Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)([O:13]CC1C=CC=CC=1)=[O:12]>C1C=CC=CC=1>[C:11]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:29])=[CH:23][CH:22]=1)([OH:13])=[O:12]
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccccc1
Reaction time: 8 h

Procedure:
2-Hydroxy-2-phenylethanamine (0.68 g) and 1-(4-carbobenzyloxyphenyl)propan-2-one (1.34 g) were refluxed in benzene (50 ml) in a Dean and Stark apparatus for 2 hours. The solvent was removed, tetrahydrofuran (50 ml), benzene (10 ml) and water (3 ml) were added followed by sodium borohydride (0.9 g). The reaction mixture was left at room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between water and ether. The layers were separated and the organic layer dried (MgSO4). Removal of the solvent gave the title compound as the benzyl ester (1.67 g). This was dissolved in ethanol amd hydrogenated at 75 psi and 50° for 4 hours. Filtration and evaporation of the solvent gave the title compound mp 180°-190° (ethyl acetate-methanol). τ (TFA-d) 8.5 (3H, d, J=7 Hz), 5.85-7.45 (5H, m), 4.72 (1H, broad), 2.6 (7H, m), 1.8 (2H, d, J=8 Hz). τ (d6DMSO+D2O+NaOD) 9.05 (3H, d, J=7 Hz), 6.9-7.7 (5H, m), 2.85 (2H, d, J=8 Hz), 2.7 (5H, s), 2.17 (2H, d, J=8 Hz).
Reaction SMILES: IC.C[N:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=S)[NH:22][CH3:23])[CH2:17][CH2:16]1)[C:5](=O)OCC1C=CC=CC=1.C(O[CH:28](OCC)[CH2:29][NH2:30])C>CO>[CH3:5][NH:4][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]([CH3:23])[CH:28]=[CH:29][N:30]=2)[CH2:19][CH2:20]1
Reactant: CCOC(CN)OCC
Reactant: CNC(=S)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Solvent: CO
Solvent: CI
Product: CNC1CCN(c2nccn2C)CC1
Reaction time: 20 h

Procedure:
A solution of iodomethane (0.22 ml, 3.4267 mmol, 1.1 eq) in methanol (5 ml) was added dropwise over a period of 5 min to a solution of benzyl methyl(1-(methylcarbamothioyl)-piperidin-4-yl)carbamate (1 g, 3.115 mmol, 1 eq) in methanol (10 ml). Stirring was then carried out for 20 h at room temperature. When the reaction was complete according to TLC monitoring, the reaction mixture was concentrated under reduced pressure. The residue was taken up in pyridine (15 ml); aminoacetaldehyde-diethylacetal (455 mg, 3.4267 mmol, 1.1 eq) was added and refluxing was carried out for 10 h. The reaction mixture was concentrated under reduced pressure, 2 N HCl solution (20 ml) was added, and the mixture was refluxed for 5 h. The reaction mixture was concentrated under reduced pressure and dried by removal of toluene by distillation. The crude product was used in the next stage without being purified further. Yield: 1.1 g (5.67 mmol)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][C:33](Cl)=[O:34])(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:31][CH2:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:11]([C:13](=[O:14])[NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[N:12]=2)=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(C)cc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Aminophenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.30 g) obtained in Example 21 was dissolved in pyridine (20 ml) and acetoxyacetyl chloride (0.1 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated and the residue was purified by silica gel chromatography using, as a mobile phase, chloroform/ethyl acetate=20:1. Theresidue was recrystallized from ethyl acetate to give 4-[5-(4-methylphenyl)-4-(2-thiazolylcarbamoyl)imidazol-2-yl]phenylcarbamoylmethyl acetate (0.13 g), melting point 250° C. or above.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)=[O:22])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:27]3[CH:28]=[C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH:24]=[N:25][CH:26]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 75 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 200 mg of 3-ethoxycarbonylpyridine-5-boronic acid pinacol ester (250 mg) and 23 mg of bis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1M Na2CO3 aqueous solution and 1.5 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 10˜100% EtOAc/hexane to yield ethyl 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate (240 mg, 75%).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]([OH:30])[CH2:26][C:27](O)=[O:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].II>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]([OH:30])[CH2:26][CH2:27][OH:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CC(=O)O)c2c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CCO)c2c1
Yield: 41.2 %

Procedure:
A solution of 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3-hydroxybutanoic acid (50.0 mg, 0.11 mmol, prepared in analogy to Example 11-3), sodium borohydride (100.0 g, 2.6 mmol) and iodine (300.0 mg, 1.2 mmol) in tetrahydrofuran (10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 20.0 mg of the desired product as a light yellow solid (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=7.58 Hz, 1 H), 7.90 (d, J=7.58 Hz, 1 H), 7.81 (brs, 1 H), 7.75-7.59 (m, 2 H), 7.59-7.41 (m, 2 H), 6.10 (s, 1 H), 5.25 (brs, 2 H), 4.53 (brs, 2 H), 4.12 (brs, 1 H), 3.82 (t, J=5.94 Hz, 2 H), 3.68 (brs, 2 H), 3.55 (dd, J=13.77, 4.17 Hz, 1 H), 3.44 (dd, J=13.64, 7.33 Hz, 1 H), 2.45 (s, 3 H), 1.97-1.73 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14]O)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:14][CH:13]([N:12]1[C:11]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
The solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL dichloromethane was cooled to 0° C. and 134 mg (0.51 mmol) triphenylphosphine and 170 mg (0.51 mmol) carbon tetrabromide were added. The reaction was stirred for 48 h at rt. and then evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the desired compound as white solid (9%). MS (Turbo Spray): m/z=453.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].[K+].[Br-]>>[OH:29][NH:28][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 37 %

Procedure:
2-(4Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of the product isolated. Yield 37%; pale yellowish solid; mp 65° C.; MS: 392.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.80 (t, J=7.2 Hz, 3H), 1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J=14.4 Hz, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm−1): 3064m, 2958s, 2871m, 1671m.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24]C(O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.ClC1C=CC(C2CCNCC2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Clc1ccc(C2CCNCC2)cc1
Product: Fc1ccc(N2CCN(CCc3[nH]nc4c3CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 2-(4,5,6,7-tetrahydro-2H-indazol-3-yl)acetic acid obtained in Starting Material Synthesis Example 2 and 1-(4-fluorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Staring Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2H-indazole is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17]>C(O)C>[N:21]1[CH:22]=[CH:23][C:18]([CH2:16][CH2:17][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: C=Cc1ccncc1
Solvent: CCO
Product: c1ccc2c(c1)CCN2C1CCN(CCc2ccncc2)CC1
Yield: 42.5 %

Procedure:
1-(4-Piperidyl)indoline (0.1 g) was dissolved in ethanol (5 ml). After adding 4-vinylpyridine (0.16 ml), the resultant mixture was heated under reflux in a nitrogen atmosphere for 12 hr. Then the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (toluene/acetone system) to give the title compound (0.064 g) as a colorless oil (yield: 42.5%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[N:1]1([CH2:25][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=3)=[CH:31][CH:32]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccc(CN3CCCc4ccccc43)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
To a solution of tetrahydroquinoline (20 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(3,4-dihydro-2H-quinolin-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (21 mg, 45%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (br. s., 1H), 7.97 (br. s., 1H), 7.84 (d, J=8.2 Hz, 2H), 7.47-7.57 (m, 1H), 7.38 (d, J=7.8 Hz, 2H), 6.72-6.93 (m, 2H), 6.36-6.50 (m, 2H), 4.53 (s, 2H), 3.34-3.43 (m, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.93 (dt, J=11.2, 5.7 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:35][CH2:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C(CCCI)c1ccccc1
Reactant: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a solution of methyl 3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.12 g, 0.33 mmol) and potassium carbonate (0.091 g, 0.66 mmol) in N,N-dimethylformamide (3 mL), was added 4-iodo-1-phenylbutan-1-one (0.09 g, 0.33 mmol). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, and isolated by Biotage flash chromatography (1-8% methanol/dichloromethane) to obtain the title compound (0.11 g, 65%); 1H NMR (DMSO-d6): δ 1.75 (d, 2H, J=10.8 Hz), 1.83 (t, 2H, J=7.2 Hz), 2.35-2.41 (m, 4H), 2.67-2.74 (m, 4H), 3.04 (t, 2H, J=7.2 Hz), 3.88 (s, 3H), 5.19 (s, 2H), 6.87 (t, 1H, J=7.6 Hz), 7.02 (d, 2H, J=8 Hz), 7.24 (t, 2H, J=8.4 Hz), 7.52 (t, 2H, J=7.2 Hz), 7.57-7.65 (m, 2H), 7.79 (dt, 1H, J=8 and 1.2 Hz), 7.90-7.99 (m, 3H), 8.58 (t, 1H, J=1.6 Hz); MS for C31H33N3O4 m/z 512.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:49](=[O:72])([O:54][C@H:55]1[C@@H:59]2[O:60][C:61]([CH3:64])([CH3:63])[O:62][C@@H:58]2[O:57][C@H:56]1[C@@H:65]1[CH2:69][O:68][C:67]([CH3:71])([CH3:70])[O:66]1)[O:50][CH:51](Cl)[CH3:52]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH:51]([O:50][C:49]([O:54][C@@H:55]3[C@H:59]4[O:60][C:61]([CH3:64])([CH3:63])[O:62][C@H:58]4[O:57][C@@H:56]3[C@H:65]3[CH2:69][O:68][C:67]([CH3:70])([CH3:71])[O:66]3)=[O:72])[CH3:52])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)OC(=O)O[C@H]1[C@@H]2OC(C)(C)O[C@@H]2O[C@H]1[C@@H]1COC(C)(C)O1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)O[C@@H]2[C@H]3OC(C)(C)O[C@H]3O[C@@H]2[C@H]2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) in dry dimethyl formamide (4 mL) was added cesium carbonate (185 mg, 568 μmol). The mixture was stirred for 10 min at room temperature. The freshly made solution of 1-chloroethyl (3aS,5S,6R,6aS)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yl carbonate (178 mg, 487 μmol) in 4 mL of dry dimethyl formamide was added to the above mixture and stirred at room temperature overnight. It was diluted with ethyl acetate and washed with water (2×) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude, which was purified with flash chromatography (0-50% ethyl acetate in hexane over 25 min) to give an off-white solid (127 mg, 82% yield). LCMS (ES+) m/z calcd. for C46H51Cl2F2N3O12 [(M+H)+]: 946, found: 946.
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:34]1[CH:39]=[CH:38][C:37]([I:40])=[CH:36][CH:35]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][N:29]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]1[N:18]=[N:19][N:20]=[C:13]1[N:12]=[C:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]([C:34]4[CH:35]=[CH:36][C:37]([I:40])=[CH:38][CH:39]=4)([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][N:29]=4)[NH2:1])[CH:9]=3)[N:14]3[N:18]=[N:19][N:20]=[C:13]3[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N
Reactant: Cn1cnnc1C(Cl)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cnnc1C(N)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 60 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
NH3/iPrOH (45 ml) was added dropwise at 5° C. to a mixture of 7-[chloro(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline (0.0076 mol) in THF (45 ml). The mixture was brought to room temperature, poured out into a pressure vessel, stirred at 60° C. for 6 hours, cooled and poured out into ice water. The precipitate was filtered off and dried under a vacuum, yielding 1.6 g of a first batch of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine (35%) The aqueous layer was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.7 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH 84/15/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.03 g (23%) of a second batch of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine. A sample (0.23 g) was crystallized from CH3CN, the precipitate was filtrated and dried yielding 0.09 g of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine, mp. 238° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C[Si]([C:15]#[CH:16])(C)C>>[C:15]([C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1)#[CH:16]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#C[Si](C)(C)C
Product: C#Cc1ccc(S(N)(=O)=O)s1

Procedure:
Prepared from 5-bromo-thiophene-2-sulfonic acid amide (1.94 g, 8 mmol) and trimethylsilylacetylene (2.2 mL, 12 mmol) by applying in analogous manner the procedures described in example D.1 (method 1, steps 1-2). Obtained after chromatographic purification of the crude product (SiO2, 0-75% AcOEt/heptane) as a light brown solid (0.49 g, 33%). MS (ISP) 186.1 [(M−H)−]; mp 114-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[N:20]4)=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].O[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCN1CCOCC1
Yield: 71.4 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (450 mg, 1.40 mmol), (prepared as described in Example 197), in DMF (50 ml) was added anhydrous potassium carbonate (773 mg, 5.60 mmol) and 4-(2-hydroxyethyl)morpholine (335 mg, 1.80 mmol), and the reaction heated under reflux for 2 hours. The DMF was evaporated in vacuo, and the residue partitioned between dichloromethane and 1N aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×200 ml), dried (MgSO4) and concentrated in vacuo. The crude product was triturated with hexane/ether to afford a solid which was filtered and dried under suction to give 6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline (430 mg, 1.00 mmol, 71%) as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:7]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH2:2][N:3]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[CH:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=CC(N3CCN(c4ncccc4C(F)(F)F)CC3)=NCN2c2cccnc2)cc1Cl
Temperature: 25 °C

Procedure:
Heat a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-pyrimidine, (47 mg, 0.1 mmol), 3-tri-n-butylstannylpyridine (92 mg, 0.25 mmol), Pd(PPh3)4 (6 mg, 0.005 mmol), in toluene (5 mL) at 110° C. for 16 hours. Let cool to room temperature, filter off the catalyst, and add water (5 mL). Extract with EtOAc, dry (Na2SO4), and evaporate. Purify using flash chromatography (9:1 hexanes/EtOAc) to give pure 4-(3-chloro-4-fluorophenyl)-3-pyridin-3-yl-6-[4-(3-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-pyrimidine as a tan solid. 1H NMR (DMSO D6): 9.75 (s, 1H). 9.21 (d, 1H), 8.97 (d, 1H), 8.62 (d, 1H), 8.58 (d, 1H), 8.40 (dd, 1H), 8.19 (d, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.58 (s, 1H), 7.21 (dd, 1H), 4.01 (br m, 8H).