Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.Cl>CO.C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)OC(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyl (2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoate of step 3 (0.38 mmol, 157 mg) in MeOH/THF/H2O (1:2:2 mL) was added LiOH monohydrate (0.96 mmol, 40 mg). The mixture was stirred at r.t. for 2 h. HCl (1N) was added until pH 1. The mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous, MgSO4 and concentrated. The crude acid was used without further purification.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:48]1[CH2:52][CH2:51][CH2:50][C@H:49]1[CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C.ClCCl>[N:54]1([CH2:53][C@@H:49]2[CH2:50][CH2:51][CH2:52][N:48]2[C:12]([C:11]2[CH:10]=[CH:9][C:8]([C:6]3[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)=[O:14])[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)cc2)s1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1
Yield: 63.7 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 100 mL 10% DMF/dichloromethane using 4-(5-cyano-thiophen-2-yl)-benzoic acid (CAS 402765-55-9) (2.75 g, 12.0 mmol), EDC-HCl (3.44 g, 18.0 mmol), HOBt (2.43 g, 18.0 mmol), DIEA (5.22 mL, 30 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.54 g, 10.0 mmol) to give the title compound (2.33 g, 64% yield). MS (ES+) 366.2 (M+H)+
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][N:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.[K+].[Br-]>>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[C:10](=[N:9][N:8]=3)[CH:11]=[C:12]3[O:13][CH2:1][O:2][C:3]3=[CH:4]4)[N:14]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN2CCCC2)c2cnnc3cc4c(cc23)OCO4)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COc1cc2c(=O)n(CCN3CCCC3)c3c4cc5c(cc4nnc3c2cc1OC)OCO5
Yield: 24 %

Procedure:
Prepared from N-(6,7-Methylenedioxycinnolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide (150 mg, 0.2 mmol) in 24% yield with a reaction time 30 min; mp 229° C.; IR (KBr) 1644; 1H NMR (CDCl3) δ 1.83 (m, 4H), 2.71 (m, 4H), 3.23 (t, 2H, J=7), 4.06 (s, 3H), 4.61 (s, 3H), 4.63 (t, 2H, J=7), 6.23 (s, 2H), 7.74 (s, 1H), 7.80 (s, 1H); 13C NMR (CDCl3) δ 23.7, 54.0, 54.2, 56.3, 56.6, 99.4, 102.7, 104.2, 106.3, 107.7, 113.5, 119.4, 129.0, 134.1, 140.2, 150.2, 151.4, 154.3, 154.3, 163.0; HRMS calcd for C24H24N4O5H, 449.1825; found 449.1822.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
4-Methylbenzaldehyde (1aa, 1.50 ml, 12.7 mmol) and acetone (19, 0.47 ml, 6.4 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.52 g, 13.0 mmol) and water (10 ml) was added and the mixture stirred for 1 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 1.30 g (78%) of a yellow solid: mp 174-176° C. [expected mp 171-172° C.]; 1H NMR: δ 2.37 (s, 6H), 7.02 (d, 2H, J=15.9 Hz), 7.20 (d, 4H, J=8.0 Hz), 7.50 (d, 4H, J=7.9 Hz), 7.70 (d, 2H, J=15.9 Hz); 13C NMR: δ 21.6, 124.6, 128.3, 129.6, 132.1, 140.8, 143.0, 188.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.O1C[CH2:23][CH2:22][CH2:21]1.[H-].[Na+].[H][H].C(Br)C=C.Cl>C(OCC)(=O)C>[CH2:23]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:19])[CH:22]=[CH2:21]
Reactant: C1CCOC1
Reactant: [H][H]
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCOC(c1ccc(OCC)cc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a suitable reaction flask was charged (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (2.93 mmoles; 1.00 g) and tetrahydrofuran (122.89 mmoles; 10.00 mL; 8.86 g) to afford a clear solution. Sodium hydride (8.14 mmoles; 325.61 mg) was then added in small portions to minimize the rate of hydrogen gas evolution. The reaction was stirred for approximately 30 minutes at room temperature, and then allyl bromide (8.55 mmoles; 0.740 mL; 1.03 g) was added slowly. The reaction was allowed to stir at room temperature until completion (as determined by GCMS analysis). To the reaction mixture was then added 1N hydrochloric acid (10 mL) and ethyl acetate (20 mL). The layers were shaken together, allowed to settle and then were separated. The organic phase was washed with saturated aqueous sodium chloride (10 mL) and then was dried over magnesium sulfate, filtered and concentrated to provide the crude product (1.07 g). The crude oil was purified by flash chromatography on silica gel eluting with a gradient of 0 to 5% ethyl acetate in hexanes to afford 858 mg of product as a clear oil (77% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].CCOCC>C(#N)C>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Temperature: 20 °C
Yield: 10.2 %

Procedure:
To prepare compound I-24 identified above, 38.3 g of p-nitrophenylhydrazine and 33 g of phthalide were heated in acetonitrile for 3 hours at 70°-80° C. After cooling to 20° C., the solid product was stirred together with ether and then the product was collected by filtration and washed with ether to obtain 7.2 g of 1-(2'-hydroxymethylbenzoyl)-2-(p-nitrophenyl)hydrazine.
Reaction SMILES: [F:1][C:2]1[C:3]([O:14][C@H:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl.O.CC#N>CO>[F:1][C:2]1[C:3]([O:14][C@H:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)c(O[C@@H](C)c2ccncc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: COc1cc(O[C@@H](C)c2ccncc2)c(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoate (290 mg, 0.95 mmol) in methanol (5 mL) was added aqueous NaOH (396 μL, 3.6M). The reaction was stirred at ambient temperature overnight and then heated to 45° C. in an oil bath for another 24 h. The reaction pH was lowered to pH 3 using 1N HCl and the reaction mixture stripped down under reduced pressure. The white foam was lyophilized from H2O/CH3CN to afford the 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoic acid as a white powder.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Br:9]N1C(=O)CCC1=O.C(OC(C)C)(C)C>C(O)(=O)C>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:9])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(N)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: Cc1nc(N)sc1Br
Yield: 89.7 %

Procedure:
To a solution of 2-amino-4-methylthiazole hydrochloride (3.0 g) in acetic acid (20 ml) was added once N-bromosuccinimide (4.0 g) at room temperature with stirring. The mixture was stirred at room temperature for 1.5 hours and the reaction mixture was poured into isopropyl ether under ice cooling. The precipitates were collected by filtration, washed with ethyl ether and dried in vacuo to give 2-amino-5-bromo-4-methylthiazole hydrochloride (4.1 g, yield: 89.1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:11](F)(F)[F:12])[C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[F:8].ClS(O)(=O)=[O:18]>>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[F:8])[C:11]([F:12])=[O:18]
Reactant: Fc1c(Cl)c(F)c(C(F)(F)F)c(F)c1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C(F)c1c(F)c(Cl)c(F)c(Cl)c1F
Yield: 82.1 %

Procedure:
A mixture of 520 g of 3,5-dichloro-2,4,6-trifluorobenzotrifluoride and 400 g of chlorosulphonic acid is heated for 4 hours, whilst stirring, as described in Example 1. 392 g of 3,5-dichloro-2,4,6-trifluorobenzoyl fluoride (82% of the theoretical yield) of boiling point 90° to 95° C./15 mbars and nD20 :1.5007 are obtained by distillation.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2

Procedure:
8 g (20 mmol) of tert.butyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 25 g (300 mmol) of hydroxymethyl-cyclopropane and 1.8 g (8 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By recrystallization from ethanol there is obtained cyclopropylmethyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 212°-213°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34]/[CH:35]=[CH:36]/[C:37]([O:39]CC)=[O:38]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15]/[CH:34]=[CH:35]/[CH2:36][C:37]([OH:39])=[O:38])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCOC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)C/C=C/Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 2 was suspended in dimethyl sulfoxide (30 ml), and to the suspension was added potassium carbonate (0.3 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl 4-bromocrotonate (0.15 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (300 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate). The resulting crude crystals were suspended in ethanol (20 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added to the suspension followed by stirring at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was extracted with water and ethyl acetate. 1N hydrochloric acid was added to the aqueous layer to a pH of 7, and the precipitated crystals were recovered by filtration to obtain the title compound (50 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].C(N(C(C)C)CC)(C)C.[CH3:38][O:39][CH2:40][CH2:41][O:42][CH2:43]Cl.C(Cl)Cl>CCCCC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCCC
Product: COCCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)OC)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A 100 ml round bottom flask, equipped with a mercury relief valve and magnetic stirrer, was flame-dried and flushed with nitrogen. The flask was charged with 2.57 mmoles (1.0 g) of 3β-hydroxy-5-cholenic acid methyl ester, 3.86 mmoles (0.50 g) of diisopropylethylamine, 3.86 mmoles (0.48 g) of methoxyethoxymethyl chloride and 10 ml of CH2Cl2. The reaction mixture was stirred for 48 hours at room temperature. After stirring, the reaction mixture was diluted with 25 ml of pentane, washed with 20 ml of 10% acetic acid and 20 ml of saturated sodium bicarbonate. The combined aqueous layers were extracted with two twenty ml portions of ether and the organic layers separated and dried with MgSO4. Concentration of the ether solution left an oily crude product (96%) which was isolated as a pure white solid (84%) by dissolving the oil in pentane, cooling to -78° C., and filtering. The pure solid had mp 44°-46° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Cl[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][C:15]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:16]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
tert-Butyl(3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with methyl chloroformate (0.049 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give tert-butyl (3S)-3-[(methoxycarbonyl)amino]pyrrolidine-1-carboxylate, LCMS [M+Na] 267.1. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the crude product (35 mg, 40%), which was used directly in the next step. LCMS calculated for C6H13N2O2 (M+H)+: m/z=145.1; Found: 145.1.
Reaction SMILES: C=O.[CH2:3](O)C.[CH3:6][NH:7][CH3:8].[Br:9][C:10]1[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[C:15]([Br:21])[C:11]=1[C:12]([OH:14])=[O:13]>C(O)(=O)C>[Br:9][C:10]1[CH:18]([OH:19])[C:17](=[CH:6][N:7]([CH3:3])[CH3:8])[C:16]([OH:20])=[C:15]([Br:21])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CCO
Reactant: CNC
Reactant: O=C(O)c1c(Br)c(O)cc(O)c1Br
Agent: C=O
Solvent: CC(=O)O
Product: CN(C)C=C1C(O)=C(Br)C(C(=O)O)=C(Br)C1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a stirred mixture of 37% of aqueous formaldehyde solution (2 mmol), absolute ethanol (0.4 mL), and glacial acetic acid (0.8 mL) was added 40% of aqueous dimethylamine (2 mmol) solution under ice bath (25° C.). The ice bath was removed and 2,6-Dibromo-3,5-dihydroxybenzoic Acid (1 mmol) was added over a period of 2 min. The mixture became darkened, and after 5 min a white solid began to appear. The mixture was stirred at 25° C. for 24 h and then at 0° C. for 2 h to allow complete precipitation of product. The precipitate was washed with ice-cold acetone (2×0.5 mL), dried under oil pump to give 2,6-Dibromo-3,5-dihydroxy-4[(dimethylamino) methylene]-benzoic Acid (98%): 1H NMR (DMSO-d6) δ 3.92 (s, 2H), 2.41 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>>[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:35])=[CH:32][N:31]=1
Reactant: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ccc(C(=O)O)cn1
Product: COc1c(OCc2ccc(S(C)(=O)=O)cc2)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 7-methoxy-8-{[4-(methylsulfonyl)benzyl]oxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 16 Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (151 mg, 77%): HPLC MS RT=2.00 min, MH+=521.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.24 (3H, s), 4.02 (3H, s), 4.23-4.28 (2H, m), 4.50-4.55 (2H, m), 5.56 (2H, s), 7.06 (1H, d), 7.58 (1H, d), 7.79 (2H, d), 8.01 (1H, d), 8.05 (1H, d), 8.50 (1H, dd), 8.79 (1H, d).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][Cl:20])=[CH:11][N:10]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[ClH:20].[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:11][N:10]=1
Reactant: FC(F)(F)c1nc(N[C@@H]2C[C@H]3CC[C@@H]2C3)ncc1CCl
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cl
Product: FC(F)(F)c1nc(N[C@@H]2C[C@H]3CC[C@@H]2C3)ncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (200 mg) and N,N-dimethyl formamide (3 mL) was added morpholine (0.57 mL), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure from the reaction mixture, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained colorless oil was dissolved in 1,4-dioxane (5 mL), and a 4 M hydrogen chloride/1,4-dioxane solution (1 mL) was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with 1,4-dioxane to obtain rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-(morpholin-4-ylmethyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride (187 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=[O:33])=O)[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6](/[CH:7]=[CH:8]/[C:9]2[N:17]([CH3:18])[C:16]3[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=2)=[C:5]([S:31]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:4]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: C1CCNCC1
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)N3CCCCC3)n2C)n(CCC)c1=O
Yield: 54.7 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 1.93 ml (19.6 mmol) of piperidine. The resulting crude crystals were recrystallized from dimethylsulfoxide/water to give 600 mg (yield 55%) of Compound 4 as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[C:32]1([NH:38][C:39]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]4[N:14]=[C:15]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][CH2:30][CH2:31]6)=[CH:20][CH:19]=5)[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 8 h

Procedure:
[5-(3-Amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (50 mg, 0.121 mmol) was dissolved in chloroform (3 ml). Phenylisocyanate (0.12 ml, 0.131 mmol) was added and the mixture stirred overnight. The solvent was removed under reduced pressure and the product was purified by preparatory HPLC to give the desired product. RT: 2.78 min, MI: 534, Method: 2. 1H NMR (DMSO, 300 MHz): 1.76 (m, 4H), 2.80 (m, 4H), 2.99 (t, 2H), 3.99 (t, 2H), 6.86 (d, 2H), 6.94 (t, 1H), 7.13 (d, 1H), 7.26 (t, 2H), 7.34-7.66 (m, 9H), 8.32 (s, 1H), 9.43 (bs, 1H), 9.68 (bs, 1H), 9.81 (s, br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Br[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC(C)C)c1=O
Yield: 77.3 %

Procedure:
Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 77.3%.