Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]([C:32]2[N:36]=[C:35]([O:37][CH2:38][O:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[N:34]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[N:33]=2)[C:16]2[C:17]([F:31])=[C:18]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].CN(C=O)C.[N+]([C:60]1C=C[C:63]([O:66][C:67](=O)[O:68]CCCC)=[CH:62][CH:61]=1)([O-])=O.C(N(CC)CC)C>O.C(OCC)(=O)C>[NH2:7][C:5](=[N:6][C:67]([O:66][CH2:63][CH2:62][CH2:61][CH3:60])=[O:68])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C@@H:15]([C:32]2[N:36]=[C:35]([O:37][CH2:38][O:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[N:34]([C:46]3[N:47]=[CH:48][CH:49]=[CH:50][N:51]=3)[N:33]=2)[C:16]2[C:17]([F:31])=[C:18]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=2)[O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:12][CH:13]=1
Reactant: CCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(OCCOC(C)=O)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCOC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a mixture of Acetic acid 2-{3-[(R)-(4-carbamimidoylphenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester acetic acid salt (23 mg) obtained in Example 67a and DMF (1 ml), carbonic acid butyl ester 4-nitrophenyl ester [CAS No. 67036-13-9] (10 mg) and triethylamine (50 μl) were added, and the resulting mixture was stirred at room temperature for 63 h. Ethyl acetate and water were added to the mixture, and the organic layer was collected. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (16.80 mg).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+].C(O)C>O>[CH2:22]([O:21][C:5](=[CH:6][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH2:10][CH2:9][CH2:8]1)[C:4]([OH:24])=[O:3])[CH3:23]
Reactant: CCOC(=O)C(=CC1(c2ccccc2C(F)(F)F)CCC1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
4.6 g of 2-Ethoxy-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-acrylic acid ethyl ester, 4.3 g of sodium hydroxide, 100 ml ethanol and 50 ml water (ethanol-water 2:1) were mixed and stirred for 2 hours at room temperature. Solvent was evaporated in vacuum, residue was distributed between water and ethyl acetate, and water solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried and concentrated by evaporation in a vacuum. 4.3 g of product was obtained and used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[NH:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:3]=1.[C:31]([O:35][C:36]([N:38]1[CH2:41][C:40]2([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[C:31]([O:35][C:36]([N:38]1[CH2:41][C:40]2([CH2:46][CH2:45][N:44]([C:2]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH:9]4[C:13]4[O:17][N:16]=[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=5)[CH:14]=4)[N:5]=[C:4]([NH:24][C:25]4[CH:26]=[C:27]([CH3:30])[NH:28][N:29]=4)[CH:3]=3)[CH2:43][CH2:42]2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)[nH]n1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CCC4(CC3)CN(C(=O)OC(C)(C)C)C4)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 160 °C
Yield: 54.8 %

Procedure:
A mixture of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-[2-(3-pyridin-2-ylisoxazol-5-yl)pyrrolidin-1-yl]pyrimidin-4-amine (Example 17) (300 mg, 0.7 mmol) and 2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane (949 mg, 4.2 mmol) in 1,4-dioxane (8 ml) was heated at 160° C. in a sealed vessel under microwave irradiation for 120 minutes. The mixture was allowed to cool and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with DCM/methanol/aqueous ammonia (100:0:0 increasing in polarity to 90:10:1) to give the product (235 mg, 55%) as a mauve solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: COc1ccccc1CNc1nc(Br)cnc1N
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1nc(-c2ccc(Oc3ccccc3)cc2)cnc1N
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A solution of 1.00 eq. of (4) in 1 mL toluene is treated with 10 mole percent tetrakis(triphenylphospine) palladium under nitrogen at room temperature. To this solution is added directly 2.50 eq. of 4-phenoxyphenyl boronic acid at room temperature and then 1 mL Na2CO3 (1.0 M) solution. The reaction vial is capped and the reaction stirred under nitrogen at 90° C. for 10 hours. The toluene layer is separated and removed under reduced pressure, and the resulting oil is purified via flash chromatography to provide (5).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:30])[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[O:20][N:19]=3)[C:9]=2[S:10][CH:11]=1.Cl>O1CCCC1.O.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][O:16][C:12]3[C:9]4[S:10][CH:11]=[C:7]([CH2:6][C:5]([OH:30])=[O:4])[C:8]=4[CH:15]=[CH:14][CH:13]=3)[CH:22]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Yield: 69 %

Procedure:
Lithium hydroxide (0.024 g, 0.58 mmol) was added to a stirred suspension of compound 77C from the preceding step (0.06 g, 0.15 mmol) in 8 mL of tetrahydrofuran/water (3:2) at room temperature. After 18 hours the resulting clear solution was diluted with 75 mL of water, stirred, and acidified with aq HCl. After −1 hour the precipitate was filtered off, rinsed 3× with water, and dried to afford 0.04 g (69% yield) of the title compound as a white solid; mp 229-230° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C@H:20]([OH:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[C@@H:14]3[C:20](=[O:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1c(N2C(=O)N3CCC(=O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To 66E (100 mg, 0.279 mmol) in CH2Cl2 was added Dess-Martin periodinane (236 mg, 0.556 mmol) and the reaction was stirred at rt overnight. Saturated aqueous Na2S2O3 and NaHCO3 were added and the whole was stirred vigorously for 0.5 h. The layers were separated, the organic layer was washed with a mixture of saturated aqueous Na2S2O3 and NaHCO3 followed by brine, dried (MgSO4), and was then filtered and concentrated to obtain the title compound (96.0 mg) as a white film.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[N:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 60 °C

Procedure:
A mixture of 4-amino-1-Boc-piperidine (commercial; 6.7 g, 35 mmol), 2-chloro-6-methoxy-3-nitro-pyridine (1 eq.) and K2CO3 (1 eq.) in MeCN (100 mL) and DMF (30 mL) was heated at 60° C. for 3 h. The mixture was filtered and concentrated in vacuo. The residue was taken up in ether/water 1:1, the org. phase dried over MgSO4 and concentrated. The residue was triturated with EA and filtered to afford 4.5 g of pure product. The filtrate was concentrated and purified by CC (Hept/EA 9:1, 4:1, 2:1) to give another 4 g of product. In total 8.5 g (70% yield) of a yellow solid were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[N:18]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:20][N:21]=2)[OH:16])[CH:12]=[CH:11][N:10]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:14]=[C:13]([C:15]([C:17]2[N:18]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:20][N:21]=2)=[O:16])[CH:12]=[CH:11][N:10]=1
Reactant: Cn1cc(-c2cnc(C(O)c3ccnc(-c4c(F)cccc4F)c3)n2COCC[Si](C)(C)C)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1cc(-c2cnc(C(=O)c3ccnc(-c4c(F)cccc4F)c3)n2COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]methanol (78 mg, 0.157 mmol, as a mixture of two regioisomers) in dichloromethane (3 mL) at room temperature was added manganese dioxide (273 mg, 3.14 mmol). The mixture was stirred at room temperature overnight before it was filtered and concentrated in vacuo. Purification by SiO2 chromatography provided [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-1-(2 trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone (75 mg, as a mixture of two regioisomers).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:8][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:6]([CH2:4][OH:3])=[CH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cnc(Cc2ccc(F)cc2)nc1-c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(Cc3ccc(F)cc3)ncc2CO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a 0° C. solution of the product from Step A (0.606 g, 1.73 mmol) in THF (8 mL) was added DIBAL-H (1.5 M in toluene; 2.5 mL, 3.8 mmol). The mixture was allowed to warm to rt, and was stirred for 18 h. The mixture was diluted with 20% aq. sodium potassium tartrate and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (40-60% EtOAc/hexanes) to give 0.330 g (62%) of the title compound. MS (ESI): exact mass calcd. for C19H17FN2O, 308.13; m/z found, 309.4 [M+H]+. 1H NMR (CDCl3): 8.77 (s, 1H), 7.58 (d, J=8.0, 2H), 7.38-7.35 (m, 2H), 7.29 (d, J=7.9, 2H), 6.99-6.96 (m, 2H), 4.70 (s, 2H), 4.29 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26](O)=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:26]([C:17]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:13]([C:11]([O:10][CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:12])=[C:14]([CH3:30])[NH:15][C:16]=2[CH3:29])=[O:27])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1

Procedure:
258 mg (0.510 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 143 mg (0.770 mmol) of 1-t-butoxycarbonylpiperazine, 117 mg (0.610 mmol) of WSC hydrochloride and 18.0 mg (0.140 mol) of 4-dimethylaminopyridine were stirred at room temperature overnight in 15 ml of dichloromethane. After adding water and 1 N hydrochloric acid, the reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.
Reaction SMILES: [CH:1]([P:4]([CH2:9][CH2:10][N:11](CC1C=CC(OC)=CC=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[CH:1]([P:4]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])([CH:6]([CH3:7])[CH3:8])=[O:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(CCP(=O)(C(C)C)C(C)C)C(=O)OC(C)(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(C)P(=O)(CCNC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl [2-(diisopropylphosphoryl)ethyl](4-methoxybenzyl)carbamate (1.06 g, 2.68 mmol) in MeCN (20 mL) was cooled to 0° C. CAN (4.40 g, 8.03 mmol) in water (10 mL) was added dropwise via addition funnel over 15 minutes, and the reaction was subsequently stirred at 0° C. for an additional 1 h. The solution was then diluted with water and extracted with EtOAc (4×). The combined organic layers were washed with 10% Na2SO3 (2×). The sodium sulfite layers were then back-extracted with additional EtOAc (2×). All of the organic extracts were combined, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded tert-butyl [2-(diisopropylphosphoryl)ethyl]carbamate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 5.59 (bs, 1H), 3.50-3.42 (dt, J=13.0, 6.5 Hz, 2H), 2.01-1.92 (m, 2H), 1.88-1.83 (m, 2H), 1.39 (s, 9H), 1.18 (dd, J=14.9, 7.2 Hz, 6H), 1.14 (dd, J=15.3, 7.2 Hz, 6H). MS: cal'd 278 (MH+), exp 278 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH3:29].[OH-].[Na+]>CO.O1CCCC1>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[C:3]([NH2:29])=[O:4]
Reactant: COC(=O)C(O)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
Methyl 2-hydroxy-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (754 mg, 1.98 mmol) obtained in Example 35 was dissolved in methanol-tetrahydrofuran (1:1, 6 ml). 28% Aqueous ammonia (3 ml) was added and the mixture was stirred at room temperature for 2 days. Thereto was added 1N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred for 1 hr. The reaction mixture was partitioned between tetrahydrofuran-ethyl acetate (1:1, 30 ml) and water (10 ml). The organic layer was washed with saturated brine (10 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (700 mg, yield 96%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][O:7]2.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.O>C(OCC)C.O1CCCC1>[CH:14]1([C:4]2([OH:13])[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[O:7][CH2:6][CH2:5]2)[CH2:16][CH2:15]1
Reactant: O=C1CCOc2cc(F)cc(F)c21
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OC1(C2CC2)CCOc2cc(F)cc(F)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 32.6 ml (16.29 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). The acetonitrile was removed from the combined product phases in a rotary evaporator, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. 0.66 g (27% of theory) of the title compound was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:17]2[N:18]=[C:19]([C@H:28]3[CH2:32][C@@H:31]([OH:33])[CH2:30][N:29]3[CH2:34][C:35]3[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=3)[O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[O:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:11]1([C:17]2[N:18]=[C:19]([C@H:28]3[CH2:32][C:31](=[O:33])[CH2:30][N:29]3[CH2:34][C:35]3[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=3)[O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[O:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccc(CN2CC(=O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of oxalyl chloride (0.050 mL) in CH2Cl2 (10 mL) was added a solution of DMSO (0.061 mL) in CH2Cl2 (0.5 mL) keeping the temperature below −55° C., and stirred for 30 minutes. To the mixture was added a solution of ethyl 3-{[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-yl]methyl}phenoxyacetate (238 mg) in CH2Cl2 (3 mL) at the same temperature, then stirred for 1 hour. To the reaction mixture was added triethylamine (0.27 mL), and warmed to room temperature over 30 minutes. After stirring at the same temperature for 30 minutes, the mixture was diluted with EtOAc, washed with water, saturated sodium hydrogen carbonate, water and brine, dried (MgSO4), evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc 2:1) to give ethyl 3-{[(2R)-2-(4,5-diphenyloxazol-2-yl)-4-oxopyrrolidin-1-yl]methyl}phenoxyacetate (191.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[N:16]2)=[C:11]([CH:32]=[CH2:33])[CH:10]=1>C(O)C.[Ni]>[CH2:32]([C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:17]2[C:12]=1[CH:13]=[N:14][C:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[CH:23][CH:24]=1)=[N:16]2)[CH3:33]
Reactant: C=Cc1cc(-c2ccccc2OC)n2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc12
Agent: [Ni]
Solvent: CCO
Product: CCc1cc(-c2ccccc2OC)n2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc12
Reaction time: 1 h
Yield: 35.8 %

Procedure:
Into a par bottle, [7-(2-Methoxy-phenyl)-5-vinyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (50.00 mg, 0.0001135 mol), and Ethanol (20 mL, 0.3 mol) were added. Raney-Nickel (0.9:0.1, Nickel:Aluminum, 10 mg, 0.0002 mol) was washed with Ethanol prior to adding to the reaction mixture. The mixture was evacuated and charged with hydrogen at 30 pSi. The reaction was shaken on the parr at 30 pSi for one hour. The solid was filtered through Celite. The organic was evaporated under vacuum to give a yellow solid. The solid was purified via ISCO column chromatography with DCM and MeOH as eluant (0 to 10% methanol). The collected fractions afforded [5-Ethyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (18 mg, 36%). MP 154-156° C. LCMS (E/I+) 443.31 (M+H). NMR 1H (DSMO-d6)-9.05 (s, 1H), 8.92 (s, 1H), 7.80 (dd, 1H, JJ=1.57, 6.50 Hz), 7.55 (d, 2H, J=8.96 Hz), 7.43 (dt, 1H, JJ=1.60, 7.00 Hz), 7.20 (d, 1H, J=8.40) 7.10 (t, 1H, J=7.57 Hz, 6.73-6.85 (m, 3H), 3.79 (s, 3H), 3.02 (t, 4H, J=4.60), 2.83 (q, 2H, JJ=7.52, 7.56 Hz), 2.44 (t, 4H, J=5.84), 2.21 (s, 3H), 1.28 (t, 3H, J=7.56 Hz).
Reaction SMILES: [O:1]=[C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[CH2:14]([O:21][CH2:22][CH2:23]C=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[OH:1][C:2]1[C:3](=[O:4])[O:5][CH:6]([CH2:23][CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CCCOCc1ccccc1
Reactant: COC(=O)C(=O)Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1OC(CCOCc2ccccc2)C(c2ccccc2)=C1O
Yield: 68.7 %

Procedure:
To a solution of methyl 2-oxo-3-phenylpropionate (2.0 g) and 3-benzyloxypropanal (1.84 g) in N,N-dimethylformamide (40 ml) was dropwise added 1,8-diazabicyclo[5.4.0]undecen-7 (1.76 ml) at 0° C. with stirring. The mixture was stirred at the same temperature for 2 hours PG,28 and the solvent was evaporated. The residue was added to diluted hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and evaporated in vacuo. The residue was recrystallized from diisopropyl ether to give 3-hydroxy-4-phenyl-5(2-benzyloxyethyl)-2(5H)furanone (2.39 g).