Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([C:33]([N:35]2[CH2:38][CH2:37][CH2:36]2)=[O:34])[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:35]1([C:33]([CH:31]2[CH2:32][N:29]([CH2:11][C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:6]=[C:5]([N:19]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]3[CH3:28])[N:4]=4)[CH2:30]2)=[O:34])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(C1CNC1)N1CCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidin-3-ylazetidin-1-ylmethanone (45 mg, 0.31 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 90:10 to 85:15) to afford 347 as a white solid (30 mg, 23%). LCMS (Method G): RT=5.33 min, M+H+=502. 1H NMR (CDCl3, 400 MHz) δ 8.07 (m, 1 H); 7.69 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 4 H); 4.13-4.00 (m, 4 H); 3.87 (m, 6 H); 3.82 (s, 3 H); 3.68-3.58 (m, 2 H); 3.53-3.45 (m, 2 H); 3.34-3.26 (m, 1 H); 2.96 (s, 3 H) and 2.33-2.23 (m, 2 H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([S:33]([OH:36])(=[O:35])=[O:34])[CH:18]=[C:19]3[C:24]=2[C:23]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:20]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>[Pd].O>[NH2:1][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([S:33]([OH:36])(=[O:35])=[O:34])[CH:18]=[C:19]3[C:24]=2[C:23]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:20]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: [Pd]
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: Cc1cc(N)ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A mixture of 20.0 g of 8-(5-nitro-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt, 90.0 ml of water and 20.0 g of 10% palladium on carbon catalyst is hydrogenated as described in Example 1. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is dissolved in a minimum amount of water, then is added dropwise to 800 ml of stirred absolute ethanol. The mixture is stirred for 2 hours and allowed to stand for 48 hours. A light yellow solid is collected, washed with ethanol and ether, then is dried to yield 15.0 g of 8-(5-amino-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19].C(Cl)Cl>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.8 %

Procedure:
2.0 g of 4-chlorobenzenesulfonic acid chloride are added to a solution of 3.8 g of 5-chloro-2-aminobenzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] in 8.6 ml of pyridine at 0° C. After the reaction mixture has been stirred for 16 hours at room temperature, 300 ml of methylene chloride are added and the resulting solution is then washed with 100 ml each of 1N HCl, H2O, saturated NaHCO3 solution and saturated NaCl solution. The organic phase is then dried with MgSO4 and concentrated by evaporation. The crude product obtained is purified by stirring in diethyl ether. In this manner 3.8 g of 5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are obtained in the form of white crystals (m.p. 191°-193° C.).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=1.[CH:14]1([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH2:16][CH2:15]1>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:22](=[NH:23])[C:21]2[CH:24]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:18]=[N:19][CH:20]=2)[CH:8]=1
Reactant: N#Cc1cncc(C2CC2)c1
Reactant: Nc1cc(Cl)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N=C(Nc1cc(Cl)ccn1)c1cncc(C2CC2)c1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M, 2.2 mL, 0.0034 mol) was added slowly for a period of 5 min to a solution of 4-chloropyridin-2-amine (0.4 g, 0.0031 mol) in anhydrous tetrahydrofuran (20 mL) at −78° C. The reaction temperature was raised to −40° C. and stirred for 15 min. The reaction mixture was cooled to −78° C. and 5-cyclopropylnicotinonitrile (0.45 g, 0.0031 mol) in tetrahydrofuran (5 mL) was added. The temperature was raised to RT and stirred it for 3 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) then extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was recrystalised with a DCM and ether mixture to afford the title compound. MS (M−1): 271.0.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:6]=[C:5]([Cl:22])[N:4]=1.[CH3:23][OH:24]>>[Cl:22][C:5]1[CH:6]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:8]=[C:3]([O:24][CH3:23])[N:4]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Reactant: CO
Agent: [Na]
Product: COc1cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(Cl)n1

Procedure:
Under a nitrogen atmosphere 0.21 g (9.3 mmol) sodium were added batchwise to 50 mL MeOH. After the sodium had dissolved completely, 1.0 g (3.1 mmol) of 6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one were added and the mixture was refluxed for 5 h. Then the reaction mixture was evaporated down i. vac., the residue was combined with 50 mL water and the precipitated solid was suction filtered. This was washed with a little water and dried.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[F:19][C:20]1([F:41])[CH2:25][N:24]([C:26]([C:28]2[N:29]=[C:30]([CH:33]([CH3:35])[CH3:34])[S:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:21]1.C(N(CC)CC)C>C(#N)C>[F:41][C:20]1([F:19])[CH2:25][N:24]([C:26]([C:28]2[N:29]=[C:30]([CH:33]([CH3:35])[CH3:34])[S:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:40][CH2:39][N:38]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][OH:11])[CH:4]=3)[CH2:37][CH2:36]2)[O:21]1
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)cs1
Reactant: OCCc1cccc(CBr)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.21 g) was added to a mixture of (2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone trifluoroacetate (example 44, step b) (0.40 g) and triethylamine (0.37 mL) in acetonitrile (15 mL). The reaction mixture was stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.40 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:14]C)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1cccc2c1CC(c1ccccc1)C=C2CN
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NCC1=CC(c2ccccc2)Cc2c(O)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-Aminomethyl-5-methoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (0.5 g, 1.7 mmol), from Step 2, was suspended in 16 mL of methylene chloride and boron tribromide (5.8 mL of a 1 M solution of BBr3 in methylene chloride) was added dropwise while the reaction mixture was being cooled (to -78° C.) in a dry ice/acetone bath. The reaction mixture was warmed to 0° C. and stirred for 0.5 h, then again cooled to -78° C. in a dry ice/acetone bath. Methanol (2.5 mL) was added dropwise to the reaction mixture, which was then allowed to warm to ambient temperature and concentrated in vacuo. Methanol was added to the residue and the solution was reconcentrated. The residue was dissolved in a small amount of methanol and chromatographed on a silica gel column eluted with ethyl acetate:formic acid:water (18:1:1, v/v/v) to give the formic acid salt of 1-aminomethyl-5-hydroxy-3-phenyl-3,4-dihydronaphthalene, m.p. 102°-104° C.; 1H NMR(d 6-DMSO) δ2.68 (dd, 1H), 3.06 (dd, 1H), 3.6-3.8 (m, 1H), 3.77 (s, 2H), 6.1 (m, 1H), 6.77 (d, 1H), 6.83 (d, 1H), 7.04 (t, 1H), 7.15-7.35 (m, 5H), 8.36 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][CH:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][C:19]3([CH3:22])[CH2:21][CH2:20]3)[N:11]=2)[CH2:3]1.C(O)(C(F)(F)F)=[O:24].C(=O)(O)[O-]>CS(C)=O.[OH-].[Na+].OO>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:17])=[O:24])=[CH:14][N:13]=[C:12]([NH:18][C:19]3([CH3:22])[CH2:21][CH2:20]3)[N:11]=2)[CH2:3]1
Reactant: C[C@@H]1CCC(Nc2nc(NC3(C)CC3)ncc2C#N)C[C@H]1O
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC3(C)CC3)ncc2C(N)=O)C[C@H]1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
4-((3R,4R)-3-Hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carbonitrile (0.181 g, 0.601 mmol) was dissolved in DMSO (6 mL). Ten drops of 50% aqueous sodium hydroxide (0.047 mL, 0.901 mmol) and ten drops of 30% aqueous hydrogen peroxide were added at room temperature. The reaction mixture was stirred at 50° C. for 1 h. Upon completion of reaction, as indicated by LCMS and TLC, the reaction mixture was cooled to room temperature and was poured into 300 mL of the ice water. The aqueous layer was extracted with 20% iPrOH/chloroform (×3) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by reverse-phased semi-preparative HPLC (0-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting residue was redissolved in methanol (5 mL), passed over Varian StratoSpheres HCO3 resin SPE tubes for TFA removal (0.9 mmol bicarbonate equiv. per tube), and then concentrated under reduced pressure to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carboxamide (0.069 g, 36% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79-8.92 (m, 1H), 8.28-8.39 (m, 1H), 7.32-7.48 (m, 1H), 4.56 (s, 1H), 3.83-3.97 (m, 1H), 2.89-3.08 (m, 1H), 2.18-2.31 (m, 1H), 1.97-2.08 (m, 1H), 1.61-1.74 (m, 1H), 1.35 (s, 4H), 1.05-1.26 (m, 1H), 0.94 (d, J=6.64 Hz, 5H), 0.66 (s, 3H), 0.54 (br. s., 3H); MS (ESI) m/z 320.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH3:13][CH:14]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:15]>C1COCC1>[CH3:13][CH:14]([C:16]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([OH:20])[CH:17]([CH3:19])[CH3:18])[CH3:15]
Reactant: CC(C)C(=O)C(C)C
Reactant: Cc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C(O)(Cc1ccccn1)C(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
2-Methyl-pyridine (1.86 g, 20 mmol) is dissolved in THF (20 mL) and cooled to −30° C. tert-Butyl lithium (11.8 mL, 1.7M in pentane, 20 mmol) is added dropwise to the solution, and the reaction is stirred for 30 min at −30° C. 2,4-Dimethyl-pentan-3-one (3.4 mL, 24 mmol) is added and the reaction is warmed to room temperature and stirred for 2 h. Add H2O (30 mL) and extract with EtOAc. Wash combined organics with brine and concentrate in vacuo. The residue is purified by flash chromatography on silica gel (EtOAc/Heptane) to afford 2,4-dimethyl-3-pyridin-2-ylmethyl-pentan-3-ol (4.14 g, quant.).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.[CH3:12][C:13](C)([O-])[CH3:14].[K+].C(Br)C#C>O1CCOCC1>[CH2:14]([S:1][C:2]1[S:3][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1)[C:13]#[CH:12]
Reactant: CC(C)(C)[O-]
Reactant: Sc1nnc(-c2cccs2)s1
Agent: C#CCBr
Agent: [K+]
Solvent: C1COCCO1
Product: C#CCSc1nnc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g of 2-mercapto-5-thienyl-1,3,4-thiadiazole are placed in 40 ml of dioxan and stirred for 15 minutes with 3.36 g of potassium tert.-butoxide. Subsequently, 5.9 g of propargyl bromide are added dropwise at 30° C. and the reaction mixture is stirred overnight at room temperature. The salts are filtered off, the filtrate is concentrated by evaporation, the residue is taken up in methylene chloride and the solution is washed with water and then with 1N sodium hydroxide solution. The solvent is removed in vacuo and the residue obtained is 6.1 g of crude title compound which, recrystallised from tert.-butyl methyl ether, yields the title compound having a melting point of 71°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)=[O:6].[H][H]>CCO.CO.[Pt]>[NH2:14][C:11]1[CH:12]=[N:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[CH:18][C:19]([F:20])=[C:2]([Cl:1])[CH:3]=2)=[N:9][CH:10]=1
Reactant: [H][H]
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccc(F)c(Cl)c1
Agent: [Pt]
Solvent: CO
Solvent: CCO
Product: Nc1cnc(NC(=O)c2ccc(F)c(Cl)c2)nc1
Yield: 80 %

Procedure:
To 1C (1.16 g, 3.92 mmol) in a mixture of 60 mL EtOH and 10 mL MeOH was added 10% Pt/C (300 mg). The reaction was stirred under 1 atmosphere of hydrogen for 1.5 h, filtered, and concentrated to give 850 mg (80% yield) ID. RP HPLC ret. t.: 1.58 min. and (M+H)+: 267.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.Cl[CH2:20][C:21](=O)[CH2:22]C(OC)=O.FC1C=CC(N=C=O)=CC=1>C(O)CCC.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH2:17][CH2:20][CH2:21][CH3:22])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Agent: O=C=Nc1ccc(F)cc1
Agent: [Zn]
Solvent: CCCCO
Product: CCCCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.13 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0062 g, 0.0065 mmol) in 1-butanol (2.0 mL) was stirred at 80° C. for 3 days then stirred at ambient temperature for further 3 days. The precipitate was collected by filtration, washed with 2-propanol and diisopropyl ether then dried to afford n-butyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.078 g, y. 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C>C1(C)C=CC=CC=1.O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N4CCOCC4)c3)cn2)cc1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (50 mg) obtained in Step A, sodium t-butoxide (50 mg) and palladium dibenzylideneacetone complex (6 mg) suspended in toluene (1.5 ml), argon gas was blown for 5 minutes. Morpholine (10 μl) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (6.9 mg) were added, followed by stirring at 110° C. for 6 hours. The reaction mixture was cooled to room temperature, and water (5 ml) was added, followed by extraction with dichloromethane (10 ml×2). The combined organic layers were washed with brine, and dried over sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), to obtain a yellow amorphous (46 mg, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:18]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])([CH3:21])([CH3:20])[CH3:19].C(OC(=O)[C@@H](OC)CC1C=CC(OCC(OC(C)(C)C)=O)=CC=1)C>>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:24]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:28])([CH3:26])[CH3:25])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OC
Product: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)OCC

Procedure:
The title compound was prepared (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (example 251, step 3) and 2-bromo-2-methyl-propionic acid tert-butyl ester via the same procedure used to prepare (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 1) to produce a yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(O)(=O)=O.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cool a solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole (387.00 g, 1.08 mol) in DCM (2.50 L) and THF (1.00 L) to 10° C. in a 10 L jacketed reactor vessel. To the resulting mixture add methanesulfonic acid (14.0 mL, 216.02 mmol), followed by 3,4-dihydro-2H-pyran (296 mL, 3.24 mol) over 0.5 hours, observing a slight exotherm. Stir the mixture at RT for 3 hours. Cool the reaction to 10° C. and quench with saturated aqueous sodium bicarbonate (2 L). Dilute the mixture with water (2 L) and extract the aqueous layer with DCM (2 L). Wash the combined organic extracts with water (2 L) and brine. Dry the organic mixture over anhydrous sodium sulfate, filter and concentrate in vacuo. Elute the residue through a silica gel pad with eluent (0 to 10% EA/hexanes) to give the title compound. Yield: 150 g (31%). MS (ES) m/z 459 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:22](Br)[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:22]([N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21])[CH3:23]
Reactant: CCBr
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Temperature: 0 °C
Yield: 91.9 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(4-nitro phenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6b, 1.17 g, 92%). Nitro compound (6b, 1.27 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 1.02 g, 89%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7c, 0.29g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]phenyl-5-nitro-2-furamide (8c, 367 mg, 86%).