Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[C:34]([CH3:36])[C:33]([O:37][CH2:38][O:39][CH3:40])=[C:32]([CH3:41])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[C:32]([CH3:41])[C:33]([O:37][CH2:38][O:39][CH3:40])=[C:34]([CH3:36])[CH:35]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)C(=O)O
Yield: 104.2 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using ethyl 2-butyl-3-[4-[2-(4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (1.01 g), which is the product of Reference example 17(c) and aqueous sodium hydroxide solution (1N, 3.60 ml) and the reaction mixture was treated to afford the title compound (1.00 g) as a foam powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([OH:34])=O)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=[O:49]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([NH:40][CH2:41][CH2:42][CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][C:45]2=[O:49])=[O:34])=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)O)c2)cc1
Reactant: NCCCN1CCCC1=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)NCCCN3CCCC3=O)c2)cc1

Procedure:
The product from Example 62C and 1-(3-aminopropyl)-2-pyrolidinone was processed as described in Example 68D to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 8.07 (m, 1 H), 7.23 (m, 8 H), 6.85-7.06 (m, 4 H), 6.45-6.79 (m, 4 H), 4.43 (s, 2 H), 4.08 (s, 2 H), 4.06 (s, 2 H), 2.99-3.39 (m, 6 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.17 (m, 2 H), 1.87 (m, 2 H), 1.56 (m, 2 H); MS (APCI) m/z 671 (M+H+).
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Br[CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O>C(O)C>[CH3:2][C:1]1[S:4][C:10]2[C:11](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]=2[N:3]=1
Reactant: O=C1CCCC(=O)C1Br
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)CCC2

Procedure:
To a solution of ethanethioamide (0.75 g, 10 mmol) in ethanol (20 mL) at room temperature was added 2-bromocyclohexane-1,3-dione (1.9 g, 10 mmol) in portions. The reaction solution was refluxed for 2 hours while stirring. After removal of solvents, the residue was diluted with water and washed with diethyl ether. The separated aqueous layer was basified with sodium carbonate solution. The resulting solid was collected by vacuum filtration, rinsed with water. The solid was suspended in methanol and followed by evaporation to dryness to produce the title compound.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(I)cc1F
Solvent: CO
Solvent: ClCCl
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(I)cc1F
Yield: 81.3 %

Procedure:
8-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (151 mg, 0.31 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue that was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (115 mg, 81%). LCMS (method A): RT=6.36 min, [M+H]+=457. 1H NMR (CD3OD): 8.27 (1H, d, J=0.85 Hz), 7.80-7.77 (1H, m), 7.57-7.53 (1H, m), 7.49-7.46 (1H, m), 6.95 (1H, t, J=8.48 Hz), 6.76 (1 H, d, J=7.37 Hz), 6.68 (1H, s), 4.00-3.94 (2 H, m), 3.75-3.71 (2 H, m).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([CH:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN1CCC(N2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3C2=O)CC1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C4CCN(C)CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=521.1. 1H NMR (300 MHz, DMSO-d6) δ: 14.57 (s, 1H), 9.86 (s, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.2 Hz, 1H), 4.58 (s, 2H), 3.94 (s, 6H), 2.92-2.84 (m, 5H), 2.21 (s, 3H), 2.08-1.66 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:41][C@:42]1([C:47]([NH:49][S:50]([CH:53]2[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:44][C@H:43]1[CH:45]=[CH2:46].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:53]1([S:50]([NH:49][C:47]([C@@:42]2([NH:41][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:44][C@H:43]2[CH:45]=[CH2:46])=[O:48])(=[O:52])=[O:51])[CH2:55][CH2:54]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.4 g, 25.3 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide p-toluenesulfonate salt (11.2 g, 27.8 mmol), and N,N-diisopropylethylamine (17.6 ml, 101 mmol) in CH2Cl2 (200 ml) was added HATU (11.5 g, 30.4 mmol). The mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel and was thrice washed with aq. 1N HCl; then brine. The organic phase was dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was subjected to silica gel chromatography to afford tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a light-orange solid foam (14.8 g, 94%).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[NH:11][C:10]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>C(Cl)Cl.CN(C=O)C>[C:31]1(=[O:41])[N:35]([CH2:7][CH2:8][C:9]2[CH:13]=[C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[NH:11][C:10]=2[C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12
Reactant: OCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CS(=O)(=O)Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A solution containing 0.75 g of methanesulfonyl chloride in 25 mL of CH2Cl2 was added to a stirred solution containing 0.8 g (3.3 mmol) of 3-(2-hydroxyethyl)-2,5-dithienylpyrrole (XX) and 3 mL of triethylamine in 25 mL of methylene chloride (CH2Cl2) maintained at 0° C. under an inert argon gas atmosphere. The mixture was stirred for 2 hours at 0° C., followed by treatment with a solution containing 8 g (40 mmol) of potassium phthalimide in 50 mL of DMF. The resulting mixture was heated at 40° C. overnight. After cooling to room temperature, the mixture was filtered, and the solvents of the filtrate evaporated in vacuo in the presence of with 20 g of SiO2 -60. The solid absorbed on the SiO2 was chromatographed on a 100 g column of SiO2 -60 that was equilibrated and eluted with a 1% dioxane-toluene solvent mixture. Fractions having volumes of 20 mL were collected, and fractions numbered 10 through 25, containing the product (XXI), were combined, then concentrated to yield 860 mg of an oil (64% yield). An analytical sample of compound XXI (mp 174°-175° C.) was recrystallized from diethyl ether.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6]1>[Ni].CO.C1COCC1>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6]1
Reactant: CN(C)CCn1ccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCn1ccc(N)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.9 %

Procedure:
A suspension of dimethyl-[2-(3-nitro-pyrrol-1-yl)-ethyl]-amine (Step 121.2) (650 mg, 3.55 mmol) and Raney Nickel (300 mg) in MeOH/THF (1:1, v/v; 150 mL) was stirred for 7 h at rt, under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1→93:6:1) to afford 440 mg of the title compound as a red oil. Title compound: ESI-MS: 154.1 [M+H]+; TLC: Rf=0.02 (DCM/MeOH, 9:1).
Reaction SMILES: Br.C(O)(=O)C.C(OC([NH:16][C:17]1([C:20]2[C:21]([F:41])=[CH:22][C:23]3[C:34](=[O:35])[C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:25]4[CH:26]([CH2:30][F:31])[CH2:27][O:28][C:29]=2[C:24]=34)[CH2:19][CH2:18]1)=O)C1C=CC=CC=1.C(OCC)C>O>[NH2:16][C:17]1([C:20]2[C:21]([F:41])=[CH:22][C:23]3[C:34](=[O:35])[C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:25]4[CH:26]([CH2:30][F:31])[CH2:27][O:28][C:29]=2[C:24]=34)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2CF
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(C4(N)CC4)c(F)cc3c1=O)OCC2CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
1 ml of a 30% hydrogen bromide-acetic acid solution was added to 52 mg of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6carboxylate. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 10 ml of diethyl ether and 20 ml of water in this order. The aqueous layer was separated and 20 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 8.5 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 35 mg (yield: 90.8%) of ethyl 10-(1-aminocyclopropyl)-9-fluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18][C:19]4[S:20][C:21]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])=[CH:22][N:23]=4)=[CH:15][CH:16]=3)[O:11][C:10](=[O:32])[CH:9]=2)=[CH:4][CH:3]=1.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:43].[Mg+2]>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([C:19]4[S:20][C:21]([C@:24]([OH:31])([C:27]([F:29])([F:30])[F:28])[CH2:25][CH3:26])=[CH:22][N:23]=4)=[O:43])=[CH:15][CH:16]=3)[O:11][C:10](=[O:32])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CC[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC[C@](O)(c1cnc(S(=O)c2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-fluorophenyl)-7-({5-[(1R)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3-thiazol-2-yl}thio)-2H-chromen-2-one (0.100 g, 0.2 mmol) in 7 ml of CH2Cl2 and 0.7 ml of MeOH, was added magnesium monoperoxyphthalate hexahydrate (0.051 g, 0.1 mmol). The mixture was stirred at rt overnight and partitioned between water and CH2Cl2. The layers were separated and the organic phase washed with brine, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel (hexane/EtOAc; 8:2) to give two diastereoisomers. 1H NMR (400 MHz, CDCl3): δ 7.9 (s, 1H), 7.85 (s, 1H), 7.67 (dd, 2H), 7.45 (m, 2H), 7.25 (m, 2H), 6.47 (s, 1H), 2.12 (m, 2H), 0.92 (t, 3H). Diastereoisomer #2: 1H NMR (400 MHz, CDCl3): δ 7.9 (s, 1H), 7.82 (s, 1H), 7.67 (dd, 2H), 7.45 (m, 2H), 7.25 (m, 2H), 6.47 (s, 1H), 2.15 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].I([O-])(=O)(=O)=[O:29].[Na+]>CO.O>[C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:26])=[O:29])=[CH:23][CH:24]=3)[N:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(SC)cc3)n2)CC1=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)=O)cc3)n2)CC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5.5 g (0.0143 mol) of 2-propionyl-3-hydroxy-5-(6-(4-(methylthio)phenoxy)-2-pyridyl)cyclohex-2-en-1-one in 250 mL of methanol was added a solution of 3.22 g (0.0151 mol) of sodium periodate in 25 mL of water. The resulting mixture was stirred at ambient temperature for 24 hours and the sodium iodate by-product was filtered off. The filtrate was reduced in vacuo and the residue dissolved in 150 mL of CH2Cl2 and washed with water (3×150 mL) and dried over Na2SO4 and the solvent removed in vacuo. The crude product was dissolved in CH2Cl2 and placed on a column of silica gel. The column was initially eluted with CH2Cl2 and then with a 90:10 CH2Cl2 :acetone mixture. The product fractions were combined and the solvent removed in vacuo giving the above named product in a yield of 3.2 g (56 percent of theoretical). The product melted at 78°-86° C.: Rf -0.24 (silica gel, 5:95 methanolCH2Cl2), 1H NMR (CDCl3) δ1.1 (t, 3H, CH3CH2 --), 2.5-3.6 (m, 7H, ring protons and CH3CH2 --), 2.72 (s, 3H, CH3S(O)--), 6.7-7.8 (m, 7H, ArH), 18.0 (s, 1H, OH).
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([C:12]([F:15])([CH3:14])[CH3:13])[N:5]=1>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([C:12]([F:15])([CH3:14])[CH3:13])[N:5]=1
Reactant: ClCl
Reactant: CSc1nc(N)nc(C(C)(C)F)n1
Solvent: CC(=O)O
Product: CC(C)(F)c1nc(N)nc(Cl)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Chlorine gas was passed at 20 to 25° C. into a suspension of 150 g of 2-amino-4-methylthio-6-(1-fluoroisopropyl)-1,3,5-triazine in 1 liter of glacial acetic acid (15 min). The reaction mixture was stirred for 30 min at approx. 20° C., flushed with nitrogen gas for 1 h at room temperature, poured into 5 liters of ice-cold aqueous solution of 350 g of sodium hydroxide and stirred for 5 min. After filtration with suction and drying, 110 g (80%) of 2-amino-4-chloro-6-(1-fluoroisopropyl)-1,3,5-triazine were obtained as a white powder (m.p. 185° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2>C(O)(=O)C.CN(C=O)C>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][NH:7][C:8]2=[O:12]
Reactant: Cc1ccc2c(=O)[nH]ccc2c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)[nH]ccc2c1N
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A suspension of 6-methyl-5-nitroisoquinolin-1(2H)-one (40 g, 196 mmol) in glacial acetic acid (1 L) was purged with N2. The suspension was treated with 10% Pd/C (10 g) and the reaction vessel was purged with H2. The mixture was stirred at room temperature under H2 (1 atm) until starting material consumed, approximately 100 h. The reaction mixture was purged with N2, then filtered through a pad of Celite. The pad was washed with MeOH (400 mL) and the combined filtrate was treated with water (80 mL) and concentrated in vacuo to ˜200 mL. The dark mixture was diluted with 200 mL MeOH and added in a thin stream to ice water (1.5 L) stirred in a large beaker. The resulting fine precipitate was collected by suction filtration. The greenish-grey powder was suspended in water (500 mL) and satd NaHCO3 (100 mL) and sonicated for 1 min. The solid was collected by suction filtration, washed with water (2×100 mL), Et2O (100 mL), and air-dried overnight to afford 28 g as a grey powder. The powder was dissolved in hot DMF (200 mL) and treated with decolorizing carbon (˜10 g). The hot suspension was filtered through Celite. The filter cake was washed with MeOH (200 mL) and the filtrate was concentrated in vacuo to ˜200 mL. The dark brown solution was added to water (1.2 L) to afford a fine crystalline precipitate. The solid was collected by suction filtration on a medium-sintered glass frit and washed with water (500 mL). A second crop precipitated in the filtrate and was collected by suction filtration, washed with water (100 mL) and added to the first crop. The combined material was washed with Et2O (400 mL), and dried on the sintered glass funnel under a stream of N2, with suction, for 16 h to afford 5-amino-6-methylisoquinolin-1(2H)-one (22 g, 64% yield) as a tan crystalline solid. MS (M+H)+ 175.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH:20]=[O:21])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[CH2:30]([Mg]Cl)[CH3:31]>C1COCC1>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH:20]([OH:21])[CH2:30][CH3:31])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: CC[Mg]Cl
Reactant: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a solution of 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzaldehyde (0.080 g, 0.224 mmol) in THF (6 mL) at −78° C. was added dropwise ethylmagnesium chloride (0.22 mL, 0.673 mmol, 1.0 M solution in THF). After stirring 15 min, the reaction mixture was quenched with brine. The mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a off-white solid (0.084 g, 91%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64-7.59 (m, 4H), 7.39 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.29 (td, 1H, J=8.0 Hz, J=1.2 Hz), 7.26-7.20 (m, 5H), 5.45 (s, 2H), 4.67 (t, 1H, J=6.6 Hz), 1.68-1.63 (m, 2H), 0.71 (t, 2H, J=7.6 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H22F3N2O2: 427.4 (M+H), Found 427.2.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:40]=[C:39]2[C:34]([C:35]3[N:43]4[C@@H:44]([CH3:48])[CH2:45][O:46][CH2:47][C:42]4=[N:41][C:36]=3[CH:37]=[N:38]2)=[CH:33][CH:32]=1.[CH:49]([S:51]([CH3:54])(=[O:53])=[O:52])=[CH2:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:48][C@@H:44]1[N:43]2[C:35]3[C:34]4[C:39](=[CH:40][C:31](/[CH:50]=[CH:49]/[S:51]([CH3:54])(=[O:53])=[O:52])=[CH:32][CH:33]=4)[N:38]=[CH:37][C:36]=3[N:41]=[C:42]2[CH2:47][O:46][CH2:45]1
Reactant: C[C@H]1COCc2nc3cnc4cc(Br)ccc4c3n21
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCc2nc3cnc4cc(/C=C/S(C)(=O)=O)ccc4c3n21
Temperature: 120 °C
Yield: 46.4 %

Procedure:
A scintillation vial was charged with palladium acetate (35.2 mg, 0.165 mmol), tri-o-tolylphosphine (96 mg, 0.32 mmol), anhydrous DMF (1.0 mL) and triethylamine (1.31 mL, 9.4 mmol). The orange homogeneous solution was then added to a solution of (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (1.00 g, 3.14 mmol) dissolved in 20 mL of anhydrous DMF followed by the addition of a solution of methyl vinyl sulfone (400 mg, 3.77 mmol) dissolved in 1.0 mL of anhydrous DMF. The mixture was transferred to a glass vessel and the vessel was purged with N2, sealed and heated to 120° C. for 18 hours. The reaction mixture was cooled and concentrated to dryness under reduced pressure to give a golden solid. The solid was treated with CH2Cl2 and saturated aqueous K2CO3 solution and the layers were separated. The organic layer was concentrated to dryness to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 0.5 g of (11S)-11-methyl-3-[(E)-2-(methylsulfonyl)ethenyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as white crystals, mp 249-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3nccs3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 33.9 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 2-tributylstannanyl-thiazole (0.1 mL, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (4 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 1 M HCl was added with stirring until pH was about 3-4, and the organic layer was washed with water and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 28 mg of the title compound. MS: (+) m/z 394.25 (M+1).