Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=1.CCCP(=O)=O.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC.C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20](=[O:21])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:23])([F:11])[F:24])[CH:14]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: Brc1ccc2c(c1)CCN2
Agent: CCCP(=O)=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Cc1cccc(C(F)(F)F)c1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To 5-bromoindoline (5.0 g, 25.2 mmol, 1 equiv) and [3-(trifluoromethyl)phenyl]acetic acid (6.18 g, 30.3 mmol, 1.2 equiv) in 13 mL of DMF was added propylphosphonic anhydride (36.9 mL of a 1.71 M solution in DMF, 63.1 mmol, 2.5 equiv) followed by DIEA (8.82 mL, 50.5 mmol, 2 equiv). The reddish mixture became warm to touch and was cooled at once in an ice bath. After 30 minutes, the cooling bath was removed and the mixture was stirred at ambient temp. After 18 h, the mixture was diluted with 200 mL of EtOAc and washed with 200 mL of water. The aq was extracted with 150 mL of EtOAc. The combined organic was dried over MgSO4, filtered, and concentrated in vacuo to give a paste residue, which was taken up in ether and hexane to provide a suspension. The suspension was filtered. The solids were washed with hexane and then ether and dried under vacuum to afford crude product (6.17 g) a brownish sticky solids. NMR showed presence of some alkyl impurities, so this lot was redissolved in DCM (150 mL) and washed with water (50 mL). The organic was dried over MgSO4, filtered, and conc in vacuo. The residue was triturated in DCM (5 mL) and ether (75 mL). The suspension was filtered, and the cake was washed with ether. The solids were dried under vacuum to afford 5-bromo-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (4.73 g) as light cream solids. The filtrate was concentrated in vacuo, and the residue was dissolved in DCM and absorbed onto a dryload cartridge. Purification was done on an SF40-150 g silica gel cartridge using gardient elution of 1% EtOAc in hexane to 45% EtOAc in hexane. The product peak eluted from 24-33% EtOAc. The product fractions were combined and concentrated in vacuo to afford product (2.80 g) as a brownish sticky solid residue. Both NMR and LCMS showed this lot had some impurities. The residue was triturated in DCM and ether. The suspension was filtered, and the cake was washed with ether. The solids were dried under vacuum to afford additional 5-bromo-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (1.62 g) as off-white solids. Both NMR and LCMS showed this lot was pure. LC-MS (ES) m/z=384 [M+H]+, 386. 1H NMR (400 MHz, DMSO-d6) ppm 3.20 (t, J=8.5 Hz, 2H), 4.00 (s, 2H), 4.23 (t, J=8.6 Hz, 2H), 7.32 (dd, J=8.7, 1.9 Hz, 1H), 7.45 (s, 1H), 7.53-7.70 (m, 4H), 7.96 (d, J=8.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C([Li])CCC.CCCCCC.CN(C)[CH:36]=[O:37]>C1COCC1>[F:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([CH:36]=[O:37])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(Br)c2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a solution of tert-butyl 4-(3-bromo-5-fluorophenoxy)piperidine-1-carboxylate (0.666 g, 1.78 mmol) in THF (9.0 mL) at −78° C. was added 2.5M n-butyllithium in hexane (0.78 mL, 2.0 mmol). The solution was stirred at same temperature for 30 minutes, then N,N-dimethylformamide (1.4 mL, 18 mmol) was added to reaction flask. The reaction solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was diluted with methanol and purified with prep-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product as an oil (75 mg, 13%). LCMS (M+H-100)+: 224.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].S(Cl)([Cl:12])(=O)=O>CCCCCC>[Cl:12][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CCC(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Product: CC(=O)C(Cl)CC(C)C
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a refluxing solution of 750 g (6.58 mol) 5-methyl-2-hexanone in 1.13 1 n-hexane at 65° C., 1.06 kg (7.89 mol) sulfuryl chloride was added over a period of 2 h. After complete addition of the sulfuryl chloride, the reaction mixture was allowed to cool to room temperature, was washed 4 times with 150 ml H2O, dried (MgSO4) and concentrated in vacuo. The residue was distilled over a 5 cm Vigreux-column (80 mbar, 67-76° C.) to give 884 g of 3-chloro-5-methyl-2-hexanone in the form of a yellowish liquid (purity: 88%, impurity: 11% 3,3-dichloro-5-methyl-2-hexanone).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCO
Product: O=S(=O)(NCCO)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 33 from 3.97-g (20 mmol) of 4-fluorobenzenesulfonyl chloride and 3.11 g (50 mmol) of ethanolamine, yielding 3.0 g of a white solid; m.p. 77-78° C.; MS (ES) m/z 219.8 (MH+); HRMS (EI) Calcd. for C8H10FNO3S (M+): 219.0366, Found: 219.0369.
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[C:12]([CH3:18])=[C:13](N)[CH:14]=[N:15][CH:16]=1.COCCOC.N(OC(C)(C)C)=O.[C:32]([O:35]C(=O)C)(=[O:34])[CH3:33]>CCCCC>[C:32]([O:35][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([Br:10])[C:12]=1[CH3:18])(=[O:34])[CH3:33]
Reactant: Cc1c(N)cncc1Br
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: CCCCC
Solvent: CCOCC
Product: CC(=O)Oc1cncc(Br)c1C
Temperature: -15 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a flask containing boron trifluoride etherate (0.35 mL, 2.8 mmol) at −15° C. was added a solution of 5-bromo-4-methylpyridin-3-amine (249.0 mg, 1.331 mmol) in 1,2-dimethoxyethane (2.0 mL, 19 mmol). Tert-butyl nitrite (0.20 mL, 1.7 mmol) was then added dropwise and the reaction mixture stirred at −15° C. for one hour. 3 mL pentane was then added and the solid material collected by vacuum filtration. The solid material was dissolved in acetic anhydride (2.0 mL, 21 mmol) and stirred at 100° C. for one hour. The solvent was evaporated in vacuo, and the residue then suspended in 2M aqueous Na2CO3 and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-40% ethyl acetate in heptanes) to yield 117.7 mg (38%) of 5-bromo-4-methylpyridin-3-yl acetate. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.35 (s, 1H), 2.37 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH2:4][CH2:3]1.[C:16]1([CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+].N#N>C(OCC)(=O)C.CN(C)C=O.C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH2:4][CH2:3]1
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN1CCN(c2ccccc2C=C(C(=O)Nc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 11.4 %

Procedure:
To a mixture of 2-(4-methylpiperazin-1-yl)benzaldehyde (0.157 g, 0.77 mmol), 2,N-diphenylacetamide (0.162 g, 0.77 mmol), benzene (1.0 mL) and N,N-dimethylformamide (1.1 mL) was added anhydrous sodium methoxide (0.087 g, 1.62 mmol). Under a nitrogen atmosphere (N2), the mixture was heated to 80° C. for 16 hours, at which time another 46 mg of sodium methoxide (NaOCH3) was added and heating continued at 130° C. for 7 hours. The reaction was cooled to room temperature and was diluted with ethyl acetate (EtOAc), washed twice with 1N lithium chloride (LiCl), once with saturated aqueous sodium chloride, and dried over calcium sulfate (CaSO4). After filtration, the crude product was absorbed onto 450 mg of silica gel and added to a 4.0×8 inch column packed with silica gel and ethyl acetate. Elution with ethyl acetate (200 mL) followed by 1% methanol: 99% ethyl acetate (100 mL) gave 35 mg of a light yellow oil which was crystallized from methylene chloride:hexanes to give the title product, 5 mg, as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([N:20]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH3:21])=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO>[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([N:20]([CH2:22][CH2:23][CH:24]([NH:1][CH2:2][CH:3]([C:5]2[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=2)[OH:4])[CH3:25])[CH3:21])=[CH:18][CH:17]=1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Reactant: CC(=O)CCN(C)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CCN(C)c1ccc(Cl)cc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 144 h

Procedure:
To a solution of 20 mmol 5-(2-amino-1-hydroxyethyl)salicylamide and 4.22 g (20 mmol) 4-(4-chloro-N-methylanilino)-2-butanone [mp 60°-1°, prepared by procedure of Craig, et al, J. Org. Chem., 29, 410 (1964)] in 100 ml methanol add 2.52 g (40 mmol) NaCNBH3. Stir 6 days, concentrate, and partition between EtOAc and 1.0 N NaHCO3 solution. Wash the organic layer with 1.0 N HCl. Neutralize the aqueous portion with NaHCO3 and extract with EtOAc. Dry, concentrate, and recrystallize the residue from EtOAc-hexane to give a white solid, mp 127°-9°.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][CH2:78][OH:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][CH2:78][OH:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCCN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 23.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) ethanol (85 mg, 0.130 mmol) was hydrolyzed by lithium hydroxide (11 mg, 0.261 mmol) in THF/methanol/water (5/2/1 ml) to yield 15 mg (23.0% yield) of the titled compound. 1H NMR (CDCl3, 400 MHz): δ 9.75 (s, 1H), 8.52-8.49 (dd, 2H), 8.149-8.144 (d, 1H), 7.88 (s, 1H), 7.80-7.77 (dd, 1H), 7.72 (s, 1H), 7.478-7.473 (d, 1H), 7.36-7.34 (q, 1H), 7.09-6.97 (m, 3H), 6.81-6.78 (d, 1H), 5.40 (s, 2H), 3.73-3.70 (t, 2H), 3.66-3.64 (t, 4H), 2.95-2.85 (bs, 1H), 2.70-2.64 (m, 6H). MS: m/z=498.3 (M+1), HPLC: 96.68% in method A.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[N:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([F:22])=[CH:14][CH:13]=2)[CH:9]=[C:8]([CH:23]([CH3:25])[CH3:24])[N:7]=1)(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([F:22])=[CH:14][CH:13]=2)[CH:9]=[C:8]([CH:23]([CH3:25])[CH3:24])[N:7]=1)(=[O:3])=[O:4]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N(S(C)(=O)=O)S(C)(=O)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 2-(bismethanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine product from Example 10B above (0.204 g) was dissolved in methanol (5 mL) and treated at room temperature with 2.5N sodium hydroxide solution (0.2 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to dryness and recrystallized to afford 2-(methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine as a crystalline material, m.p. 276°-276.9° C. (prior decomposition at 273° C.).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:24](=[O:26])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([F:20])[CH:22]=3)[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cccc(F)c2)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 3-fluorobenzoic acid (29 mg, 0.21 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered and dried to afford 91 mg (98%) of N-biphenyl-4-yl-3-[4-(3-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 446.18 (M+1)+ 98.1%, 1H NMR: (CDCl3): δ 9.6 (s, 1H), 7.6 (m, 6H), 7.46 (m, 3H), 7.34 (m, 1H), 7.16 (m, 3H), 3.7 (bs, 7H), 3.54 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:14]=[CH:13]2)([O-:9])=[O:8].Cl.NC1C(C)=CC(C(OC)=O)=C(C)C=1.Cl[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>O1CCCC1>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:11]1[C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH3:45]
Reactant: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1cc(C)c(N)cc1C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c([N+](=O)[O-])ccc2c1cnn2C1CCCCO1
Temperature: -40 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of potassium tert-butoxide (2.02 g, 18.0 mmol) in tetrahydrofuran (20 ml) was added dropwise to a solution of the 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.85 g, 7.48 mmol) obtained in Example 317, (d) and ethyl chloroacetate (960 μl, 9.01 mmol) in tetrahydrofuran (10 ml) at −40° C. over a period of 15 minutes, and stirred at −40° C. for 1 hour. The reaction was terminated by pouring 1N-hydrochloric acid, and the reaction solution was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain ethyl(5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetate (1.93 g, 78%).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccnc2[nH]ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid (0.2 g, reference Example 69) in dry dimethylformamide (5 mL), under nitrogen, was treated with 1,1′-carbonyldiimidazole (0.2 g). After stirring at room temperature for 1 hour the resulting tan coloured solution was treated with tert-butanol (260 μL) and DBU (203 μL). This mixture was stirred at 40° C. overnight then evaporated. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueous layer was then extracted twice with ethyl acetate (10 mL). The combined organics were washed twice with brine (10 mL), then dried over sodium sulfate and then evaporated to give the title compound (0.21 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[C:30]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:28][CH:27]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NCc2cccc(F)c2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: C[C@@H]1CC[C@H](C(=O)NCc2cccc(F)c2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Yield: 45.5 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[(3-fluorophenyl)methyl]-6-methyl-3-piperidinecarboxamide (201 mg, 0.435 mmol), 5 mL of EtOH, Hunig's base (0.304 mL, 1.738 mmol), and hydrazine anhydrous (0.082 mL, 2.61 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum to afford the title compound (94 mg) as a light yellow solid. LC-MS (ES) m/z=475 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.16 (m, 3H), 1.60-1.92 (m, 4H), 2.29-2.44 (m, 1H), 2.84-3.07 (m, 1H), 4.20-4.45 (m, 2H), 5.36 (s, 2H), 6.08 (s, 2H), 6.60 (s, 1H), 7.10 (m, 3H), 7.32-7.50 (m, 1H), 7.54-7.63 (m, 1H), 7.70 (s, 1H), 7.95 (s, 1H), 8.49-8.59 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Br[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COC(=O)CCc1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: COC(=O)CCc1ccc(OC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Intermediate 5 (4.50 g) in DMF (20 ml) was added with 60% sodium hydride (440 mg, KANTO) under ice cooling. The reaction mixture was stirred for 10 minutes, then added with bromocyclopentane (1.61 ml, TCI), warmed to room temperature, stirred for 1.5 hours, then warmed to 60° C., and further stirred for 16 hours. The reaction mixture was added with water (50 ml) and isopropyl ether (300 ml)) for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:isopropyl ether=7:1) to obtain the title compound (Compound No. A-5, 2.50 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1)=[O:4].ClCC(Cl)=O.[C:23]1(N2CCNCC2)[C:32]2C(=CC=CC=2)C=C[CH:24]=1.C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[C:13](=[CH:24][CH:23]=[CH:32][CH:17]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: O=C(CCl)N1CCN(c2cccc3ccccc23)CC1
Yield: 92 %

Procedure:
Compound 49A is prepared according to the procedure described for compound 12A using the following reactants: chloroacetyl chloride (270 ml, 3.45 mmol); 1-(1-naphthyl)piperazine (610 mg, 2.88 mmol); calcium carbonate (860 mg, 8.64 mmol); methyl ethyl ketone (20 ml).
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])[OH:19])#[N:8].[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40].CO>CN(C)C=O>[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:39]([C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[O:30][CH3:29])(=[O:41])=[O:40])[C:13](=[O:18])[C:12]2([OH:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])#[N:8]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
1.7 g (15 mmol) of potassium tert-butanolate were added in portions to 4 g (13.6 mmol) of the intermediate 1b in 40 ml of anhydrous dimethylformamide at 0° C., and the mixture was stirred for about 90 minutes. Then 3.4 g (14.3 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were rapidly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h. This solution was then poured into an ice-water/K2CO3 solution, resulting in a precipitate which was isolated. The resulting residue was treated with a little methanol, filtered off with suction and dried, resulting in 3.3 g of the product.