Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[O:14][CH2:13][C@H:12]3[N:8]2[C:9](=O)[C@@H:10]2[CH2:15][C@@H:11]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH2:7]([N:8]1[CH2:9][C@H:10]2[C@H:11]([CH2:15]2)[C@H:12]1[CH2:13][OH:14])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1[C@@H]2C[C@@H]2[C@H]2CO[C@H](c3ccccc3)N12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@@H]1[C@H]2C[C@H]2CN1Cc1ccccc1

Procedure:
At 0° C. a solution of (1aS,1bS,4R,5aR)-4-Phenyl-tetrahydro-3-oxa-4a-aza-cyclopropa[a]pentalen-5-one (13.9 mmol) in THF (15 mL) is added dropwise to a suspension of lithium aluminum hydride (20.9 mmol) in THF (14 mL) and the mixture is stirred at reflux for 1 h. After cooling to 0° C. water (0.80 mL), aq. NaOH solution (15%, 0.80 mL), THF (15 mL) and additional water (2.0 mL) are added with caution and the mixture is stirred vigorously for 2 h. Na2SO4 is added, the suspension is filtered through celite and the solvents are removed in vacuo to give the desired product. LC-MS (basic): tR=0.84 min; [M+H]+=204.4.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11](=O)[CH2:12]Cl)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:15][C:16](=[N:18][C:19]([NH2:21])=[S:20])[NH2:17]>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:21]=[C:19]([N:18]=[C:16]([NH2:17])[NH2:15])[S:20][CH:12]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)CCl)o1
Reactant: NC(=S)N=C(N)N
Solvent: CCO
Product: CC(=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 46.6 %

Procedure:
A solution of 5-acetylaminomethyl-2-chloroacetylfuran (39.9 g) and diaminomethylenethiourea (21.9 g) in ethanol (400 ml) was refluxed for two hours with stirring. The solvent was evaporated in vacuo and the residue was dissolved in water (300 ml). The solution was basified with an aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of methanol, tetrahydrofuran and diisopropyl ether to afford 4-(5-acetylaminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (24.1 g).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][NH:16][C:17]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[S:18]
Reactant: CCCCCCCCN
Reactant: COc1cccc(CN=C=S)c1
Solvent: CCO
Product: CCCCCCCCNC(=S)NCc1cccc(OC)c1
Temperature: 4 °C

Procedure:
N-Octyl amine (3.09 g, 23.9 mmol) in 83 ml ethanol at 40° C. was reacted with an excess of 3-methoxybenzyl isothiocyanate (4.7 g, 26.2 mmol) for 2 h under N2 with stirring, then transferred to a 100 ml beaker, cooled to 4° C. and the crystals filtered off using Whatman 541 filter paper. The filtrate was evaporated to 20 ml and cooled to 4° C. to obtain a second crop of crystals. The remaining supernatant was dried and weighed. The first and second crop of crystals yielded 6.32 g, or 85.5% of the theoretical amount of 1-(3-methoxybenzyl-3-octyl thiourea. Calculated elemental analysis of 1-(3-methoxybenzyl)-3-octyl thiourea: C, 66.19; H, 9.15; N, 9.08; S, 10.39. Found: C, 66.21; H, 9.04; N, 9.07; S, 10.59.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 12.4 %

Procedure:
The title compound (17.2 mg) was prepared as in Example 177, Steps C and D, using 206.5 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 193.2 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C19H24FN3, 313.41; found, m/z 314.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.28 (m, 4H), 3.91-3.84 (m, 1H), 3.43-3.38 (m, 2H), 3.32-3.27 (m, 2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.79 (m, 6H), 1.69-1.63 (m, 1H), 1.30-1.19 (m, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.C([O:17][C:18]([C:20]1[CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=O)C>C1COCC1>[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:18]([C:20]2[CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=2)=[O:17])=[CH:10][CH:9]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(SC)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.02 h
Yield: 80 %

Procedure:
To a solution of potassium tert-butoxide (1 M in THF, 66 mL, 66 mmol) in THF (66 mL) in an ice bath was added 4-fluoroaniline over 1.5 min. The solution was stirred for 1 min, then a solution of 2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (3.745 g, 18.9 mmol) in THF (30 mL) was added via syringe over 4 min. The syringe was washed with 4 mL THF, and the reaction allowed to proceed for 5 min. The reaction was quenched with 1% HCl (450 mL) resulting in a solid precipitate. The solution was filtered, and the solids washed with water. After drying, the solids were triturated with 10% ethyl acetate/hexane to afford 4.0 g (80% yield) of the titled product as a pale yellow solid, which was used in the following preparations.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1.[C:11](=[O:13])=[O:12].C[OH:15]>>[C:11](=[O:15])([OH:13])[OH:12].[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1
Reactant: CO
Reactant: O=C=O
Agent: Cc1ncc(CN)c(N)n1
Product: O=C(O)O
Temperature: 20 °C

Procedure:
A solution of 50 g of crude 2-methyl-4-amino-5-aminomethylpyrimidine (purity: 95.0%, 0.344 mole) dissolved in 250 g of methanol was charged into a four-necked flask equipped with a stirrer, an introducing tube for carbon dioxide, a reflux condenser and a thermometer, followed by maintaining the temperature of the solution at 20° C. Subsequently, 64 g (1.45 mole) of carbon dioxide was blown into the solution over about one hour and the reaction was carried out to precipitate a white crystal of a 2-methyl-4-amino-5-aminomethylpyrimidine carbonate with extreme easiness. Then, the resulting crystal was filtered off, washed with a small amount of methanol, and dried at 20° C. until it may have constant weight to give 61.8 g of 2-methyl-4-amino-5-aminomethylpyrimidine carbonate.
Reaction SMILES: [CH3:1][N:2](C)C=O.Cl[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([Cl:17])=[CH:9][N:8]=1>[C-]#N.[Zn+2].[C-]#N.O>[Cl:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]([C:1]#[N:2])=[N:8][CH:9]=1
Reactant: FC(F)(F)c1cc(Cl)ncc1Cl
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c(Cl)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To 14 ml of N,N-dimethylformamide were added 1 g of 2,5-dichloro-4-trifluoromethylpyridine, 1.71 g of zinc cyanide and 0.34 g of tetrakistriphenylphosphine palladium, and the mixture was stirred at 90° C. for 10 hours. After allowing to cool, the reaction solution was poured into water, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.7 g of 5-chloro-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: CN(C(O[N:9]1N=[N:16][C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:9][CH2:10][CH2:11][NH:16][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:50]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Reactant: 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: Cc1c(C(=O)NCCN)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
HATU (0.157 g, 0.41 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.145 g, 0.38 mmol) and Hünig's base (65 μL, 0.38 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. Tert-butyl-N-(2-aminoethyl) carbamate (296 μL, 1.88 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the crude product dissolved in DCM. The organic layer was washed with water, concentrated in vacuo (10 mL) and trifluoroacetic acid added (3.0 mL). The mixture was stirred at ambient temperature overnight, concentrated in vacuo and purified by ion-exchange chromatography (SCX-2 eluting with hydrochloric acid/MeOH→ammonia/MeOH). Further purification by flash-column chromatography (100% DCM→10% ammonia/MeOH/DCM) yielded the title compound as pale yellow solid (0.063 g, 39%).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)[CH:9]=2)[S:5][C:4](=[S:25])[N:3]1[NH:26][C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[S:29](=[O:37])(=[O:36])[N:28]=1.C(OCC)(=O)C.[ClH:44]>>[ClH:44].[O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][NH2:17])[CH:9]=2)[S:5][C:4](=[S:25])[N:3]1[NH:26][C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[S:29](=[O:37])(=[O:36])[N:28]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C=C2SC(=S)N(NC3=NS(=O)(=O)c4ccccc43)C2=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCOc1cccc(C=C2SC(=S)N(NC3=NS(=O)(=O)c4ccccc43)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(4-Oxo-5-(3-(2-t-butoxycarbonylaminoethyloxy)benzylidene)-2-thioxothiazolidin-3-yl)amino]-1,2-benzothiazole 1,1-dioxide (220 mg) obtained in Example 167 was dissolved in 4M hydrogen chloride-ethyl acetate solution (10 ml), and the solution was stirred at room temperature for 3 hr, and concentrated under reduced pressure to give 3-[(4-oxo-5-(3-(2-aminoethyloxy)benzylidene)-2-thioxothiazolidin-3-yl)amino]-1,2-benzothiazole 1,1-dioxide hydrochloride (167 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:36][CH3:37])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23](C(OCC2C=CC=CC=2)=O)[CH2:22][CH2:21]1>[Pd].C(O)C>[CH2:12]([NH:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[C:5]([O:36][CH3:37])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[C:2]([NH2:1])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Yield: 57.3 %

Procedure:
A solution of phenylmethyl 4-{4-[6-amino-2-(butylamino)-8-(methyloxy)-9H-purin-9-yl]butyl}-1-piperidinecarboxylate ammoniate (372 mg, 0.730 mmol) and 10% palladium on carbon (155 mg, 0.146 mmol) in ethanol (5 ml) was hydrogenated at atmospheric pressure and room temperature for 18 hours. The catalyst was filtered through Celite and the filtrate concentrated in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (3 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as a white gum (157 mg).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:18][CH2:17]2)[CH:13]([CH3:15])[CH3:14])[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([N:19]3[CH2:20][CH2:21][CH:16]([N:12]([CH2:11][C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=4)[CH:13]([CH3:14])[CH3:15])[CH2:17][CH2:18]3)[S:23][C:24]=2[CH:30]=1
Reactant: COC(=O)Cc1cccc(CN(C(C)C)C2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(Cc1cccc(CC(=O)O)c1)C1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]isopropylamino]methyl]phenyl]acetic acid methyl ester (90 mg), 2N sodium hydroxide (0.5 mL), tetrahydrofuran (2 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. After neutralizing with 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (28 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]3)=[C:19]3[CH:25]=[CH:24][N:23](S(C4C=CC=CC=4)(=O)=O)[C:20]3=[N:21][CH:22]=2)=[O:15])[N:13]=1.C1COCC1>CO.[OH-].[Na+].CCOC(C)=O>[NH2:41][C@H:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:18]2[C:17]([NH:16][C:14]([C:12]3[N:13]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[S:10][CH:11]=3)=[O:15])=[CH:22][N:21]=[C:20]3[NH:23][CH:24]=[CH:25][C:19]=23)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a solution of tert-butyl {(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (175.3 mg, 0.2523 mmol) in MeOH (2.0 mL), aq. NaOH (1.0 M, 2.0 mL) was added, followed by THF (2.0 mL). After stirring at room temperature for 5 h, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (59.1 mg, 52%). LCMS calc. for C22H22F2N6OS (M+H)+: m/z=455.1. found 455.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](OC(C(OCC)=O)(C)C)[CH:5]=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].[Cl-:20].[Al+3].[Cl-].[Cl-]>>[Cl:20][C:6]1[CH:5]=[CH:4][C:3]([C:17](=[O:19])[CH3:18])=[C:2]([OH:1])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(O)c1
Reactant: [Cl-]
Agent: [Al+3]
Product: CC(=O)c1ccc(Cl)cc1O
Temperature: 200 °C

Procedure:
3-chlorophenyl acetate (starting material 2) was mixed with aluminium chloride (3 eq). The mixture was heated at 200° C. for 1 hour. The reaction medium was cooled to room temperature then poured in ice. The aqueous phase was extracted with methylene chloride which was dried on magnesium sulfate then vacuum evaporated.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:15][CH2:14]3)=[N:7][CH:6]=1)=[O:4].[OH-].[Li+:29]>O1CCCC1.CO.O>[Li+:29].[C:22]1([CH3:27])[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:8]3[S:9][C:5]([C:3]([O-:4])=[O:2])=[CH:6][N:7]=3)[CH:12]=2)[O:17]1
Reactant: COC(=O)c1cnc(Oc2ccc3c(c2)CCC(c2ccccc2C)O3)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C1CCc2cc(Oc3ncc(C(=O)[O-])s3)ccc2O1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester (300 mg, 0.8 mmol) in tetrahydrofuran (5.5 ml) and methanol (1.0 ml) at room temperature a solution of lithium hydroxide (18.9 mg, 1.0 eq) in water (1.0 ml) was added and the mixture stirred for 3 h. The solvent was removed under reduced pressure and the resulting residue dissolved in water and lyophilized. The obtained white 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid lithium salt (100% yield) was used in the formation of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid amides without further purification. For the preparation of the free acid, the crude lithium salt was dissolved in water and the resulting solution acidified with aqueous hydrochloric acid. The resulting suspension was filtered and the precipitate washed with water. The obtained 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid was dried under reduced pressure. It can be used in the next step without further purification as described for the lithium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH2:7][NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-benzyloxybenzaldehyde (7.2 g) and ethyl 2-[4-aminophenyl]acetate (4.45 g) were heated on a steam bath for 2 hours. The mixture was cooled and dissolved in ethanol (100 ml) and NaBH4 (0.94 g) was added. The mixture was stirred at ambient temperature for 30 minutes, NaBH4 (0.5 g) added and stirred at ambient temperature for 2 hours. Acetic acid (2 ml) was added dropwise and the solvent evaporated to half volume. The mixture was partitioned between water (100 ml) and diethyl ether (3×75 ml) and the combined organic extracts washed with NaHCO3 (2×50 ml), dried (MgSO4) and evaporated. The residue was subjected to chromatography eluting with CH2Cl2 to give ethyl 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]acetate: (yield 6.4 g, m.p. 73° C.).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Br:8][C:9]1[C:10]([O:19][C@H:20]2[CH2:24][N:23](C(OC(C)(C)C)=O)[C@H:22]([C:32]([OH:34])=[O:33])[CH2:21]2)=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C(Cl)Cl>[Br:8][C:9]1[C:10]([O:19][C@H:20]2[CH2:24][NH:23][C@H:22]([C:32]([OH:34])=[O:33])[CH2:21]2)=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2nc3ccccc3cc2Br)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@@H](Oc2nc3ccccc3cc2Br)CN1
Temperature: 25 °C

Procedure:
TFA (5.0 ml, 65 mmol) was added to a solution of (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (300 mg, 0.686 mmol) in DCM (5 mL) and stirred at RT until LCMS analysis indicated complete conversion. The solution was concentrated to afford the product (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid, TFA (310 mg) as a sticky oil. Yield was assumed to be 100%. ESI-MS(+) m/z=337 (M+H).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5](Cl)[N:4]=1.[OH-].[Na+].[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2ncn(CC(=O)O)c2n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccccc2)c2ncn(CC(=O)O)c2n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Sodium (2.0 g; 87.0 mmol) was dissolved in benzyl alcohol (20 ml) and heated to 130° C. for 2 h. After cooling to 0° C., a solution of 2-amino-6-chloro-9-carboxymethylpurine (23, 4.05 g; 18.0 mmol) in DMF (85 ml) was slowly added, and the resulting suspension stirred overnight at 20° C. Sodium hydroxide solution (1N, 100 ml) was added and the clear solution was washed with ethyl acetate (3×100 ml). The water phase then was acidified to a pH of 3 with 4 N hydrochloric acid. The precipitate was taken up in ethyl acetate (200 ml), and the water phase was extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with saturated sodium chloride solution (2×75 ml), dried with anhydrous sodium sulfate, and taken to dryness by evaporation, in vacuo. The residue was recrystallized from ethanol (300 ml). Yield after drying, in vacuo, over sicapent: 2.76 g (52%). M.p. 159-65° C. Anal. (calc., found) C(56.18; 55.97), H(4.38; 4.32), N(23.4; 23.10). 1H-NMR (DMSO-d6): 4.82 ppm. (s, 2H); 5.51 (s, 2H) 6.45 (s, 2H); 7.45 (m, 5H); 7.82 (s, 1H).
Reaction SMILES: ClC1N=CC2C(=CC=C(OC)C=2)N=1.C[S-].[Na+].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:24][S:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:36])[CH:32]=2)[N:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]([NH:56][CH3:57])=[O:55])[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:57][NH:56][C:54]([C:50]1[CH:49]=[C:48]([O:36][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([S:25][CH3:24])[N:35]=[CH:34]3)[CH:53]=[CH:52][N:51]=1)=[O:55]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CSc1ncc2cc(O)ccc2n1
Agent: COc1ccc2nc(Cl)ncc2c1
Agent: C[S-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)ncc3c2)ccn1
Temperature: 25 °C
Yield: 75 %

Procedure:
The mixture of 2-chloro-6-methoxyquinazoline (1 eq) and sodiumthiomethoxide (2 eq) in ethanol (0.5 M) was refluxed for 3 hours. The reaction was cooled down to room temperature and evaporated. The mixture was taken in ethyl acetate and washed with water and brine, dried in sodium sulfate and concentrated. The resulting crude was treated with dry methylene chloride and ethane thiol (5 eq) was added to it at room temperature. Aluminium chloride (5 eq) was added carefully at 0° C. The reaction was warmed to room temperature and stirred vigorously over night. The reaction was diluted with methylene chloride and saturated Rochelles's salt solution was added and stirred for about 3 hours until 2 layers separated. The organic layer was separated, washed with Rochelle's salt solution (2×), followed by water and brine, dried and evaporated. The crude 2-methylthioquinazolin-6-ol (1 eq) was taken in DMF (0.5 M) and Potassiumbis(trimethylsilyl)amide (2 eq) was added and stirred for 10 min at room temperature. 4-chloro(2-pyridyl)-N-methylcarboxamide (1.1 eq) was added followed by potassium carbonate (1 eq) and stirred at 85-90° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and evaporated. The crude was subjected to column chromatography (4:1 Hexanes in ethyl acetate followed by 2:1 and 1:1 Hexanes in ethyl acetate) to afford the product in 75-85% yield.