Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:32][C:29]2[CH:30]=[N:31][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:2][CH2:3]5)(=[O:6])=[O:5])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in 1,2-dichloroethane (5 mL) was added 1-acetylpiperazine (65 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (140 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (114 mg, yield 92%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (19:1, volume ratio). MS: 577 (MH+).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:10]1[CH:11]=[CH:12][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccncc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
0.336 g of 5% Pd/C is added to 0.821 g of tert-butyl 3,6-dihydro-4,4′-bipyridine-1(2H)-carboxylate, dissolved in 65 ml of methanol, in a high-pressure reactor under nitrogen. The reaction mixture is placed under a pressure of 3 atmospheres of hydrogen at 25° C. and stirred mechanically for 1 h. The palladium is filtered off on Whatman paper (registered trademark) and is washed with methanol. The solvent is evaporated and the residue is then chromatographed on silica gel, heptane/ethyl acetate (8/2) to heptane/ethyl acetate (1/1) elution gradient. 0.552 g of tert-butyl 4-(pyridin-4-yl)piperidine-1-carboxylate is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][C:34](OC)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:33][C:34]1[NH:22][C:20](=[O:21])[C:3]2[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nc21
Yield: 74.1 %

Procedure:
6 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.095 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate have been added, the phases are separated. Purification by chromatography gives 6.6 mg (68%) of a solid, Rf=0.25 (dichloromethane/methanol=15:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](O)=[O:28])[CH2:22]2)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](=[O:28])[NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:22]2)[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)CNC(=O)C1CN(CC2=C(C(=O)OCC)C(c3ccc(F)cc3Br)N=C(c3nccs3)N2)CCO1
Yield: 82.1 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid (0.8 g, 1.45 mmol) was reacted with ethyl 2-aminoacetate hydrochloride (0.31 g, 2.17 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.76 g, 82%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8-Chlorotheophylline (50 g, 0.23 mol) was suspended in 600 ml of DMF and benzyl bromide (31 ml, 0.26 mol) and potassium carbonate (64 g, 0.46 mol) were added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was dissolved in 250 ml of water and 400 ml of DCM. The layers were separated and the aqueous layer was extracted with 150 ml of DCM. The combined organic layer was washed with 100 ml of brine, dried over magnesium sulphate, filtered, and the solvent was evaporated to give compound (2A) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CS(C)=O>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([CH:24]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2cc(OC)ccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methoxybenzo[b]thiophene-3-carboxylate, 2,4-difluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(5-fluoro-2-nitroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH2:2]1.Br[CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)=[CH:15][C:14]=1[CH3:35].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:25]=[C:24]([O:33][CH3:34])[CH:23]=[C:22]2[C:27]=1[C:28](=[O:30])[NH:29][C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([O:12][CH2:11][CH2:10][N:1]3[CH2:4][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH2:2]3)=[C:14]([CH3:35])[CH:15]=1)=[N:21]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: CC(=O)NC1CNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CC(NC(C)=O)C4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-azetidin-3-yl-acetamide (0.30 g crude, 1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.43 g, 1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. Solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered. The aqueous phase was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4. Solvent was evaporated, and crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.30 g (63%). MP 111.8-113.6° C. 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.34 Hz, 1H), 6.46 (d, J=2.34 Hz, 1H), 6.10 (d, J=7.81 Hz, 1H), 4.71-4.44 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.85-3.67 (m, 4H), 3.26-3.13 (m, 2H), 2.90 (t, J=5.46 Hz, 2H), 2.36 (s, 6H), 2.01 (s, 3H). MS (ES+) m/z: 467.20 (M+1).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([N:15]2[C:16]3[C:21](=[CH:20][C:19]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[CH:22]=[C:14]2[C:12]([N:9]2[CH2:8][CH2:7][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:11][CH2:10]2)=[O:13])[CH:38]=[CH:37][N:36]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from (4-cyclopropanecarbonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 25) and 2-chloropyridine-4-boronic acid to afford the desired product as a colorless foam (43%). MS (ISP): 563.5 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:64])([F:63])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:54][CH3:55])=[N:35][CH:36]=[C:37]([C:39]5[C:51]([CH3:52])=[CH:50][C:42]([C:43]([O:45]C(C)(C)C)=[O:44])=[CH:41][C:40]=5[CH3:53])[CH:38]=4)=[CH:31][CH:30]=[C:29]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[N:28]=3)[C@H:21]2[CH3:62])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>C(Cl)Cl>[F:19][C:16]([F:17])([F:18])[C:14]1[CH:13]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:54][CH3:55])=[N:35][CH:36]=[C:37]([C:39]5[C:40]([CH3:53])=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:50][C:51]=5[CH3:52])[CH:38]=4)=[CH:31][CH:30]=[C:29]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[N:28]=3)[C@H:21]2[CH3:62])[CH:11]=[C:10]([C:9]([F:64])([F:63])[F:8])[CH:15]=1
Reactant: COc1ncc(-c2c(C)cc(C(=O)OC(C)(C)C)cc2C)cc1-c1ccc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1ccc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Yield: 69.1 %

Procedure:
A solution of TFA (0.095 mL, 1.240 mmol) and tert-butyl 4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-methoxy-6′-(morpholin-4-yl)-3,3′-bipyridin-5-yl]-3,5-dimethylbenzoate (EXAMPLE 55, 44 mg, 0.055 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature overnight, after which time TLC and LCMS showed the reaction to be complete. After solvent was removed in vacuo, the crude was dissolved in CH3CN and purified by reverse phase HPLC (C18 stationary phase, using a gradient from 10-100% CH3CN/water (modified with 0.05% TFA) to give the titled compound (33 mg, 0.038 mmol, 70% yield) as white solid after lyophilization. LCMS (M+H)+: 731.0. 1H NMR (CD3OD, 500 MHz): δ 8.18 (d, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.91 (d, 1H), 7.89 (s, 2H), 7.63 (d, 1H), 7.51 (d, 1H), 7.38 (d, 1H), 6.88 (d, 1H), 5.79 (d, 1H), 4.73 (d, 1H), 4.20-4.31 (m, 1H), 4.03-4.17 (m, 1H), 3.99 (s, 3H), 3.83 (t, 4H), 3.60 (t, 4H), 2.38 (s, 3H), 0.66 (brd, 3H). RTA IC50: 9 nM.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=4[CH:17]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Product: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2CO1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: O1CC(C([O-])=O)OC1C([O-])=O.[Na+].[Na+].[O:14]=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17].Br[CH:21]([CH2:26][OH:27])[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[CH3:25][O:24][C:22]([CH:21]1[CH2:26][O:27][CH:15]([C:16]([Cl:19])([Cl:18])[Cl:17])[O:14]1)=[O:23]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COC(=O)C(Br)CO
Agent: O=C([O-])C1COC(C(=O)[O-])O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Product: COC(=O)C1COC(C(Cl)(Cl)Cl)O1
Reaction time: 8 h

Procedure:
This compound was prepared as a possible alternate precursor to the title compound of Example 5 (c). Chloral 15.1 g (0.102 mol) and 22 g of methyl 2-bromo-3-hydroxypropionate, as prepared in Example 5(a) were mixed, and after returning to room temperature the mixture was treated with hexane 50 ml and 14.1 g (0.102 mol) potassium carbonate (added in portions over 0.5 hour). After stirring for 6 hours an additional 5 g of potassium carbonate was added and the mixture allowed to stir overnight.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:21][CH2:20][N:19]4[C@H:14]([CH2:15][O:16][CH2:17][C:18]4=[O:22])[CH2:13]3)[CH2:9]2)C=CC=CC=1.C(O)=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:21][CH2:20][N:19]3[C@H:14]([CH2:15][O:16][CH2:17][C:18]3=[O:22])[CH2:13]2)[CH2:9]1
Reactant: O=C1COC[C@@H]2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O=CO
Product: O=C1COC[C@@H]2CN(C3CNC3)CCN12
Temperature: 120 °C

Procedure:
(9aS)-8-[1-(Diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one (85 mg, 0.22 mmol) was dissolved in ethanol (18 mL). The solution was transferred to a 25 mL vial, which contained ethanol (2 mL), 10% palladium on carbon (0.1 g), formic acid (0.1 g, 2.2 mmol) and ammonium formate (0.2 g, 3.17 mmol). The mixture was heated for 5 min at 120° C. using microwave single node heating. The catalyst was filtered off and the solution of crude (9aS)-8-azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one was used in the next step without purification and quantification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].I[CH2:19][CH2:20][CH3:21].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
A mixture of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (Example 135, step A) (0.50 g, 2.1 mmol) and 1-iodopropane (0.72 g, 4.22 mmol) was stirred in acetonitrile (42 mL) at rt under N2. To this mixture was added NaHCO3 (0.27 g, 2.5 mmol). The reaction was then heated to reflux and stirred for 24 h. The reaction was cooled to rt, concentrated under vacuum and the residue chromatographed on silica gel to give the title compound of step A (206 mg, 0.74 mmol, 35%) as a yellow oil. MS (ESI): 280 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:11][CH2:10][C:3]1[C:2]([C:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=3[CH3:30])[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(B(O)O)c2)c(C)c1
Reactant: CSc1ncc(Br)c(CO)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3CO)c2)c(C)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed [5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methanol (130 g, 560 mmol, 1.00 equiv), [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (87.5 g, 0.5 equiv), Pd(PPh3)4 (32.3, 28 mmol, 0.05 equiv), Cs2CO3 (365.1 g, 2.00 equiv), water (300 mL), 1,4-dioxane (1200 mL). The resulting solution was stirred for 5 hour at 100° C., then added 2nd batch of [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (50 g, 0.3 equiv). The last batch (37 g, 0.2 equiv) was added after 2 hours. The resulting solution was stirred for 3 h at 100° C. The reaction mixture was cooled to room temperature and diluted with 1000 mL of water. The resulting solution was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8). This resulted in 81 g (35.7%) of methyl 4-[3-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4-methoxyphenyl]-3-methylbenzoate as a yellow solid. LCMS (ES, m/z): 411 [M+H]+. 1H NMR (CDCl3, 300 MHz): δ 8.398 (1H, s), 7.976 (1H, s), 7.916 (2H, d), 7.410 (1H, d), 7.284-7.325 (1H, m), 7.066-7.114 (2H, m), 4.583 (2H, s), 3.954 (3H, s), 3.853 (3H, s), 2.663 (3H, s).
Reaction SMILES: COC1C=CC([C@H](N2C[C@H](C3CO3)CC2=O)C)=CC=1.C[O-].[Na+].[OH:23][C@@H:24]([C@H:28]1[CH2:32][N:31]([C@@H:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH3:34])[C:30](=[O:43])[CH2:29]1)[CH2:25][O:26][CH3:27]>CO>[OH:23][CH:24]([C@H:28]1[CH2:32][N:31]([C@@H:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH3:34])[C:30](=[O:43])[CH2:29]1)[CH2:25][O:26][CH3:27]
Reactant: COC[C@@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Agent: COc1ccc([C@@H](C)N2C[C@H](C3CO3)CC2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 55 °C

Procedure:
To a solution of (4R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-(oxiran-2-yl)pyrrolidin-2-one 1.13 (150 mg, 0.57 mmol) in MeOH (5 mL) was added NaOMe (125 mg, 25% in MeOH), and the solution was heated at 55° C. for 3 hours. The reaction was concentrated and purified by flash chromatography (EtOAc→10% MeOH in EtOAC) to afford the product as a mixture of diastereomers. The isolated mixture was purified by RP-HPLC (C18 Gemini Column) to afford the later eluting diastereomer, which was assigned as (R)-4-((S)-1-hydroxy-2-methoxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.15.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.Cl>[OH-].[Na+]>[CH3:12][CH:7]1[N:8]2[C:9]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH3:13])[C:4]=3[CH2:5][CH2:6]1)[C:17](=[O:16])[C:18]([C:19]([OH:21])=[O:20])=[CH:24]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1c(F)ccc2c1CCC(C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 9.3 g of 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine and 17 ml of diethyl ethoxymethylenemalonate was heated at 150°-160° C. for 3.5 hours, and then cooled to 100° C. To this solution was added 56 g of polyphosphoric acid, and the mixture was stirred for one hour while heating on a steam bath. The mixture was then cooled to room temperature and allowed to stand for about 72 hours. To this mixture, containing ethyl 1,2-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, was added 250 ml of 20% aqueous sodium hydroxide to make the solution basic. The solution was then heated at its reflux temperature for 2 hours, cooled, and acidified with concentrated hydrochloric acid. The solid was separated by filtration and recrystallized from aqueous N,N-dimethylformamide. Washing with ethanol followed by drying provided 6,7-dihydro-5,8-dimethyl-9- fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as an off-white solid, m.p. 269-272° C. Analysis: Calculated for C15H14FNO3: %C, 65.4; %H, 5.1; %N, 5.1; Found: %C, 65.0; %H, 5.0; %N, 5.0.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:22]([OH:36])[CH2:23][NH:24][C:25]([CH3:35])([CH3:34])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=2[CH:21]=1)C1C=CC=CC=1>CO.[Pd]>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([NH:24][CH2:23][CH:22]([C:11]2[C:12]3[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=3[CH:21]=[C:9]([OH:8])[CH:10]=2)[OH:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1
Reactant: CC(C)(Cc1ccc(F)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: CC(C)(Cc1ccc(F)cc1)NCC(O)c1cc(O)cc2c1OC(C)(C)C(=O)N2

Procedure:
280 mg (0.57 mmol) 6-benzyloxy-8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one are dissolved in 7 mL methanol and hydrogenated with palladium on charcoal (10%) at ambient temperature. Then the catalyst is separated off and the filtrate is freed from the solvent. The residue is dissolved in dichloromethane and precipitated by the addition of methanol/water. White solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])([CH3:12])[CH3:9])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: CC(=O)c1nc(Cl)ncc1F
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirred, −78° C. solution of 1-(2-chloro-5-fluoro-pyrimidin-4-yl)ethanone (10.06 g, 57.6 mmol) in tetrahydrofuran (100 mL) under nitrogen is added methyl magnesium bromide in diethyl ether (3 M, 124 mL, 72.04 mmol) and the resulting mixture is stirred at −78° C. for 20 minutes. The reaction is quenched with aqueous saturated ammonium chloride and the mixture is warmed to room temperature. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The crude product is purified using silica gel column chromatography using a 5-100% gradient of ethyl acetate in hexanes to give the title compound (7.06 g, 64%). ES/MS (m/e): 191 and 193 (M+1).