Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12]CC)=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH3:15]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH2:15])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: N
Product: CCOP(=O)(CC(N)=O)OCC
Temperature: 5 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In 400 ml of 25% aqueous ammonia is dissolved 100 g (0.446 mol) of ethyl diethylphosphonoacetate at an temperature of not higher than 10° C. The solution is allowed to stand overnight at an temperature of not higher than 15° C. and concentrated under reduced pressure. To the residue is added 25 ml of toluene and the water is azeotropically removed off under reduced pressure. To the residue is added 300 ml of toluene and 100 ml is azeotropically removed off under atmospheric pressure for complete dehydration. The residual solution is cooled and seed crystals are added at 50° C. for crystallization. After cooling to 5° C., the crystals are collected by filtration. The crystals are washed with 100 ml of toluene and dried in vacuo overnight to give 76.7 g of diethylphosphono-acetamide (a carbamoyl-containing Wittig reagent) (Yield 88.0%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(Cl)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 4-chlorobenzyl bromide in the same manner as in Example 32.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:13])([F:12])[C:5]1[N:6]=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:10]1[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=1[C:4]([F:3])([F:12])[F:13]
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cnc(C(F)(F)F)c1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Bromine (4.62 g) was added in one portion to a stirred solution of 4-trifluoromethylpyrimidin-6-one (4.3 g) and sodium acetate (10.53 g) in acetic acid (43 ml). After stirring for 2 hours, the reaction mixture was left to stand for a period of 3 days, after which time it was heated to 80° C. for 1 hour. After cooling to the ambient temperature (ca 22° C.), the solvent was evaporated under reduced pressure. The resultant orange solid was dissolved in ethyl acetate, and washed several times with water. The combined agueous washings were extracted with ethylacetate, and the combined organic layers were washed with aqueous sodium thiosulphate solution, followed by aqueous sodium bicarbonate solution and brine. After drying over magnesium sulphate, evaporation of the solvent under reduced pressure gave 5-bromo-4-trifluoromethylpyrimidin-6-one as white solid (4.8 g, mpt 226-227° C.); H NMR (CDC13), 8.05(s); 19 NMR (CDC13), -67.4(s). Preparation 4
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([NH:7][CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)C(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of Benzyl-[1-(4-butylamino-benzenesulfonyl)-azetidin-3-yl]-carbamicacid tert-butyl ester (0.19 g, 0.4 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (0.31 ml, 4 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with saturated sodium carbonate solution, and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated. The crude product was chromatographed on silica gel (ethyl acetate-hexanes/3:2) to give 0.09 g of a colorless foam; MS (ES) m/z 374.1 (MH+); HRMS (El) Calcd. for C20H27N3O2S (M+): 373.1824, Found: 373.1822.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)C4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexanecarbonyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}cyclohexylcarboxamide (0.53 g, 72%) as a white solid: mp 142-144° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.86-7.77 (m, 2H), 7.64-7.61 (m, 1H), 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.47 (m, 2H), 2.26-2.17 (m, 1H), 2.08-2.03 (m, 1H), 1.79-1.61 (m, 5H), 1.43-1.12 (m, 5H); 13C NMR (DMSO-d6) δ 175.58, 172.75, 169.82, 167.49, 166.96, 139.68, 134.75, 132.76, 131.49, 126.99, 121.73, 48.83, 43.90, 37.43, 30.92, 29.20, 25.43, 25.24, 21.96; Anal. Calcd. For C21H23N3O5: C, 63.47; H, 5.83; N, 10.57. Found: C, 63.12; H, 5.68; N, 10.41.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[ClH:1].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:11]=1
Reactant: NCCO
Reactant: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Product: Cl
Product: OCCNc1cc(N2CCc3ccccc3C2)c2ccccc2n1

Procedure:
The title compound, MS: m/e=320.3 (M+H+), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and ethanolamine.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([N:17]2[C:21](=[S:22])[N:20]=[N:19][NH:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.Br[CH2:24][C:25]([O:27]C)=[O:26]>CS(C)=O.CCOC(C)=O>[C:7]1([N:17]2[C:21]([S:22][CH2:24][C:25]([OH:27])=[O:26])=[N:20][N:19]=[N:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CBr
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Pyridine (0.83 mL, 10.3 mmol) and 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (2.14 g, 9.38 mmol) were added to a solution of methyl 2-bromoacetate (977 μL, 10.3 mmol) in DMSO (50 mL). The resulting light yellow solution was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (300 ml) and was successively washed with water (2×250 ml) and brine (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude ester was dissolved in THF and aqueous 1 N NaOH solution was added. The solution was stirred at room temperature for 30 min. The THF was evaporated under reduced pressure and the residue was dissolved in aqueous 1 N NaOH solution. The solution was slowly acidified to pH 2 at 0° C. with aqueous 1 N HCl solution. The suspension was filtered and the resulting solid was rinsed with water and dried under reduced pressure to give the title compound (2.48 g, 92% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:37][CH:38]([CH3:40])[CH3:39]>CCOC(C)=O>[CH3:37][CH:38]([CH3:40])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(O)cc1)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (219 mg, 0.686 mmol), potassium carbonate (K2CO3, 568 mg, 4.12 mmol, 6.00 equiv.), 2.00 mL of dimethylformamide (DMF), and 1-bromo-2-methylpropane (Aldrich, 300 mg, 2.18 mmol, 3.20 equiv.) were stirred at room temperature for 2 h, and then heated at 40° C. for 22 h. Additional potassium carbonate (568 mg, 4.12 mmol, 6.00 equiv.), and 1-bromo-2-methylpropane (Aldrich, 300 mg, 2.18 mmol, 3.20 equiv.) were added, and heating continued for another 28 h. The mixture was diluted with EtOAc, washed with 2× sat. aq. NaHCO3, 2× sat. aq. NaCl, and dried (Na2SO4). Purification by silica gel chromatography using 20% EtOAc in hexanes afforded the title compound (190 mg, 73.6% yield): ES-MS (m/z) 376 [M+1]+.
Reaction SMILES: N1C=C([CH:7]=[O:8])C=CC=1.[CH3:9][C:10]1([CH3:32])[CH2:19][C:18]([CH3:21])([CH3:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][N:25]=3)[CH:16]=2)[O:11]1.CO.O.[C:36]1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[CH3:9][C:10]1([CH3:32])[CH2:19][C:18]([CH3:20])([CH3:21])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]([O:8][CH3:7])[O:31][CH3:36])=[CH:26][N:25]=3)[CH:16]=2)[O:11]1
Reactant: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc2O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cccnc1
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(OC)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)nc1
Temperature: 25 °C

Procedure:
A round-bottomed flask is fitted with a Dean-stark apparatus under a reflux condenser protected by a drying tube. A mixture of 3.58 g (12 mmol) of 2-[2,2,4,4-tetramethyl-chroman-6-yl)-ethynyl]-pyridine-5-carboxaldehyde (Compound 52) 4.80 mg (15 mmol) of anhydrous methanol, 2 mg of p-toluenesulfonic acid monohydrate and 10 ml of anhydrous benzene is placed in the flask and the mixture heated at reflux under nitrogen until close to the theoretical amount of water is collected in the Dean-Stark trap. The reaction mixture is cooled to room temperature and extracted successively with 5 ml of 10% sodium hydroxide solution and two 5 ml portions of water and then dried (MgSO4). The solution is then filtered and the solvent removed in vacuo. The residue is purified by chromatography and then recrystallization to give the title compound.
Reaction SMILES: ClC1C=CC(COC2C=CN(C3C=CC([O:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]4)=CC=3)C(=O)C=2)=NC=1.[F:32][CH2:33][C@@H:34]1CCCN1C(OC(C)(C)C)=O.FCCO[C@@H]1CCN(C(OC(C)(C)C)=O)C1>>[F:32][CH2:33][CH2:34][O:30][C@@H:27]1[CH2:28][CH2:29][N:25]([CH2:24][CH2:23][OH:22])[CH2:26]1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCN2CC[C@H](O)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CF
Agent: CC(C)(C)OC(=O)N1CC[C@@H](OCCF)C1
Product: OCCN1CC[C@@H](OCCF)C1

Procedure:
Steps (2) and (3) of Example 89 were repeated except that tert-butyl (2S)-2-(fluoromethyl)pyrrolidine-1-carboxylate used in the Step (2) was replaced with tert-butyl (3R)-3-(2-fluoroethoxy)pyrrolidine-1-carboxylate, to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].CCO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([C:12](=[NH:13])[NH:18][OH:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Temperature: 60 °C

Procedure:
A 5 L round bottom flask equipped with an overhead stirrer, and 500 mL addition funnel was charged with 3-(t-butyloxycarbonylamino)benzonitrile (264.4 g, 1.21 mol), hydroxylamine hydrochloride (294.6 g, 4.24 mol) and 95% EtOH (1 L). The resulting suspension was treated with a solution of potassium carbonate (711.8 g, 5.15 mol) in water (1 L) and the suspension heated to 60° C. The reaction was followed by TLC and HPLC for starting material consumption to completion. The reaction mixture was then cooled to ambient temperature the organic layer was separated and concentrated to approximately 500 mL, then diluted with water (1 L). The resulting precipitate was collected by vacuum filtration and dried to yield the title compound as an off white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=2)[N:11]=1.CCN(C(C)C)C(C)C.[CH3:46][O:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[C:25]2[C:17]([C:12]3[N:11]=[C:10]([NH:9][CH2:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])[C:15]([F:16])=[CH:14][N:13]=3)=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled mixture of N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (0.060 g, 0.093 mmol) and iPr2NEt (0.057 mL, 0.330 mmol) in CH2Cl2 (2 mL) at 0° C., was added 2-methoxyacetyl chloride (0.010 g, 0.098 mmol). After 5 min, the solution was allowed to warm to room temperature. After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1 mL) and treated with LiOH (0.326 mL, 1.0 M solution) at 120° C. for 10 min. The resulting mixture was cooled to room temperature and partitioned and the aqueous layer extracted with EtOAc and the combined organics were concentrated in vacuo. Preparative HPLC provided the desired product, 556, as a racemic mixture of TFA salts (8.6 mg, 17% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][NH:8][CH3:9])([CH3:3])[CH3:2].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][N:8]([CH3:9])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1cccc(OC)c1OC(C)C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c1OC(C)C
Yield: 47 %

Procedure:
According to the procedure of Example 1, except substituting 2-isopropoxy-3-methoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 47%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.41-10.21 (m, 1H), 10.13 (br s, 1H), 8.41-8.31 (m, 1H), 8.01-7.93 (m, 1H), 7.51-7.43 (m, 1H), 7.31-7.11 (m, 1H), 7.01-6.91 (m, 2H), 6.70-6.59 (m, 1H), 4.76-4.52 (m, 5H), 4.11-3.85 (m, 7H), 3.84-3.60 (m, 3H), 3.59-3.51 (m, 21), 3.40-3.31 (m, 2H), 3.07-2.86 (m, 4H), 1.23 (m, 6H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Br)cc1F
Product: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Yield: 82 %

Procedure:
4-Bromo-2-fluorobenzonitrile and 4-methoxyphenylboronic acid were processed as described in Example 164A to provide the title compound (82% yield). 1HNMR (300 MHz, CDCl3) δ3.73 (s, 3H); MS (DCI) m/z 228 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[CH3:37][NH2:38]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([NH:38][CH3:37])=[O:35])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14])[CH2:7]2
Reactant: CN
Reactant: C[C@@H]1CN2c3c(cc4c(-n5cc(C(=O)O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Product: CNC(=O)c1cnn(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)c1

Procedure:
Starting material: 1-[(2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-1H-pyrazole-4-carboxylic acid (Example 186) and methyl amine (0.16 mL, 2.0M in THF, 0.320 mmol).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[C:4]=2[N:3]=1.[C:12]([Cl:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[ClH:20].[CH3:11][CH:10]1[C:4]2[N:3]=[C:2]([CH2:1][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:19])[NH:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2c([nH]1)CCCC2C
Solvent: CC#N
Product: CC1CCCc2[nH]c(CC(=O)c3ccccc3)nc21
Product: Cl

Procedure:
The compound is prepared as described in example XVII with 1.00 g (6.66 mmol) 2,4-Dimethyl-4,5,6,7-tetrahydro-1H-benzimidazole (example XI, step 1), 3.09 g (21.97 mmol) of benzoyl chloride and 2.36 g (23.30 mmol) of TEA in 20 ml acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][CH2:15][CH:16]([C:18](OC)=[O:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.COC(=O)[C@H](CO)[NH:28]C(=O)C1C=CC(OC2C=CC(F)=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][CH:15]=[C:16]([C:18]([NH2:28])=[O:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1COC(c2ccc(Oc3ccc(F)cc3)cc2)=N1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: NC(=O)c1coc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
Methyl 4,5-dihydro-2-[4-(4-fluorophenoxy)phenyl]oxazole-4-carboxylate. To a solution of N-[4-(4-fluorophenoxy)benzoyl]-L-serine methyl ester (assumed to be 37 mmol from the previous reaction) and triphenylphosphine (0.38 g, 6.8 mmol) in acetonitrile (40 mL) was added diisopropylethyl amine (1.2 ml, 6.8 mmol) and carbon tetrachloride (0.66 mL, 6.8 mmol). The resulting solution was stirred at room temperature for 48 hours when TLC analysis indicated incomplete reaction. Triphenylphosphine (1.9 g, 7.2 mmol), diisopropylethyl amine (1.2 mL, 6.8 mmol) and carbon tetrachloride (0.66 mL, 6.8 mmol) was added to the reaction. The solution was stirred at room temperature for 16 hours and concentrated to dryness. The resulting solid was purified by column chromatography affording 910 mg (89%) of the desired product. 1H NMR (DMSO-d6): 7.88 (d, J=8.7 Hz, 2H), 7.29 (t, J=9.3 Hz, 2H), 7.20-7.17 (m, 2H), 7.03 (d, J=8.7 Hz, 2H), 4.95 (dd, J=8.1 Hz, 1H), 4.64-4.25 (m, 2H), 3.71 (s, 3H).
Reaction SMILES: [F:1][CH2:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:12][C:11](S)=[N:10][N:9]=1.F[CH2:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23]N)=O.F[CH2:26]N1C=CC=C1C(OC)=O.N1C=CC=C1C(OC)=O>>[N:16]12[CH2:20][CH2:19][CH:18]([CH2:26][CH2:15]1)[N:23]([C:11]1[O:12][C:8]([C:4]3[N:3]([CH2:2][F:1])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]=1)[CH2:21][CH2:17]2
Reactant: FCn1cccc1-c1nnc(S)o1
Reactant: COC(=O)c1cccn1CF
Reactant: NNC(=O)c1cccn1CF
Agent: COC(=O)c1ccc[nH]1
Product: FCn1cccc1-c1nnc(N2CCN3CCC2CC3)o1

Procedure:
May be prepared according to Methods A-D from 5-[1-(fluoromethyl)pyrrol-2-yl]-1,3,4-oxadiazole-2-thiol (Method A), from 1-(fluoromethyl)pyrrole-2-carbohydrazide (Method B), from methyl 1-(fluoromethyl)pyrrole-2-carboxylate (Method C), and from methyl 1H-pyrrole-2-carboxylate (Method D).
Reaction SMILES: O=[O+][O-].[Si:4]([O:21][CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])(C(C)(C)C)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[C:23]([C:22](=[C:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])[O:21][SiH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:27])([CH3:24])[CH3:22]
Reactant: CC(C)(C)[Si](OC=C(CCO)CCO)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O[SiH](c1ccccc1)c1ccccc1)=C(CCO)CCO

Procedure:
Ozone was bubbled through a -78° C. dry methanol (500 mL) solution of 3-(tert-butyldiphenylsilyloxymethylene)-1,5-pentanediol (17 g, 47 mmol) until a blue tint persisted (30 minutes). The reaction was purged with nitrogen (20 min.) and NaBH4 (17.6 g, 47 mmol) was added. The cold bath was removed and the reaction brought to room temperature. The reaction was concentrated in vacuo and the residue partitioned between ether and brine. The ether layer was concentrated and the residue eluted over a silica plug with 0-50% ethyl acetate/hexanes. The minor component was pooled and concentrated to yield the diol, 3-(tertbutyldiphenylsilyloxymethylene)-pentane-1,5-diol, 3.8 g (22%) of the desired diol as a colorless oil. Overall the yield for the three steps is 17%. MS.