Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26](C3C=CN(C)C(=O)C=3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:22])[CH2:3][CH2:2]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1>>[CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([C:38]3[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:22])[CH2:3][CH2:2]1
Reactant: Cn1ccc(-c2ccc(C(C3CC3)N3CCC(CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O
Reactant: Cn1cc(Br)ccc1=O
Product: Cn1cc(-c2ccc(C(C3CC3)N3CCC(CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O

Procedure:
The title compound was prepared from 3-{cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (for preparation see Example 3) and 5-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.34 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:11]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])[CH3:12]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:11][CH3:12])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCOC(=O)C1CCNC1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2OCC)C1
Yield: 83 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 2-ethoxy-benzoyl chloride to afford the title compound as a pale yellow oil (5.13 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH:30]3[CH2:32][CH2:31]3)(=[O:29])=[O:28])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH:30]3[CH2:31][CH2:32]3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NS(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(NS(=O)(=O)C2CC2)cc1

Procedure:
In analogy to example 151, step 3, cyclopropanesulfonic acid {4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenyl}-amide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 7% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=500.3 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[H-].[Na+].[CH3:23]I.O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:23])([CH3:18])[CH2:13]1
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.1 g, 0.36 mmol) in THF (5 ml) was added to NaH (60% in oil, 79.0 mg, 1.79 mmol) which was previously washed with heptane. The reaction mixture was stirred at 70° C. for 1 h and then cooled to RT followed by dropwise addition of a solution of methyl iodide (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continued for 1 h. Water was slowly added and the reaction mixture extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:32])[CH:20]=[C:19]1[CH2:34][C:35]([NH2:37])=[O:36])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:32])[CH:20]=[C:19]1[CH2:34][C:35]([NH2:37])=[O:36])[CH:2]=[CH2:3]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCONC1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1CC(N)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-2-carbamoyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 175, 1.36 g, 2.52 mmol) and potassium carbonate (1.742 g, 12.60 mmol) in acetonitrile (20.0 mL) at 0° C. was added benzenethiol (1.389 g, 12.60 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the resulting residue was triturated with DCM. The solids were removed by filtration. The filtrate was concentrated to a pale yellow film, which was subjected to silica gel column eluting with 0-50% MeOH/DCM to give a pale yellow solid, 330 mg, 36.9%.
Reaction SMILES: [CH2:1]([N:17]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[C:18](=[O:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.CN([CH:34]=[O:35])C>>[CH:34]([C:23]1[S:22][C:21]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18](=[O:20])[CH3:19])=[CH:25][CH:24]=1)=[O:35]
Reactant: CCCCCCCCCCCCCCCCN(C(C)=O)c1cccs1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
27 g of N-Hexadecyl-N-(2-thienyl)-acetamide are dissolved in 22 cc. of anhydrous DMF and 14 g of phosphorus oxychloride are added dropwise thereto under cooling with ice, thereby avoiding increase of the temperature of the reaction mixture above 20° C. Stirring is continued for 1 hour at 20° C. and the reaction mixture finally is stirred for 3 hours at 80° C. Ice is added to the reaction mixture and 5 N soda lye is added thereto until reaching a pH of 6. The resulting mixture is extracted with ether, the ethereal phase is separated, washed with water and dried over Na2SO4. The ether is separated and the residue is purified chromatographically on a column of silicic acid gel using hexane/ethyl acetate as eluant.
Reaction SMILES: [C:1]1([C:11]([O:13][CH3:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:14][O:13][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-:20])=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1nccc2ccccc12
Solvent: ClCCl
Product: COC(=O)c1c2ccccc2cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a suspension of methyl isoquinoline-1-carboxylate (11.2 g, 59.8 mmol) in DCM (150 mL) was added 3-chloroperoxybenzoic acid (15.5 g, 89.7 mmol) at 0° C. The mixture was warmed to RT and was stirred at RT for 24 hours. The reaction was quenched with saturated aqueous NaHCO3 and the mixture was extracted with DCM. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography eluting with petroleum ether and EtOAc (1:1) to give the title compound as a white solid (9.5 g, 78%). ESI-MS m/z [M+H]+ 204.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:3]([CH2:2][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:13])=[O:14])#[N:4]
Reactant: N#CCCl
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1ccccc1S(N)(=O)=O
Reaction time: 16 h
Yield: 66 %

Procedure:
8 g (0.1 mol) of chloroacetonitrile are added dropwise to a stirred suspension of 18 g (0.1 mol) of 2-hydroxybenzenesulphonamide and 15 g (0.1 mol) of potassium carbonate in 250 ml of acetonitrile, and stirring is continued for a further 16 hours at 55° C. to 60° C. when the addition is complete. The reaction mixture obtained is filtered under suction, and the residue is evaporated down and triturated with water. The solid obtained is dried on clay. 14 g (66% of theory) of 2-cyanomethoxyphenylsulphonamide of melting point 184° to 185° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13]>C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:16]([O:18][CH3:19])=[O:17])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Product: COC(=O)C(C(=O)OC)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a stirred ethanol solution (40 mL) of dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (4.0 g, 14.76 mmol, 1.0 eq) 10% Pd—C (400 mg) was added and the mixture was stirred under a H2 gas balloon at RT for 2 h, then the mixture was passed through a celite bed and the solvent of the filtrate was evaporated to get dimethyl 2-(4-amino-2-fluorophenyl)malonate (3.2 g, 87%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.3).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[S:55][C:56]2[CH2:57][NH:58][CH2:59][CH2:60][C:61]=2[N:62]=1)=[O:53]>CN(C=O)C>[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[S:55][C:56]2[CH2:57][N:58]([C:7]([C:4]3[CH:3]=[CH:2][C:1]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:6][CH:5]=3)=[O:9])[CH2:59][CH2:60][C:61]=2[N:62]=1)=[O:53]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)c1ccc(-c3ccccc3)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of biphenyl-4-carboxylic acid (1.0 mmol) in dry 10 mL DMF, were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C.N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example 1 (1.1 mmole.) was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to yield the title compound.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]([S:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH:45]=O)[CH:29]=1.C(=O)(O)[O-].[Na+]>CCOCC>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]([S:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH:45]=[CH2:2])[CH:29]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Sc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1ccccc1Sc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
Methyl triphenylphosphonium iodide (1.56 g, 3.87 mmol) was dissolved in 25 mL ether in a 50 ml round-bottom flask at 0° C. under dry nitrogen. To the mixture was added in one portion potassium tert-butoxide (0.46 g, 4.15 mmol) and was stirred for 10 min at room temperature. 2-(3-naphtylsulfanyl)benzenecarbaldehyde (0.73 g, 2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred for additional 2.5 h at room temperature. The mixture was added to 50 mL, of saturated sodium bicarbonate solution, and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The light yellow oil of the crude product was further purified by chromatography on silica gel using 9:1 petroleum ether 60-80: ether as eluent to afford a colorless oil (0.58 g, 81%). 1H-NMR (500 MHz, CDCl3): δ 5.35 (dd, J=1.3, 11.0 Hz, 1H), 5.77 (dd, J=1.3, 17.5 Hz, 1H), 7.24-7.51 (m, 7H), 7.67-7.81 (m, 5H) ppm. 13C-NMR (125 MHz, CDCl3): δ 116.28, 125.85, 126.20, 126.50, 127.22, 127.48, 127.68, 127.97, 128.24, 128.49, 128.70, 131.91, 132.81, 133.72, 133.78, 133.81, 134.52, 139.71 ppm. E1-MS: m/z M+ Calc. 262.3, found 262.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1ccccc1F
Product: CCN1c2ncc(COc3ccccc3F)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 52 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 109°-110° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 2-fluorophenol. The yield was 52% of theory.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([OH:20])([CH2:13]3)[CH2:11]1)[CH2:17]2)(O)=[O:8]>O1CCCC1>[OH:8][CH2:7][C:10]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][C:12]([OH:20])([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 15 mmole of lithium aluminium hydride was suspended into 15 mL of tetrahydrofurane (THF). To the resultant mixture was slowly added 10 mmole of 1-carboxy-3-adamantanol obtained by the method of Example 2 while keeping the temperature of the mixture at 10° C. or below by using an ice bath. After warming the mixture to room temperature, the mixture was refluxed for 16 hours. As a result, 1-hydroxymethyl-3-adamantanol (yield 95%) was obtained. The conversion of 1-carboxy-3-adamantanol was 99%.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:19]1[CH2:22][C:21]([OH:26])([C:23]([OH:25])=[O:24])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27]O>CCOC(C)=O>[CH:6]([N:19]1[CH2:20][C:21]([OH:26])([C:23]([O:25][CH3:27])=[O:24])[CH2:22]1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C

Procedure:
Sulfuric acid (4.00 mL, 47.3 mmol) was added to a mixture of 1-benzhydryl-3-hydroxyazetidine-3-carboxylic acid (2.13 g, 7.50 mmol) in MeOH (20 mL). The mixture was heated to 80° C. for 18 h, diluted with EtOAc, extracted with water, 1N NaOH, dried over MgSO4, and evaporated. The solid was rinsed with Et2O to give methyl 1-benzhydryl-3-hydroxyazetidine-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ ppm 7.43-7.49 (m, 4H), 7.24-7.31 (m, 4H), 7.15-7.23 (m, 2H), 4.54 (s, 1H), 3.90 (s, 3H), 3.59-3.72 (m, 2H), 3.24-3.39 (m, 2H). MS (ESI) m/z: Calculated; 297.14 Observed: 298.1 (M++1).
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS([C@@:15]1(O)[C@:19](S(C)(=O)=O)(O)[C@@H:18]([CH:25](S(C)(=O)=O)[OH:26])[O:17][C@H:16]1[N:31]1[CH:38]=[C:37]([CH3:39])[C:35](=[O:36])[NH:34][C:32]1=[O:33])(=O)=O.Br.CC(O)=O>CN(C=O)C.[Zn]>[C:1]([CH:25]([OH:26])[C@H:18]1[O:17][C@@H:16]([N:31]2[CH:38]=[C:37]([CH3:39])[C:35](=[O:36])[NH:34][C:32]2=[O:33])[CH:15]=[CH:19]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@](O)(S(C)(=O)=O)[C@]2(O)S(C)(=O)=O)c(=O)[nH]c1=O
Reactant: O=C([O-])c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C=C[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 5.5 h

Procedure:
To a slurry of powdered sodium benzoate (3.5 g, 24.3 mmol) in DMF (25 ml) at 90° C. was added tris(methanesulfonyl)-5-methyluridine (IX, 5.0 g, 10.2 mmol). The reaction was stirred for 5.5 hours at 90° C. HBr/HOAc (30-32%, 5 ml, 25.1 mmol) was added and the reaction was stirred for one hour. The reaction mixture was cooled to 25° C. and zinc dust (2.0 g, 30.6 mmol) was added. The reaction was stirred for 30 minutes. The excess zinc was removed by filtration and washed with 2×100 ml methanol. To the filtrate was added 100 ml ice-cold water. The resulting slurry was stirred at 0° C. for 30 minutes and then filtered, dried to give 5'-benzoyl-d4T, 2.34 g (71%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]CC=C)[N:10]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:9](=[O:23])[CH2:8][CH2:7]2)[CH:2]=[CH2:3].[CH2:24]1[C:33]2C(=CC=CC=2)CC[CH2:25]1>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:33][CH:24]=[CH2:25])[C:13]=1[OH:14])[N:10]([CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[C:9](=[O:23])[CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: c1ccc2c(c1)CCCC2
Reactant: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2CC=C(C)C
Product: C=CCc1cc2c(c(CC=C)c1O)N(CC=C(C)C)C(=O)CC2
Reaction time: 3 h
Yield: 78 %

Procedure:
10 Grams of 6-allyl-7-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone obtained in Example 20 was dissolved in 50 ml of tetralin and stirred at 200° to 230° C. for 3 hours. After cooling, the reaction mixture was subjected to purification by passing through a silica gel column, there was obtained 7.8 g (78%) of 6,8-diallyl-3,4-dihydro-7-hydroxy-1-prenyl-2(1H)-quinolinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[BH4-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][CH:11]([C:10]#[N:14])[C:12]#[N:13]
Reactant: N#CCC#N
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
First, 0.93 g of 3-bromobenzaldehyde and 0.33 g of malononitrile were dissolved in 5 ml of ethanol, to which 1.5 ml of water was added, followed by stirring at room temperature for 4 hours. Then, after cooling at −5° C., a suspension of 57 mg of sodium borohydride in 3 ml of ethanol was added dropwise, followed by stirring at −5° C. for 30 minutes. 10% hydrochloride acid was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.94 g of (3-bromobenzyl)malononitrile (the intermediate (28)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][C:18]2[CH:19]=[N:20][N:21]([CH2:37][CH:38]([F:40])[F:39])[C:22]=2[N:23]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)C(F)(F)F)[CH2:25][CH2:24]2)=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:3]([C:15]([NH:17][C:18]2[CH:19]=[N:20][N:21]([CH2:37][CH:38]([F:40])[F:39])[C:22]=2[N:23]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25][CH2:24]2)=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1ccc(-c2ccccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCC[C@@H](N)CC1

Procedure:
(R)-3-amino-N-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide (98 mg, 0.17 mmol) was stirred with potassium carbonate (144 mg, 1.03 mmol) in methanol (5 mL) at 50° C. overnight. The mixture was filtered and the filtrate was purified on reversed phase HPLC to give 180. 1H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 8.00 (td, J=8.3, 1.8 Hz, 1H), 7.86 (s, 1H), 7.74 (dd, J=8.7, 2.2 Hz, 1H), 7.43 (dt, J=7.2, 3.8 Hz, 1H), 7.38-7.20 (m, 4H), 7.08 (s, 2H), 6.38 (tt, J=55.3, 4.1 Hz, 1H), 4.43 (td, J=14.5, 4.1 Hz, 2H), 3.55 (s, 1H), 3.21-3.07 (m, 4H), 2.92 (dd, J=19.4, 10.4 Hz, 1H), 1.89-1.69 (m, 3H), 1.69-1.37 (m, 3H). MS (ESI) m/z: 474.2 [M+H+].
Reaction SMILES: Br[CH2:2]Br.[CH2:4]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16](=O)[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16](=[CH2:2])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCBr
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A 8.44 ml (77 mmol) portion of titanium tetrachloride was added dropwise to 350 ml of tetrahydrofuran solution containing 36.6 g (600 mmol) of zinc at 0° C., and the mixture was stirred for 60 minutes at the same temperature. To the reaction solution cooled at 0° C. was added dropwise 24.32 ml (350 mmol) of dibromomethane dissolved in 100 ml of tetrahydrofuran, followed by stirring at room temperature overnight. To the reaction solution was added dropwise tetrahydrofuran (100 ml) solution of 15.35 g (70 mmol) 1-benzyloxycarbonyl-3-pyrrolidone at room temperature, followed by 50 minutes of stirring at the same temperature. After completion of the reaction, the reaction solution was mixed with 500 ml of 1 N hydrochloric acid and extracted with ethyl acetate (500 ml×2), and the organic layer was washed with saturated brine (300 ml×1). After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The resulting residue was subjected to a silica gel column chromatography to yield 12.4 g (82%) of the title compound as an oily product from the eluate of n-hexane:ethyl acetate=2:1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[CH:25]=[N:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][N:21]=1.[H-].[Na+].Cl>CN(C=O)C>[CH3:29][O:28][C:26]([C:23]1[CH:22]=[N:21][C:20]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:25][N:24]=1)=[O:27]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=O)OC)cn3)cc(C)c21
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol) and methyl 2-chloro-5-pyrazinecarboxylate (1.95 g, 12 mmol) in DMF (40 mL) at 0° C. was added NaH (0.8 g, 20 mmol). The reaction mixture was allowed to warm up to room temperature slowly and heated at 50° C. for 1 h. The reaction mixture was cooled down and acidified to pH 3 with 6N HCl, extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, DCM/MeOH=9:1) affording the title compound (1.9 g, 61%) as a light yellow solid. 1H NMR (CDCl3) δ 8.82 (s, 1H), 8.53 (s, 1H), 7.38 (d, 1H), 7.07 (d, 1H), 5.69 (dd, 1H), 4.10 (q, 2H), 4.02 (s, 3H), 3.06 (dd, 1H), 2.43 (m, 1H), 2.39 (s, 3H), 1.23 (t, 3H).