Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[SH:14].[OH:15][C@:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[S:14][C:27]1[CH:28]=[C:23]([C@@:16]2([OH:15])[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CN1C(=O)CCc2cc(S)c(F)cc21
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Product: C[C@H]1C[C@@](O)(c2cccc(Sc3cc4c(cc3F)N(C)C(=O)CC4)c2)CCO1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 6, 7-fluoro-6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-[3-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 55% yield, m.p. 90-92° C. (recrystallised from diethyl ether);
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1.Cl.[C:20](=O)(O)[O-:21].[Na+]>O1CCCC1.CN(C)C=O>[Cl:6][C:7]1[C:12]([CH2:20][OH:21])=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: Clc1ccc(-c2ccccc2)nc1
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCc1nc(-c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
tert-Butyl Lithium (1.7M pentane solution, 15 ml) was added slowly to a solution of 5-chloro-2-phenylpyridine (4.70 g) in tetrahydrofuran (50 ml) at −78° C. under a nitrogen atmosphere, which was stirred for 1 hour. N,N-Dimethylformamide (2.3 ml) was added to the mixture slowly, which was stirred for 1 hour while raising the temperature to room temperature. After addition of dilute hydrochloric acid the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Sodium borohydride (946 mg) was added slowly to a mixture of the residue, tetrahydrofuran (50 ml) and methanol (50 ml) at room temperature, which was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloro-6-phenyl-2-pyridylmethanol (2.35 g, yield 43%) as pale yellow crystals from the fraction eluted with ethyl acetate-hexane (1:6, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 69–70° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:24][CH:21]([CH3:23])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCCCCOc1ccc(OCc2ccccc2)cc1
Product: CC(C)NCCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
As described in Example 19, 1-benzyloxy-4-(4-bromobutoxy)benzene was reacted with isopropylamine at 100° (12 hours; 500 psi) to give 1-benzyloxy-4-[4-(1-methylethyl)aminobutoxyl]benzene. The crude product was not distilled.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CCOCC>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Yield: 120.9 %

Procedure:
72.8 g of 2-(4-methylbenzenesulfonylamino)-5-methoxynitrobenzene, prepared in A), are added to 56.5 ml of 4N sodium hydroxide solution and 29.2 g of 4-chlorobenzyl chloride. The mixture is refluxed for 4 hours, a further 43.7 g of 4-chlorobenzyl chloride are then added and the resulting mixture is refluxed for another 45 minutes. After cooling, 12.2 ml of 35% sodium hydroxide solution are added to the reaction mixture, the latter is refluxed for three hours 45 minutes and then cooled and water and ether are added. The insoluble material is filtered off and washed with water and ether to give 98 g of N-(4-chlorobenzyl)-N-(4-methylbenzenesulfonyl)-2-nitro-4-methoxyaniline in the form of crystals melting at 124° C. Evaporation of the ether phase yields an additional 10 g of crystals melting at 124° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:49](Cl)(=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2cc(S(=O)(=O)Oc3c(C)cc(-c4c5ccccc5c(Br)c5sc(C)c(C)c45)cc3C)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
At ambient temperature, to a stirred solution containing 4-[4-(9-bromo-2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.402 g, 0.602 mmol) and pyridine (0.292 mL, 3.61 mmol) in CH2Cl2 (6.02 mL) was added a solution of p-anisoyl chloride (0.208 g, 1.20 mmol) in CH2Cl2 (1.20 mL). After 18 h, the reaction was quenched with H2O (30 mL) and extracted with ether. The combined ethereal extracts were washed with sat. aq. NaHCO3 (3×), with sat. aq. CuSO4 (3×), with brine (3×), dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 15% acetone/hexane to give 0.354 g (73%) of the title compound. 1H NMR (DMSO-d6) δ 1.33 (s, 9 H), 1.54 (s, 3 H), 2.16 (s, 6 H), 2.34 (s, 3 H), 3.90 (s, 3 H), 7.13-7.19 (m, 4 H), 7.46-7.48 (m, 2 H), 7.60-7.70 (m, 1 H), 8.08-8.13 (m, 4 H), 8.20 (d, 2 H).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[CH3:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10]([O:12][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:11])[CH2:5][CH2:4]1
Reactant: CC1CCN(C(C(=O)O)c2ccccc2)CC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
2-(4-Methylpiperidin-1-yl)-2-phenylacetic acid hydrochloride (105 mg, 0.39 mmol), HOBT (119 mg, 0.78 mmol), and DCC (161 mg, 0.78 mmol) were dissolved in dry THF (5 ml). (R)-quinuclidin-3-ol (149 mg, 1.17 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. THF was evaporated, the residue was dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(4-methylpiperidin-1-yl)-2-phenylacetate (58 mg, 43.5% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21](=[O:26])[N:20]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21](=[O:26])[N:20]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH:19]=[CH:18]3)=[O:44])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cn2ccc3cc(SC4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(S(=O)C4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1

Procedure:
206 mg 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (285) in 6 ml of dichloromethane were treated with 83 mg m-Chloroperbenzoic acid over 2 h. The mixture was diluted with dichloromethane and washed with sodium hydrogen carbonate solution and brine. After drying over sodium sulfate all volatiles were evaporated and the crude product purified by chromatography 2:1 (ethyl acetate/Heptane) to obtain 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-6-sulfinyl]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:8])[CH2:6][OH:7].C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C1COCC1>[CH2:4]([CH:5]1[CH2:6][O:7][C:16](=[S:17])[NH:8]1)[CH2:3][CH2:2][CH3:1]
Reactant: S=C(Cl)Cl
Reactant: CCCCC(N)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC1COC(=S)N1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a stirred cold solution of DL-2-amino-1-hexanol (1.1 ml) in dry THF (10 ml) was added triethylamine (2.8 ml) followed by dropwise addition of thiophosgene (0.81 ml) in dry THF (9 ml). The mixture was then stirred for 18 h at 20° C., evaporated under reduced pressure and the residue partitioned between water and diethyl ether. The ether extract was dried with sodium sulphate filtered and evaporated. The residue was dissolved in the minimum of hot 1:1 dimethylether-hexane and crystallised on cooling to give 4-butyloxazolidine-2-thione, mp 71-2°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C:23]2([O:25][CH2:24]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C:23]([OH:25])([CH2:24][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:13])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CO2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(=O)n(CC3(O)CCN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 70 °C
Yield: 47 %

Procedure:
A solution of 7-methoxy-1H-quinolin-2-one (650 mg, 3.7 mmol) and 1-oxa-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1 eq., commercial) in DMF (10 mL) was treated with Cs2CO3 (1 eq.) and heated at 70° C. overnight. The mixture was partitioned between EA and water, the org. phase washed with water and brine, dried over MgSO4 and concentrated. The product was purified by CC (EA/Hept 1:1, EA) to give the desired intermediate as a yellowish oil (650 mg, 47% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][OH:13])[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=[O:13])[CH2:3][CH2:2]1
Reactant: OCCC1CCOc2ccccc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CCC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethanol (1.45g, 8 mmol), N-methylmorpholine-N-oxide (1.41 g, 12 mmol) and 4 A molecular sieves (4.0 g) in methylene chloride (20 ml), tetrapropylammonium perruthenate (0.140 g, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 15 min., diluted with an equal volume of ethyl acetate (20 ml) and flash filtered through silica gel (eluant: methylene chloride/ethyl acetate 1:1). Concentration of the filtrate in vacuo afforded the title compound as an oily gum (0.92 g, 64%). NMR (300 MHz/CDCl3) 9.87 (1 H, s).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:38]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:37](=[O:39])[CH3:38])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a stirred solution 0.72 mmol 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) in 3 ml dioxane were added 0.05 mmol palladium(II) acetate and 0.22 mmol triphenylarsine and the mixture was stirred at RT for 10 min. 1.01 mmol 1-ethoxyvinyltributylstannane was then added and the mixture was heated at 100° C. for 16 h. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was resuspended in THF, 25% aqueous hydrochloric acid was added, and the mixture was stirred at RT for 3 h. The mixture was then partitioned between ethyl acetate and water and the phases were separated. The aqueous phase was made alkaline to pH 14 by addition of 30% aqueous NaOH solution and then extracted with ethyl acetate. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the title compound as a brown solid (95% yield). MS (m/e): 162.6 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](=S)=[S:15].[OH-].[K+]>C(O)C>[CH2:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:14]([SH:15])=[N:1][C:2]=2[CH:7]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: S=C=S
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc2oc(S)nc2c1

Procedure:
To a solution of 1-amino-5-ethylsulfonyl-2-hydroxybenzene (20.13 g, 100.0 mmol, 1.0 equiv) in ethanol (200 mL) were added carbon disulfide (190.0 g, 150 mL, 2494 mmol, 25.0 equiv) and potassium hydroxide (6.73 g, 120 mmol, 1.2 equiv) and the reaction mixture heated to reflux over night. The solvent was evaporated, the residue treated with 1 M hydrochloric acid, extracted with ethyl acetate (3×150 mL) and the combined organic fractions dried over MgSO4. Evaporation of the organic solvent gave the crude product which was recrystallized from ethyl acetate to yield the title compound as yellowish solid. MS (ISN): 242.4 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C([BH3-])#N.[Na+]>CCO.CC(O)=O>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH:16]2[CH2:17][CH2:18]2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 6-amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.860 g, 3.16 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.703 g, 15.79 mmol) in EtOH (25 mL) and HOAc (2.5 mL) was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.073 g, 1.159 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 3) to give 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.560 g, 41%). The racemic product was separated by chiral SFC (Table 2, Method 6) to give 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 22%) and 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 20%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[C:13]2[NH:14][C:15]([CH2:24][NH2:25])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][O:17][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(Cl)Cl.C(N(CC)C(C)C)(C)C>[N+:5]([C:8]1[C:13]2[NH:14][C:15]([CH2:24][NH:25][C:1](=[O:3])[CH3:2])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][O:17][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Acetyl chloride (15 μL, 0.21 mmol) was added to a mixture of 1-(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methanamine (50 mg, 0.2 mmol) in methylene chloride (3 mL), N,N-diisopropylethylamine (60 μL) and was stirred at room temperature for 1 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (0.040 g. 70%). LCMS calculated for C16H17N4O4 (M+H)+: m/z=329.1. found: 329.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[CH:3]([C:8]([F:9])([F:10])[F:11])[CH:4]([NH:7][S:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH2:5][OH:6]
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1cccs1
Temperature: 25 °C

Procedure:
To a solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (prepared according to the method of Example 28, Part A, 105 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added pyridine (100 μL) and 2-thiophenesulfonyl chloride (90.5 mg, 0.5 mmol) in CH2Cl2 (1 mL). The solution was stirred for about 8 to about 16 h at 25° C. and then concentrated. EtOAc (1 mL) was added and the solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by the Biotage Flash™ 12 chromatography system, eluting with EtOAc/hexanes (2:3), to give thiophene-2-sulfonic acid (3,3,3-trifluoro-1-hydroxymethyl-2-trifluoromethyl-propyl)-amide (26.5 mg) as a white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[O:9])[NH:8][C:3]1=[O:2]
Reactant: N#Cc1ncccc1-c1c[nH]c(=O)[nH]c1=O
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cccnc2C#N)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of 3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-pyridine-2-carbonitrile hydrochloride (Prep103, 500 mg, 2 mmol), and K2CO3 (413 mg, 3 mmol) in DMF (7 ml) was stirred for one hour at room temperature. 3-Bromo-1,1dimethoxy-propane (402 mg, 2.2 mmol) was added and stirring continued for 48 hours. Water was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 210 mg of a yellow oil (33% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2([CH3:26])[CH2:25][O:24]2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].[Na].[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([OH:24])([CH3:26])[CH2:25][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)C1=C(COCC2(C)CO2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCC(C)(O)Cn2cncn2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.4 %

Procedure:
A mixture of 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxymethyl}-2-methyloxirane (0.80 g), 1,2,4-triazole sodium salt (0.60 g) and "18-Crown-6" (20 mg) in tetrahydrofuran (25 ml) was stirred at room temperature for two days and then partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (12 g) using toluene plus 0-100% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue was triturated with ether. The resulting solid was collected, washed with ether and dried to give the title compound (0.49 g), m.p. 149°-160° C.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:17]2[CH2:20][CH:19]([OH:21])[CH2:18]2)=[CH:4][CH:5]=1
Reactant: OC1CNC1
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 1.5 h

Procedure:
The reaction mixture of 22.30 g (70.5 mmol) of 1-[bromo(4-chlorophenyl)methyl]-4-chlorobenzene, 5.67 g (77.6 mmol) of azetidin-3-ol (2) and 18.4 mL (105.75 mmol) of N,N-diisopropylethylamine in 250 mL of acetonitrile was rapidly stirred for 1.5 h at rt to 91° C. Reaction mixture was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate/ammonia (2M in MeOH)=100/30/0.5 to afford the title compound; 1NMR (CDCl3) δ 2.03 (br s, 1H), 2.81 (m, 2H), 3.55 (m, 2H), 4.34 (s, 1H), 4.50 (m, 1H), 7.29 (m, 4H), 7.34 (m, 4H).