Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:5])C.[OH-].[Li+]>>[C:24]1([N:7]2[CH2:8][CH:9]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])(=[O:12])=[O:13])[CH2:10][CH:6]2[C:4]([OH:5])=[O:3])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc2ccccc12

Procedure:
In analogy to the procedure described in example 253e, 1-naphthalen-1-yl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=450.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:11][CH:12]([OH:14])[CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 147a (1.0 g, 5.1 mmol), 10% palladium on carbon (10% wet, 100 mg), and ethanol (40 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 5 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 147b as a yellow solid (792 mg, 85%). MS-ESI: [M+H]+ 166.1.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:44](P(=O)(OCC)OCC)[P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48].CN(C)C=O.[H-].[Na+]>O>[CH2:47]([O:46][P:45](/[CH:44]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:49][CH2:50][CH3:51])=[O:52])[CH3:48]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)cc1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.45 g), tetraethyl methylenediphosphonate (0.25 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.04 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl {4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as a colorless oil (0.28 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (6:1, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](=[O:29])[N:23]([CH2:25][C:26]([OH:28])=O)[CH:24]=2)=[CH:15][CH:14]=1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:9]([CH3:10])[C:26](=[O:28])[CH2:25][N:23]1[CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH:20]=[CH:21][C:22]1=[O:29]
Reactant: COc1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Reactant: CNCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(=O)n(CC(=O)N(C)Cc3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
According to Scheme 9 Step 3: To a solution of (3-chlorophenyl)-N-methylmethanamine (1 eq, 0.19 mmol, 0.03 g), 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetic acid (1 eq, 0.19 mmol, 0.05 g) and hydroxybenzotriazole (1.1 eq, 0.21 mmol, 0.03 g) in CH2Cl2 (2 mL) at room temperature was added EDCI.HCl (1.5 eq, 0.29 mmol, 55 mg). The reaction was stirred at room temperature for 12 hours then diluted with AcOEt. The reaction washed with brine and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt (50/50) as eluent to afford the N-(3-chlorobenzyl)-2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-N-methylacetamide (0.11 mmol, 44 mg, 57%) as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:21]=[C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])[S:18][CH:19]=2)=[CH:23][CH:24]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NS(=O)(=O)c3ccc(Cl)cc3Cl)cc2)cs1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (1.5 ml) was added to a solution of methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 160 mg) in DCM (4 ml), and reaction mixture was stirred for 5 minutes. 2,4 dichloro benzenesulfonyl chloride (130 mg) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated to obtain sticky solid, was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 215 mg (82%); 1H NMR (CDCl3, 300 MHz): δ 7.97 (d, 1H), 7.81 (d, 2H), 7.75 (d, 1H), 7.63 (s, 1H), 7.51 (d, 1H), 7.33 (dd, 1H), 7.21 (d, 2H), 7.13 (bs, 1H), 4.73 (m, 1H), 3.78 (s, 3H), 2.32 (m, 1H), 1.04 (dd, 6H); MS (ESI) m/z 542.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=[C:7]([O:9]C)[CH:8]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(NS(C)(=O)=O)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
N-(3,5-Dimethoxyphenyl)methanesulfonamide (1.7 g, 6.53 mmol) was dissolved in dichloromethane (28 ml). A solution of boron tribromide (1 M in dichloromethane, 33 mL, 33 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Boron tribromide (1M in dichloromethane, 10 ml, 10 mmol) was added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 344 mg (26% yield) of the title compound. Purity 99%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:9]=1)=[O:7])=O.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1.[BH3-]C#N.[Na+]>O1CCOCC1>[CH:36]1([NH:40][CH2:1][C:3]2[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=2)[C:6]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[N:9]=2)=[O:7])[CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(CNC2CCC2)c1

Procedure:
A mixture of Example 158C (100 mg, 0.2 mmol), cyclobutanamine (30 mg, 0.4 mmol) and NaCNBH3 (13 mg, 0.2 mmol) in dioxane (5 mL) was heated at 70° C. for two days. The volatiles were removed, and the residue was purified by HPLC (Zorbax C-18, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound. MS (DCI/NH3) m/z 529 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=3)=[O:26])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N2CCN(c3cccc4nc(N)nc(N)c34)CC2)cc1
Yield: 41 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and p-toluoyl chloride (63.4 mg; 0.41 mmol) to obtain 29.5 mg. (41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.37 (m, 2H), 7.26 (m, 3H), 7.14 (br s, 1H), 6.98 (d, J=6.4 Hz, 1H), 6.86 (d, J=5.6 Hz, 1H), 5.92 (br s, 2H), 4.58 (br s, 1H), 4.35 (br s, 1H), 3.66 (br s, 1H), 3.44 (m, 1H), 3.11 (m, 3H), 2.77 (m, 2H), 2.35 (s, 3H). ESIMS+363.8 m/z
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:12]2[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:11]=2[C:10]=1[C:35]#[N:36].O.C(=O)([O-])[O-:52].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[C:12]2[N:24]=[CH:25][NH:26][C:11]=2[C:10]=1[C:35]([NH2:36])=[O:52]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)c4ncn(COCC[Si](C)(C)C)c4c3C#N)c(Cl)c2)CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)cc2Cl)nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To the product of Example 42E (200 mg, 0.27 mmol) in concentrated sulfuric acid (4 mL) at 0° C. was added water (0.4 mL) and the mixture was stirred at 0° C. for 10 minutes and at 80° C. for 40 minutes. After cooling to ambient temperature, the mixture was poured into ice-water, adjusted to pH 9 by saturated aqueous sodium carbonate and extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.66 (s, 1H), 11.86 (s, 1H), 9.58 (s, 1H), 8.76 (brs, 2H), 8.63 (s, 1H), 7.83-7.78 (m, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.49-7.43 (m, 2H), 7.01 (d, J=2.4 Hz, 1H), 6.43 (dd, J=9.0, 2.4 Hz, 1H), 4.73 (s, 2H), 3.27 (s, 8H). MS: 530 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14].[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=2[C:13]([F:15])([F:16])[F:14])=[CH:25][CH:24]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)c(C(F)(F)F)c1
Product: N#Cc1ccc(N(CCOc2ccc(F)cc2)CC(F)(F)F)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-3-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (APCI) m/z 407 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:11]([S:14](Cl)(=[O:16])=[O:15])([CH3:13])[CH3:12]>ClCCl>[CH:11]([S:14]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:16])=[O:15])([CH3:13])[CH3:12]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
Add 4-methoxy-benzylamine (11.7 m, 89.5 mmol) to a solution of isopropyl sulfonyl chloride (5.0 mL, 44.74 mmol) in dichloromethane (100 mL) and stir for 18 hours at ambient temperature. Wash solution with 1 N hydrochloric acid (3×100 mL), dry with magnesium sulfate and concentrate. Purify on silica gel with hexane/ethyl acetate mixtures to give 4.73 g (43%) of the title compound as a white solid. MS(ES−): m/z=242.1 (M−H)−
Reaction SMILES: O[C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>C1COCC1>[C:7]1([C:2]2[CH2:6][CH2:5][CH2:4][CH:3]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC1(c2ccccc2)CCCC1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCC1
Yield: 85 %

Procedure:
The same experiment as in Example 3 was carried out, except for using 50 ml of THF instead of 50 ml of CPME. The resulting reaction mixture was analyzed by gas chromatography to confirm that the target 1-hydroxy-1-phenylcyclopentane and phenylcyclopentene were obtained in a yield of 85% in total.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]([O:18][CH2:19][CH3:20])[CH2:16][N:15]([C:21]([O:23][CH3:24])=[O:22])[CH2:14]2)=[N:5][C:6]([CH2:10][CH3:11])=[C:7]([I:9])[N:8]=1)[CH3:2].C(C1C(N[C@H]2[C@@H](OCC)CN(C(OC[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=O)C2)=NC(CC)=CN=1)C>>[CH2:1]([C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]([O:18][CH2:19][CH3:20])[CH2:16][N:15]([C:21]([O:23][CH2:24][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:22])[CH2:14]2)=[N:5][C:6]([CH2:10][CH3:11])=[C:7]([I:9])[N:8]=1)[CH3:2]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)cnc1CC
Reactant: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(I)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(I)nc1CC

Procedure:
Following the procedure for the preparation of methyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate but substituting benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.30–7.25, 5.06, 4.96, 4.53, 3.96, 3.86, 3.64–3.47, 3.35, 3.25–3.13, 2.68, 2.51, 1.20–1.12; IR (liq.) 2972, 2338 (w), 1949 (w), 1708 (s), 1554 (s), 1537 (s), 1475 (s), 1456 (s), 1447 (s), 1421 (s), 1394 (s), 1351 (s), 1165, 1126, 1097 (s) cm−1 HRMS (ESI) calcd for C22H29N4O3I+H1 25.1364. found 525.1359. Anal. Calcd for C22H29IN4O3: C, 50.39; H, 5.57; N, 10.68. Found: C, 50.48; H, 5.60; N, 10.44.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCN3CCOCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 83.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and 4-(2-chloroethyl)morpholine hydrochloride (0.33 g) as starting materials, 5-benzyloxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.34 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:5]1[C:14]2[C:9](=[C:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:24])[CH:6]=1)[OH:4].[CH3:27][N:28]=[C:29]=[O:30].C(N(CC)CC)C>ClCCl>[F:26][C:2]([F:1])([F:25])[CH:3]([O:4][C:29](=[O:30])[NH:28][CH3:27])[C:5]1[C:14]2[C:9](=[C:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:24])[CH:6]=1
Reactant: Cc1cc(C)c(-c2cccc3c(C(O)C(F)(F)F)cc(C)nc23)c(C)c1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OC(c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12)C(F)(F)F

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-methyl-8-(2,4,6-trimethyl-phenyl)quinolin-4-yl]-ethanol (50 mg), methyl isocyanate (0.5 ml), triethylamine (0.1 ml) in dichloromethane (2 ml) was heated at reflux for 2 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give the crude material which was purified by silica gel column chromatography using chloroform as eluent to give the title compound as a white solid.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25]C1C=CC(CN)=NC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: Cc1ccc(CN)nc1
Agent: Cl
Product: Cc1ccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)nc1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(5-methylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97-1.33 (m, 5H), 1.51-1.69 (m, 5H), 1.87 (s, 3H), 2.24 (d, J=6.0 Hz, 6H), 3.73 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 7.20 (d, J=7.79 Hz, 1H), 7.56 (d, J=8.06 Hz, 2H), 8.06 (t, J=5.6 Hz, 1H), 8.33 (s, 1H), 12.90 (bs, 1H); MS (ESI) m/z 326.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(F)cc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:28]=[C:27]([CH2:37][C:38]([O-])=[O:39])[N:26]=1.[Na+]>CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:38](=[O:39])[CH2:37][C:27]1[N:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:28]=1
Reactant: Fc1cccc2c1CCN2
Reactant: COc1cc(N2CCOCC2)nc(CC(=O)[O-])n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(N2CCOCC2)nc(CC(=O)N2CCc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.2 g of 4-fluoro-2,3-dihydro-1H-indole and 1.9 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 1.7 g of sodium (4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetate in 15 ml of DMF and 5 ml of pyridine. The reaction medium is stirred at ambient temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and then diluted in 80 ml of water and 15 ml of ethyl acetate. The precipitate formed is washed with 15 ml of ethyl ether and then with 15 ml of petroleum ether. After drying under reduced pressure, 1.53 g of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)ethanone are obtained in the form of a pink solid used as it is in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.N1C=CC=CC=1.[CH3:52][N:53]([CH3:58])[S:54](Cl)(=[O:56])=[O:55]>O1CCCC1>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][S:54]([N:53]([CH3:58])[CH3:52])(=[O:56])=[O:55])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(=O)(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 70 °C
Yield: 10 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (71 mg, 0.11 mmol) was treated with pyridine (30 μl, 0.36 mmol), dimethylsulfamoyl chloride (31 μl, 0.28 mmol) and 1.1 ml tetrahydrofuran as a solvent according to the method described in Preparation 175 but heating at 70° C. overnight. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 8 mg (10% yield) of the title compound.