9.00 (m, 1H), 8.69-8.57 (m, 3H), 7.91 (t, J=8.3 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 4.39 (s, 2H), 2.84 (s, 3H), 1.44 (s, 6H). MS 291 (M+)
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>CN(C)C=O.O>[C:4]([C:3]1[C:2]2[O:1][CH2:20][CH2:19][O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: BrCCBr
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc2c1OCCO2
Temperature: 65 °C

Procedure:
A mixture of 10.8 g (70 mmol) of 2,3-dihydroxybenzoic acid, 38.6 g (280 mmol) of dry potassium carbonate and 24 ml (278 mmol) of 1,2-dibromoethane in 40 ml of N,N-dimethylformamide is heated at 65° C. for 24 hours under an inert atmosphere. After cooling, the reaction mixture is diluted with water and then extracted with ether. The aqueous phase is then acidified with a 3N hydrochloric acid solution and subsequently extracted with dichloromethane. After removal of the solvent by evaporation in vacuo, the residue obtained is recrystallised from toluene to yield the title acid in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Product: C[C@@H](Nc1cncc(-n2cnc3ccccc32)n1)c1ccccc1
Yield: 57.6 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (240 mg, 1.03 mmol) and benzimidazole (130 mg, 1.10 mmol) furnished the product (187 mg, 59%).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.ClC[CH2:20][CH2:21][S:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[N:25]1([S:22]([CH2:21][CH2:20][CH2:2][O:3][C:4]2[CH:5]=[CH:6][C:7]3[C:8]4[N:9]([CH2:15][CH2:16][N:17]=4)[C:10]([NH2:14])=[N:11][C:12]=3[CH:13]=2)(=[O:24])=[O:23])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Reactant: COc1ccc2c(c1)N=C(N)N1CCN=C21
Agent: Br
Product: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12

Procedure:
The procedure used for the preparation of Example 24, Step 2 was used to prepare the title compound from 5-amino-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (Intermediate I) and 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E). Yield 190 mg (61%). Rf=0.68 in 10% MeOH/CH2Cl2, HPLC MS RT=1.13 min, MH+=394.4.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[N:16]=3)=[N:12][C:11]=2[CH3:30])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[N:16]=3)=[N:12][C:11]=2[CH3:30])=[O:9])=[CH:31][CH:32]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2cncc(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
Part B. To a solution of 2-{6-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (150 mg, 0.33 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd/C (70 mg, 10%). The flask was first purged with nitrogen, then with hydrogen in a Parr apparatus. The reaction mixture was stirred at ambient temperature for 12 hr at 50 psi. Upon completion by LCMS, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-{6-[2-(4-fluoro-phenyl)-ethyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (113 mg, 75%). 1H NMR (400 MHz, CD2Cl2) δ 9.15 (s, 1H), 8.36 (s, 1H), 7.33-7.37 (m, 2H), 7.13-7.16 (m, 2H), 7.03-7.08 (m, 2H), 6.92-6.96 (m, 2H), 6.20 (bs, 1H), 4.56 (d, J=4.0 Hz, 2H), 3.08-3.14 (m, 4H), 2.72 (s, 3H); HRMS (M+H)+=451.15.
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20].[OH-].[Na+]>CCN(C(C)C)C(C)C.C(Cl)Cl>[N:2]1([C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][N:13]([S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])[CH2:12][CH2:11]2)=[O:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: N#CC1(C(=O)N2CCOCC2)CCNCC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(C#N)(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(morpholin-4-ylcarbonyl)piperidine-4-carbonitrile hydrochloride (I-3) (10.40 g, 40 mmole) in DIEA-DCM (1:4, 200 mL) was added n-C3H7SO2Cl (6.28 g, 44 mmole) at 0° C. The resultant mixture was stirred for 1 h at 0° C. After this time, LCMS indicated that the reaction was complete. 2N NaOH (60 mL) was added to the reaction. The resultant reaction mixture was stirred for 1 h at rt. After this time, the DCM layer was separated. The aqueous solution was extracted with DCM (3×150 mL). The combined DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound (I-4) which was pure enough for next step reaction. Analytical LCMS: single peak (214 nm), 2.406 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].[F:15][C:16]([F:27])([F:26])[C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CCCC)CCCC)CCC>CN(C=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:17]([C:16]([F:26])([F:27])[F:15])[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:9]2[C:10]([F:13])([F:12])[F:11]
Reactant: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A yellow solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (1.32 g, 4.94 mmol, Intermediate 8, step b) and 1,1,1-trifluoro-3-phenylpropan-2-one (0.980 g, 5.21 mmol) in DMF (4.95 mL) was treated with tributylamine (1.23 mL, 5.19 mmol) and stirred at 130° C. under air (capped) for 2 hours. The homogeneous orange solution was then cooled to room temperature and partitioned with ether (8 mL) and 1 M NaH2PO4 (8 mL). The organic layer was washed with 1 M NaH2PO4 (1×8 mL), dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a heptane to 30% DCM/heptane gradient to yield the title compound as a nearly colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C@H:9]([CH2:11]OS(C3C(C)=CC=CC=3)(=O)=O)[CH2:8][C:7]=2[CH:23]=1.[CH3:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CO>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C@H:9]([CH2:11][N:33]3[CH2:34][CH2:35][C:30]([CH2:29][C:28]4[CH:27]=[CH:26][C:25]([CH3:24])=[CH:38][CH:37]=4)([OH:36])[CH2:31][CH2:32]3)[CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc2c(c1)C[C@@H](COS(=O)(=O)c1ccccc1C)O2
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C[C@@H](CN1CCC(O)(Cc3ccc(C)cc3)CC1)O2
Temperature: 110 °C
Yield: 87.2 %

Procedure:
(S)-Toluenesulfonic acid 5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester (2.30g, 6.88 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (1.62 g, 7.9 mmol) and Na2CO3 (1.10 g, 10.3 mmol) were suspended in DMF and heated at 110° C. for 1 hr. After cooling to ambient temperature distilled H2O and EtOAc were added (100 ml) and the mixture shaken, the organic phase was then separated and the aqueous phase extracted with EtOAc (10 ml). The combined organic extracts were then washed with satd. NaCl solution (100 ml) and the organic phase dried with Na2SO4, filtered and evaporated to afford a yellow oil. This foam was chromatographed over SiO2 (Merck 230-400 mesh) with CH2Cl2, and then with CH2Cl2—MeOH (97:3) to afford (S)-1-(5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (2.20 g, 6.0 mmol, 87% yield) as a yellow oil MS: m/e=368.2 (M+H+) [α]=+45.8° (c=1.0, CHCl3).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])#[N:2].[OH-:15].[Na+].OO>CS(C)=O.C(O)C>[NH2:2][C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])=[O:15]
Reactant: COc1c(C#N)ccc(C(=O)O)c1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1c(C(N)=O)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
To a solution of 4-cyano-2-methyl-3-(methyloxy)benzoic acid (80 mg, 0.42 mmol) in DMSO:ethanol (1:4, 1 mL) was added 1N aqueous sodium hydroxide (1 mL), and hydrogen peroxide (30% wt. in water, 1 mL). The mixture was stirred at room temperature for 72 hours, then partitioned between 1N aqueous sodium hydroxide and ethyl acetate and the organic layer discarded. The pH of the aqueous portion was adjusted to 7 using 1N aqueous hydrochloric acid. The aqueous portion was extracted several times using ethyl acetate, and the combined organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 55 mg, 0.26 mmol (63%) of 4-(aminocarbonyl)-2-methyl-3-(methyloxy)benzoic acid. 1H NMR (400 MHz, d6-DMSO): 7.77 (br s, 1H), 7.60 (br s, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 3.72 (s, 3H), 2.41 (s, 3H). MS (EI) for C10H9NO3: 190 (M−H).