Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH2:33]O)[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:10]1[OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.O.[H-].[Na+]>N1C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C@@:9]12[CH2:33][O:32][C@@H:10]1[C@H:11]([N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[O:12][C@@H:13]2[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CO)(OCc3ccccc3)[C@@H]2O)c(=O)[nH]c1=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@]3(OCc4ccccc4)CO[C@H]23)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
A solution of compound 27 (2.26 g, 4.83 mmol) in anhydrous pyridine (20 cm3) was stirred at −40° C. and a solution of methanesulphonyl chloride (0.482 cm3, 4.83 mmol) in anhydrous pyridine (10 cm3) was added. The reaction mixture was stirred at room temperature for 17 h, water (5o cm3) was added, and the mixture was extracted with dichloromethane (2×100 cm3). The combined organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give an intermediate which after evaporation of the solvents was dissolved in anhydrous DMF (15 cm3). This solution was added dropwise to a suspension of 60% sodium hydride (461 mg, 11.5 mmol) in anhydrous DMF (15 cm3) at 0° C. The reaction was stirred at room temperature for 30 min, then quenched with water (60 cm3). After neutralisation using dilute aqueous hydrochloric acid, the mixture was dissolved in dichloromethane (150 cm3), washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3) and dried (Na2SO4). The solvents were evaporated and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 28 as a white foam (2.00 g, 93%). δH (CDCl3) 9.13 (1H, br s, NH), 7.55 (1H, d, J 1.4, 6-H), 7.40-7.26 (Bn), 5.99 (1H, d, J 2.5, 1′-H), 5.30 (1H, d, J 2.7, 2′-H), 4.88-4.57 (6H, m, 1″-Ha, 1″-Hb, Bn), 4.22-4.19 (1H, m, 4′-H), 3.92 (1H, dd, J 6.2, 10.8, 5′-Ha), 3.82 (1H, dd, J 3.7, 10.8, 5′-Hb), 1.91 (3H, d, J 1.3, CH3). δC (CDCl3) 163.8 (C-4), 150.3 (C-2), 137.6 (C-6), 137.5, 137.0 (Bn), 128.7, 128.6, 128.2, 128.0, 127.8, 127.3 (Bn), 109.8 (C-5), 85.7 (C-3′), 84.1 (C-1′), 83.5 (C-4′), 79.7 (C-1″), 73.9 (C-2′), 73.6 (C-5′), 68.6, 67.8 (Bn), 12.4 (CH3). FAB m/z 451 [M+H]+, 473 [M+Na]+. Found: C, 66.3; H, 5.9; N, 6.1; C25H26N2O6 requires C, 66.7; H, 5.8; N, 6.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:21]5[CH:22]=[CH:23][C:18]([CH3:32])=[CH:19][CH:20]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, light brown foam (78 mg, 61%), MS (ISP) m/z=369.2 [(M+H)+], was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (90.2 mg, 447 μmol).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH:6]1[CH:15]=[CH:14][C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=O>Cl>[NH:3]1[C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH2:14][CH2:15][C:6]=2[NH:5][C:2]1=[O:1]
Reactant: NC1C=Cc2cnccc2C1=O
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: O=c1[nH]c2c([nH]1)-c1ccncc1CC2
Reaction time: 2 h
Yield: 25.8 %

Procedure:
Potassium cyanate (8.63 g, 0.106 mole) was added to a solution of 6-aminoisoquinolin-5-one (5.0 g, 0.0213 mole) in hydrochloric acid (pH=1) while maintaining the acidity constant by subsequent addition of concentrated hydrochloric acid. After stirring for about 11/2 hours, the product precipitated andwas obtained by filtration. Recrystallization from 50% aqueous ethanol gave 1.03 g (25%) of the desired product, m.p. >310° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=O)=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:53]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20]([Cl:53])=[N:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1ccc(C2CC(C(Cl)=Nc3ccc(C(F)(F)F)cc3)=NN2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.2 %

Procedure:
To a solution of 2.50 g (0.0054 mol) of 1-(4-chlorophenyl)-5-(4-fluorophenyl)-N-[4-(trifluoromethyl)-phenyl]-1H-pyrazole-3-carboxamide dissolved in 15 mL of acetonitrile was added 1.80 g (0.0067 mol) of triphenylphosphine and 0.83 g (0.0054 mol) of carbon tetrachloride. The yellow solution was stirred at room temperature overnight and concentrated to afford 4.0 g of a yellow solid. The crude product was chromatographed on silica gel using ethyl acetate (10%) and hexanes (90%) as eluents which afforded 0.64 g of a yellow solid, mp 154° C. to 156° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[F:21][C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28]>>[F:21][C:22]1[S:26][C:25]([NH:27][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:24][C:23]=1[CH3:28]
Reactant: Cc1nc(N)sc1F
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(C)c(F)s2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 5-Fluoro-4-methyl-thiazol-2-ylamine instead of 3-Chloroaniline acid to yield the final compound as an orange solid, MS (ISP): m/e=364.2 (M+H)+.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO.[NH4+].[OH-]>O.CO.C(Cl)(Cl)Cl>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[C:19]2[C:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4F)c3c2CC1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
3-Benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (3.50 g, 9.1 mmol), potassium hydroxide (11.80 g, 183 mmol), and ethylene glycol (80 mL) were heated to 170° C. for 6.6 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give a red oil which was passed through a column of silica gel with 1:19 methanol/chloroform with 1% NH4OH to give 2.43 g (95%) of a white solid as the title compound: mp 121.8-126.3° C. 1H NMR (400 MHz, CDCl3) δ 8.02 (br s, 1H), 7.42-7.34 (m, 3H), 7.26-7.16 (m, 3H), 6.98 (d, J=7.2 Hz, 1H), 3.16-2.86 (m, 6H), 2.58-2.53 (m, 1H), 2.46-2.39 (m, 1H); MS m/z 281.2 (M++H).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[Cl:34])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:34][C:25]1[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:24]=1[CH:11]([C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3Cl)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3Cl)c[nH]c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
176 mg (2.70 mmol) of potassium cyanide and 8.2 mg (0.07 mmol) of 4-N,N-dimethylaminopyridine were added to 664 mg (1.35 mmol) of the compound from Example 108A in 29 ml of DMSO. The mixture was stirred at 120° C. for 1 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 460 mg (81% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[F:42][C:43]1[CH:44]=[C:45]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(F)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 59.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-fluorobenzenesulfonyl chloride (0.0260 mL, 0.195 mmol) to obtain 4-(3-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0241 g, yield 60%).
Reaction SMILES: Cl.[CH2:2]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:19][O:20][CH:21]([C:26](OC)=[O:27])[C:22](OC)=[O:23]>C(O)(=O)C>[OH:23][C:22]1[C:21]([O:20][CH3:19])=[C:26]([OH:27])[N:16]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=2)[N:15]=1
Reactant: CCCCCCCCc1ccc(C(=N)N)cc1
Reactant: COC(=O)C(OC)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(-c2nc(O)c(OC)c(O)n2)cc1
Yield: 89.3 %

Procedure:
Metal sodium (23.4 g, 1.02 mol) was added to methanol (500 ml) to obtain sodium methoxide, followed by adding thereto 4-octylbenzamidine hydrochloride (84 g, 0.31 mol) and dimethyl methoxymalonate (55 g, 0.31 mol), refluxing the mixture for 8 hours, pouring the reaction mixture in acetic acid (500 ml), filtering off deposited crystals, washing them with water and drying to obtain 4,6-dihydroxy-5-methoxy-2-(4-octylphenyl)pyrimidine (91.5 g).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.CC[O-].[Na+].[CH3:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]>C(O)C>[CH2:8]([O:7][C:5](=[O:6])[C:4]([CH2:15][C:16](=[O:17])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])[CH3:9]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
146 g (1 mol) of oxalic acid diethyl ester are added dropwise to 367.2 g of a 20% strength sodium ethylate solution in ethanol at 5° C. in the course of one hour, whilst stirring. 100 g of technical grade pinacolin are allowed to run in and the mixture is stirred for a further 15 minutes. It is then heated to 80° C. and heated under reflux for 3 hours. The solution is subsequently evaporated to dryness in a rotary evaporator. The residue is suspended in 200 ml of toluene and the suspension is stirred with 253 g of aqueous sulphuric acid (20.9% strength by weight) at 50° C. for 1 hour. The organic phase is separated off and distilled. 177 g of pivaloylpyruvic acid ethyl ester (88.2% of the theoretical yield) are obtained with a purity of 99.6% (by analysis by gas chromatography).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClCCl.S(Cl)(Cl)=O.[CH3:50][NH2:51].CO>CN(C)C=O>[CH:10]1[C:11]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:51][CH3:50])=[O:41])[CH2:15]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
5-[4-(9H-9-Carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-pentanoic acid (0.12 g, 0.21 mmol) prepared in Example 128 was mixed with dichloromethane (5 ml), N,N-dimethylformamide (100 μl) and thionyl chloride (24 μl). The resulting mixture was stirred at 50° C. for 30 minutes and then cooled on ice, followed by addition of a 40% methylamine/methanol solution (1 ml), and stirring was continued at room temperature for an additional 4 hours. The reaction mixture was partitioned between ethyl acetate and saturated brine, washed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/4) to give the titled compound (0.10 g, yield: 83%) as a white crystal (cis:trans=4:1).
Reaction SMILES: C([O:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:31])=[O:8]
Reactant: O=C(OCc1ccccc1)c1ccccc1Oc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccccc1Oc1ccccc1O
Reaction time: 8 h

Procedure:
2-(2-Benzyloxy-phenoxy)-benzoic acid benzyl ester (440 mg, 1 mmol) was dissolved in ethanol (30 mL), and 10% palladium on carbon (44 mg) was added. The mixture was stirred overnight under nitrogen protection. The suspension was filtered, evaporated by a rotatory evaporator to produce 2-(2-hydroxy-phenoxy)-benzoic acid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([O:32][C:33](=[O:43])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:43])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:26])[CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(N)c1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(CCC(=O)OC(C)(C)C)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Yield: 63.2 %

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) (364 mg, 1.00 mmol) was reacted with 3-(3-amino-phenyl)-propionic acid tert-butyl ester (243 mg, 1.10 mmol) according to the procedure of Example 70, step c to afford the product as a colourless foam (359 mg, 63%). 1H NMR (300 MHz, CDCl3) 9.14 (1H, br s), 9.07 (1H, br s), 7.59-7.51 (3H, m), 7.35-7.22 (4H, m), 6.94 (1H, d), 3.16 (2H, m), 2.92 (2H, m), 2.60 (3H, s), 2.56 (2H, m), 1.99 (3H, s), 1.76-1.44 (23H, m).
Reaction SMILES: C[O:2][C:3](=O)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:12][C:11]1[N:10]=[C:9]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[O:2]
Reactant: COC(=O)NN=Cc1nc(-c2cccc(C(F)(F)F)c2)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2c(=O)[nH]ncc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 155.2 %

Procedure:
3-{[5-Methyl-2-(α,α,α-trifluoro-m-tolyl)-4-imidazolyl]-methylene}carbazic acid methyl ester (3.0 g) is added rapidly to diphenyl ether (50 ml) preheated to 297° C., and the mixture is then kept at 297° for 15 minutes. The mixture is rapidly cooled to room temperature, hexane (50 ml) is added and the mixture filtered to yield 4.2 g yellow solid. This material is chromatographed on a silica gel column using a hexane-ethyl acetate mixture as eluent. The fractions found to be identical by TLC are combined to afford 1.86 g of the title product, m.p. 194°-194.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]([CH:37]1[CH2:40][NH:39][CH2:38]1)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][O:34][C:35]([CH:37]1[CH2:40][N:39]([C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[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]2)=[O:30])[CH2:38]1)=[O:36]
Reactant: COC(=O)C1CNC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), azetidine-3-carboxylate methyl ester hydrochloride (200 mg, 1.32 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to yield 1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid methyl ester (26 mg, 10.7%). The ester was taken directly to the hydrolysis step by dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid (11.8 mg, 46.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H27Cl2F2N3O3+H [(M+H)+]: 550.1471. found: 550.1471.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:41])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([CH:38]=[CH:39][N:40]=4)[N:20]=[C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[CH:22]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[NH2:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([NH:23][C:21]2[CH:22]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:41])=[CH:15][CH:14]=3)[C:18]3[N:19]([CH:38]=[CH:39][N:40]=3)[N:20]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccc(NC(=O)Nc4ccccc4)cc3)c3nccn3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(NC(=O)Nc4ccccc4)cc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 2 dram vial was added tert-butyl(trans)-4-(8-(4-(3-phenylureido)phenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (0.035 g, 0.06 mmol) from 1d and 4.0M HCl in 1,4 Dioxane (2.0 ml). The reaction was stirred for 1 hr at 25° C., concentrated and then triturated with diethyl ether. The titled compound was filtered off as an HCl salt (0.018 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 9.36 (1H, s), 9.00 (1H, s), 8.88 (1H, s), 8.67 (1H, s), 8.60 (1H, s), 8.10 (1H, s), 7.87 (2H, d, J=5.09 Hz), 7.54 (1H, d, J=9.16 Hz), 7.44 (2H, t, J=7.63 Hz), 7.34 (1H, s), 7.20-7.31 (2H, m), 6.85-7.04 (2H, m), 6.27 (1H, s), 3.38 (1H, s), 3.02 (1H, s), 2.04 (2H, m), 1.95 (2H, m), 1.31-1.53 (2H, m), 1.11-1.29 (2H, m). LC/MS, m/e 457 (M+1). HPLC Rt, 1.93 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@:22]([CH:27]4[CH2:29][CH2:28]4)([C:25]#[N:26])[C:21]3=[O:30])[CH:17]=[CH:16][N:15]=2)[CH:10]=[N:9]1)([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:38][O:39][CH2:40][C:41]([Cl:43])=[O:42].O>O1CCCC1>[ClH:43].[C:25]([C@@:22]1([CH:27]2[CH2:28][CH2:29]2)[CH2:23][CH2:24][N:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]3[CH:10]=[N:9][N:8]([C:5]([CH3:7])([CH3:6])[CH2:4][NH:3][C:41](=[O:42])[CH2:40][O:39][CH3:38])[CH:12]=3)[N:19]=2)[C:21]1=[O:30])#[N:26]
Reactant: CC(C)(CN)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCC(=O)NCC(C)(C)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.1 %

Procedure:
To a solution of (3S)-1-(2-((1-(1-amino-2-methylpropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile dihydrochloride (100 mg) obtained in Example 115 in tetrahydrofuran (5 mL) were added successively dropwise triethylamine (0.15 mL) and methoxyacetyl chloride (26 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). To a solution of the residue (89 mg) in ethanol (5.0 mL) was added 1 M hydrochloric acid (0.20 mL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (81 mg).