Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:43]([CH:39]1[CH2:42][CH2:41][CH2:40]1)=[O:44])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C(Cl)C1CCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)C1CCC1
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and cyclobutanecarboxylic acid chloride as the starting materials in 51% yield. LCMS for C23H23ClN5O (M+H)+: m/z=420.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][O:23][C:24]([C:26](Cl)=[O:27])=[O:25]>>[CH3:22][O:23][C:24](=[O:25])[C:26]([NH:21][C:18]1[CH:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:27]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Product: COC(=O)C(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 60 %

Procedure:
As described for example 179b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) was converted, using methyloxalylchloride instead of acetyl chloride, to the title compound (118 mg, 60%) which was obtained as a white solid after purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1). MS: m/e=368.0 [M+H]+.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O1CCCCC1[O:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:30]=[C:31]([NH:38][C:39]2[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[N:40]=2)[CH:32]=[C:33]2[C:37]=1[NH:36][N:35]=[CH:34]2>CO.CCOC(C)=O>[NH2:45][C:41]1[N:40]=[C:39]([NH:38][C:31]2[CH:32]=[C:33]3[C:37](=[C:29](/[CH:28]=[CH:27]/[CH2:26][CH2:25][OH:24])[CH:30]=2)[NH:36][N:35]=[CH:34]3)[CH:44]=[CH:43][N:42]=1
Reactant: Nc1nccc(Nc2cc(/C=C/CCOC3CCCCO3)c3[nH]ncc3c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nccc(Nc2cc(/C=C/CCO)c3[nH]ncc3c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
PPTS (0.019 g, 0.075 mmol) was added to a mixture of 4-{7-[(E)-4-(tetrahydro-pyran-2-yloxy)-but-1-enyl]-1H-indazol-5-ylamino}-pyrimidine-2-amine (prepared from Example #N.2.7 reacted with trans-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyoxy]-tetrahydropyran using general procedure F, 0.037 g, 0.100 mmol) in MeOH (3.0 mL). The reaction mixture was stirred at about 25° C. for about 5 hours. The reaction mixture was diluted with EtOAc (5 mL) and was washed with aqueous Na2CO3 solution (5 mL). The organic portion was evaporated under reduced pressure to afford (E)-4-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-yl]-but-3-en-1-ol (0.015 g, 0.051 mmol) as an off white solid; RP-HPLC (Table 1, Method e) Rt 0.62 min; m/z: (M+H)+ 297.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:17]2[N:16]3[C@H:18]([CH3:23])[CH2:19][NH:20][C:21](=O)[C@@H:15]3[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:8]>O1CCCC1>[CH2:7]([C:9]1[C:17]2[N:16]3[C@H:18]([CH3:23])[CH2:19][NH:20][CH2:21][C@@H:15]3[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1cccc2c1N1[C@H](C)CNC(=O)[C@@H]1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c1N1[C@H](CNC[C@H]1C)C2
Yield: 38.5 %

Procedure:
Lithium aluminium hydride (37 mg, 0.97 mmol) was added to a solution of (4R,10aS)-6-ethyl-4-methyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one (56 mg, 0.24 mmol) in tetrahydrofuran (3 mL) and the resulting suspension was heated to reflux for 1 h. After cooling the reaction was quenched by careful addition of 1 M aqueous sodium potassium tartrate solution (5 mL). Then methanol (5 mL) and ethyl acetate (5 mL) were added, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography on 20 g SiO2 (CH2Cl2/MeOH/NH4OH 95:5:0.1) yielded the title compound (20 mg, 38%). White solid. ISP-MS: m/e=217.3 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[OH:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[OH:17]
Reactant: COC(=O)c1c(O)cnc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2ncc(O)c(CO)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A solution of 3-hydroxy-6-methoxyquinoline-4-carboxylic acid methyl ester (5 g, 21.44 mmol, 1.0 eq) in tetrahydrofuran (40 mL) is added at 0° C. to a stirred solution of lithium aluminium hydride (1.63 g, 42.88 mmol, 2.0 eq) in tetrahydrofuran (200 mL). After 1 hour stirring at 0° C., the reaction mixture is cautiously quenched with ice-water (5 mL). After 30 minutes stirring at room temperature, the pH is adjusted to 6 by the addition of a 1N hydrochloric acid aqueous solution, the resulting mixture is filtered and the filtrate is concentrated to afford 4-hydroxymethyl-6-methoxy-quinoline-3-ol as a yellow solid (4 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][N:21]=[C:25]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCC(=O)c1ccncc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)CCC(=NOCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccncc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), ethyl 4-oxo-4-(4-pyridyl)butyrate (367 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyrate (740 mg, yield 92%) as a colorless oil from an ethyl acetate-hexane (3:2, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[K+]>>[N+:16]([C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([O-:18])=[O:17]
Reactant: Brc1ccc2nccn2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24 gms. (.122 mole) of 6-bromoimidazo [1,2-a] pyridine in 80 ml. of concentrated sulfuric acid is treated dropwise with 24 ml. of concentrated nitric acid while maintaining a temperature of 15° C with external cooling. When the addition is complete, the reaction mixture is stirred at room temperature for 1/2 hour and poured onto 450 gm. of ice. The pH of the mixture is adjusted to pH 4 with aqueous potassium hydroxide and the resultant solids are collected by filtration. The filter cake is washed with water and dried. Recrystallization from methylene chloride-hexane yields pure 3-nitro 6-bromoimidazo [1,2-a] pyridine m.p. 160°-161° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCC2C(=O)O)cc1

Procedure:
Proline is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 1-[(4-methoxyphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH2:3]1.[N:18]#CBr>C1C=CC=CC=1>[C:1]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:10])[CH2:3]1)#[N:18]
Reactant: CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Reactant: N#CBr
Solvent: c1ccccc1
Product: N#CN1CCCC(CC(=O)c2ccc(F)cc2)C1

Procedure:
The above reaction scheme generally follows the procedure of E. L. Engelhardt, J. Med. Chem., 11, 325 (1968). Briefly, 1-methyl-3-(4-fluorophenacyl)piperidine in benzene solution is treated at essentially ambient temperature with excess cyanogen bromide under a nitrogen purge. Volatile materials are distilled under reduced pressure and the residue is dissolved in chloroform. The chloroform solution is washed, dried, and filtered. Distillation of the chloroform gives 1-cyano-3-(4-fluorophenacyl)piperidine. Hydrolysis of the cyano compound with hydrochloric acid-containing aqueous acetic acid gives the 1-carbamoyl derivative and the completely hydrolyzed and decarboxylated piperidine derivative (wherein the cyano group effectively is replaced with hydrogen). Increasing the amount of hydrochloric acid employed and increasing reaction time appear to favor complete hydrolysis and decarboxylation.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:9]1[C:17]2[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[C-:29]#[N:30].[K+]>CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:8]([C:9]2[C:17]3[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:6][C:29]#[N:30])=[CH:23][CH:24]=1
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
445 mg (1.01 mmol) of the compound from Example 59A and 131 mg (2.01 mmol) of potassium cyanide were dissolved in 23 ml of DMF and stirred at 80° C. for three days. The mixture was 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 102 mg (27% of theory) of the title compound. Also obtained were 180 mg (0.47 mmol) of 3-[3-chloro-1-(4-chlorophenyl)propyl]-5-fluoro-7-[(methylsulfanyl)methyl]-1H-indole.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:22]([C:21]1[CH:20]=[C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:35])=[O:2])=[O:16])[CH3:23]
Reactant: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[3-Ethyl-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (74.7 mg, 0.14 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (61 mg, 1.45 mmol) in water (5 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 61.1 mg (87%). MS m/e 501.9 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[N:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([O:26][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]5[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:35][N:34]=2)[CH:30]=[CH:31]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(CCF)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCN1CCN(CCF)CC1
Temperature: 85 °C
Yield: 56.1 %

Procedure:
4-Chloro-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyquinazoline (172 mg, 0.47 mmol) was dissolved in dimethylacetamide (5 ml). 5-Hydroxy-7-azaindole (69 mg, 0.51 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (71 mg, 0.51 mmol) were added and the mixture heated to 85° C. for 4 hours. The reaction mixture was cooled, filtered and concentrated. The resulting residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (94/6). The fractions containing the expected product were evaporated under vacuum and the residue was suspended in acetone, filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyquinazoline (123 mg, 56%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1([F:53])[CH2:14][CH2:13][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][C:37]([OH:40])=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[C:16]=2[CH:41]([F:52])[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)[CH2:11][CH2:10]1>>[F:53][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:26])([CH3:27])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]4[N:39]=[CH:38][C:37]([O:40][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[C:16]=2[CH:41]([F:52])[C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:51])[F:50])=[CH:46][CH:47]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Product: CCOC(=O)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 13 were performed except for using ethyl bromoacetate instead of ethyl iodide, and from 82 mg (0.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 61 mg of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(2-ethoxy-2-oxoethoxy)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol was obtained. To a solution of 61 mg (0.083 mmol) of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(2-ethoxy-2-oxoethoxy)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol obtained above in 5 ml of diethyl ether, 0.30 ml (0.33 mmol) of 1.1 N methyl magnesium bromide-diethyl ether solution was added at 0° C. The temperature of the reaction solution was raised to room temperature and the reaction solution was stirred for 1 hour. After completion of the reaction, an ammonium chloride aqueous solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography [n-hexane/ethyl acetate=5/6 (V/V)] to provide 18 mg of the title compound as a white solid (yield: 30%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O.[C:17]([O:21][C:22]([NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C(=O)CCC1=O.[CH3:41][O:42][C:43]1[C:48]([O:49][CH3:50])=[C:47]([O:51][CH3:52])[CH:46]=[CH:45][C:44]=1[CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(N(CC)CC)C.C(Cl)Cl>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[C:30]([N:57]1[CH2:56][CH2:55][N:54]([CH2:53][C:44]2[CH:45]=[CH:46][C:47]([O:51][CH3:52])=[C:48]([O:49][CH3:50])[C:43]=2[O:42][CH3:41])[CH2:59][CH2:58]1)=[O:32]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Under cooling with ice, a methylene chloride solution (30 ml) of N,N'-dicyclohexylcarbodiimide (41.2 g) was added dropwise to a methylene chloride solution (70 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (4.98 g) and N-hydroxy succinimide (2.30 g), and the mixture was stirred at room temperature for 4 hours. While cooling again with ice, 1-(2,3,4-trimethoxyphenylmethyl)piperazine=dihydrochloride (6.79 g) was added, and triethylamine (8.5 ml) was then added dropwise. The mixture was stirred overnight at room temperature. After removal of methylene chloride by distillation under reduced pressure, ethyl acetate was added to the residue, and any insoluble matters were removed by filtration. The filtrate was washed first with an aqueous sodium bicarbonate solution and then with an aqueous saturated sodium chloride solution, dried over sodium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained as an oily viscous substance. This substance was purified by silica gel column chromatography (developing solvent: chloroform:methanol=20:1) to yield 9.5 g of tert-butyl (s)-3-methyl-1-[4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl]butylcarbamate as a colorless oily viscous substance (yield: 99%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:33]3[CH:34]=[CH:35][C:36]([CH:39]4[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]4)=[CH:37][CH:38]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Yield: 94.9 %

Procedure:
The title compound was synthesized according to the method of Example A43, except reacting a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (192 mg, 0.446 mmol) with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (190 mg, 0.49 mmol). The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by flash chromatography using EtOAc/hexanes as eluent (1:4 to 7:3) to give the title compound as a yellow solid (239 mg, 80%). 1H NMR (400 MHz, MeOD) δ 7.93-7.90 (m, 3H), 7.36-7.34 (m, 3H), 7.02 (d, J=8.0 Jz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.58 (dd, J=8.0, 4.0 Hz, 1H), 5.55 (s, 1H), 4.39-4.20 (m, 2H), 3.35-3.46 (m, 1H), 3.29 (s, 3H), 2.89-2.79 (m, 2H), 2.76-2.67 (m, 1H), 2.08-2.02 (m 2H), 1.91-1.83 (m, 2H), 1.75-1.61 (m, 2H), 1.51 (s, 9H); MS ESI 565.3 [M+H]+, calcd for [C34H36N4O4+H]+ 565.27.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=1.O>CC(N(C)C)=O>[CH3:25][N:24]1[C:20]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([N:5]3[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]3)[N:14]=2)=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[N:23]1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(-n2cc(C(F)(F)F)cn2)n1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
0.262 g of 4-trifluoromethylpyrazole is introduced under nitrogen in 7 ml of dimethylacetamide and at 0° C. 0.057 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.5 g of 2-fluoro-6-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine is added and the mixture is heated at 140° C. for 7 h, cooled to RT and poured into water. The product is extracted twice with ethyl acetate/heptane (1:1), washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel gives 0.349 g of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Temperature: 80 °C
Yield: 53.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888 mg, 4 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47 g, 6 mmol), bis(triphenylphosphine)palladium(II)dichloride (280 mg, 0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8 mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture was heated at 80° C. for 3 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography (ethyl acetate/hexane gradient) then purified again by column chromatography (methylene chloride/ethyl acetate gradient) to yield 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (738 mg, 53.5% yield):