Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].IC.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Yield: 35.7 %

Procedure:
A solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (150 mg, 0.38 mmol), iodomethane (28 μL, 0.45 mmol) and potassium carbonate (78 mg, 0.56 mmol) in dimethylformamide (1.5 mL) was stirred at 75° C. for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium carbonate (2×), brine and dried (Na2SO4). Flash column chromatography (20:1 methylene chloride/ethyl acetate) provided 56 mg (36%) of the more mobile 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester as a white solid. 19F NMR (376 MHz, CD3OD)—133.5 (s). MS APCI (+) m/z 412, 414 (M+, Br pattern) detected. Also isolated is 54 mg (35%) of 6-4(-bromo-2-chloro-phenylamino)-7-fluoro-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a white solid. 19F NMR (376 MHz, CD3OD)—139.9 (s). MS APCI (+) m/z 412, 414 (M+, Br pattern) detected.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][C:12]3=[CH:15][NH:16][N:17]=[C:11]3[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:18][C:19]1[N:24]=[CH:23][C:22]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:14][CH2:13]3)=[N:17]2)=[CH:21][CH:20]=1
Reactant: c1ccc(CN2CCc3c[nH]nc3CC2)cc1
Reactant: OB(O)c1ccc(Br)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccc(-n2cc3c(n2)CCN(Cc2ccccc2)CC3)cn1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 6-(phenylmethyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 5) (200 mg, 0.88 mmol), (6-bromo-3-pyridinyl)boronic acid (355 mg, 1.76 mmol), copper acetate (478 mg, 2.64 mmol), pyridine (0.142 ml, 1.76 mmol) and molecular sieves (600 mg) in dichloromethane (10 ml) was allowed to stir at room temperature in a flask open to the atmosphere for 240 hours. The reaction mixture was filtered through a pad of celite, washing with dichloromethane and methanol. The filtrate was evaporated, redissolved in methanol and passed down a 10 g SCX cartridge, eluting with methanol, then a 2 M solution of ammonia in methanol. The basic fractions were combined, evaporated and purified by column chromatography, eluting with a mixture of 2M ammonia in methanol and dichloromethane (0-10%). The impure product was re-purified using reverse phase chromatography, eluting with a mixture of acetonitrile and water (5-100% and 3-60%) to afford the product (D15); MS (ES+) m/e 383 & 385 [M+H]+.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[O:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[ClH:20].[O:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32][CH2:31]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: C1CNCCOC1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCCOCC3)cc12

Procedure:
6-(2-[1,4]oxazepan-4-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 45% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and [1,4]oxazepane.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].C[Li].[CH2:17]([Li])CCC.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].C(Cl)(=O)C(C)=C>>[C:22]([O:7][CH2:6][CH:5]([CH3:17])[CH2:4][C:3]([C:9]([F:10])([F:11])[F:12])([OH:8])[C:2]([F:13])([F:14])[F:1])(=[O:25])[CH:23]=[CH2:24]
Reactant: [Li]CCCC
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=CC(=O)Cl
Agent: C=C(C)C(=O)Cl
Agent: [Li]C
Product: C=CC(=O)OCC(C)CC(O)(C(F)(F)F)C(F)(F)F
Yield: 86 %

Procedure:
1,1,1-Trifluoro-2-trifluoromethyl-2-hydroxy-4-methyl-5-pentyl acrylate was synthesized according to the method of Example 4 but substituting (a) 60 g (0.25 mol) of 1,1,1-trifluoro-2-trifluoromethyl-4-methyl-2,5-pentanediol (2) for diol (4), (b) 311 mL (0.497 mol) of methyllithium (1.6M in ether) for the n-butyllithium, and (c) 22.3 g (0.248 mol) of acryloyl chloride for the methacryloyl chloride, to yield 58 g (86%) of the title compound as a clear colorless oil.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C(N(C(C)C)CC)(C)C>ClCCl>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
Cyclohexanecarbonyl chloride (4.38 g, 30 mmol) was added dropwise to a solution of 2-aminothiazole (3.00 g, 30 mmol) and di-isopropylethylamine (3.87 g, 30 mmol) in dichloromethane (50 ml) at 0° C. The mixture was warmed to room temperature, stirred for 18 h, washed with 1 N--HCl (2×50 ml) and 1 N--NaOH (2×50 ml), dried (MgSO4), and evaporated in vacuo to give the product (4.59 g) as white crystals.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2[N+]([O-])=O)CCCC1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CO.[Pd]>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:29](=[O:31])[CH3:30])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CCCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: O=[N+]([O-])c1ccccc1C1CCCC1
Solvent: CO
Product: CC(=O)Nc1ccc(C2CCCC2)cc1
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of 1-cyclopentyl-4-nitrobenzene and 1-cyclopentyl-2-nitrobenzene (Preparation 96, 28.92 g, 151.2 mmol) in methanol (300 mL) was added acetic anhydride (20.1 mL, 213 mmol) and palladium (2 g, 20 mmol) (10% on carbon, Degussa type) and the reaction mixture hydrogenated at a pressure of 40 psi for 5 hours. The mixture was filtered through celite concentrated in vacuo, and purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/hexanes gradient. The isomers separated at this stage to give (16.52 g, 54%) of product as a brown solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CB(O)O.ClCCl.[CH:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]2[CH:28]=[CH:29][C:30](Br)=[C:31]([CH3:32])[C:21]1=2)=[O:19])([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]2[CH:28]=[CH:29][C:30]([CH3:1])=[C:31]([CH3:32])[C:21]1=2)=[O:19])([CH3:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)ccc2c1N(C(=O)OC(C)C)CCCC2=O
Agent: CB(O)O
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(c1C)N(C(=O)OC(C)C)CCCC2=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add cesium carbonate (456 mg, 3.0 mmol), methyl boronic acid (90 mg, 1.5 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (82 mg, 0.1 mmol) to a solution of 8-bromo-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (341 mg, 1.0 mmol) in dioxane (8 mL). Stir the mixture under nitrogen at 110° C. for 1 h and 30 min. Cool down the mixture to room temperature and filter over Celite® washing with ethyl acetate. Evaporate the solvent and purify the crude by chromatography, eluting with hexane/ethyl acetate to afford the title compound (239 mg, 87%). MS (ES+): 276 (M+H).
Reaction SMILES: FC1N=CC(C(N2CCN(C3C=C(C)C(C)=CC=3C)CC2)=O)=C(C)C=1.COC1C=CC(CN)=CC=1.Cl[CH2:37][CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41].[NH2:44][C:45]1[N:50]=[CH:49][C:48]([C:51]([N:53]2[CH2:58][CH2:57][N:56]([C:59]3[CH:64]=[C:63]([CH3:65])[C:62]([CH3:66])=[CH:61][C:60]=3[CH3:67])[CH2:55][CH2:54]2)=[O:52])=[C:47]([CH3:68])[CH:46]=1>>[O:41]=[S:40]1(=[O:42])[CH2:39][CH2:38][CH2:37][N:44]1[C:45]1[N:50]=[CH:49][C:48]([C:51]([N:53]2[CH2:54][CH2:55][N:56]([C:59]3[CH:64]=[C:63]([CH3:65])[C:62]([CH3:66])=[CH:61][C:60]=3[CH3:67])[CH2:57][CH2:58]2)=[O:52])=[C:47]([CH3:68])[CH:46]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3cnc(N)cc3C)CC2)cc1C
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3cnc(F)cc3C)CC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cc3C)CC2)cc1C

Procedure:
Using (6-fluoro-4-methylpyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 180, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.23 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (185 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[N:15]=3)[C:10]([F:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[H][H]>CCO.CCOC(C)=O.[OH-].[Pd+2].[OH-]>[F:13][C:10]1[C:9]([C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:15]=2)=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][N:11]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4=CCOCC4)cnc3F)n2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3F)n2)cc1
Reaction time: 18 h
Yield: 76.3 %

Procedure:
A solution of 4-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (300 mg, 0.569 mmol) in 5 mL of EtOH and 5 mL of EtOAc was placed with palladium hydroxide (20% wt.) (80 mg, 0.114 mmol) and hydrogenated with a balloon full of hydrogen. After 18 h, the mixture was filtered through a pad of Celite® (diatomaceous earth) and rinsed with 2×10 mL of EtOAc. The filtrate was concentrated and the residue was purified on a silica gel column and eluted with 20-65% EtOAc in hexanes to provide 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (230 mg, 76% yield) as an off white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (dd, J=9.4, 1.6 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.24 (m, 4H), 6.90 (m, 4H), 4.79 (s, 2H), 4.75 (s, 2H), 3.94 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.45 (m, 2H), 2.95 (m, 1H), 2.47 (s, 3H), 1.70 (m, 4H). m/z (ESI, positiive ion) 530.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[CH:26][CH:25]=3)=[S:30])[CH:3]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1N
Reactant: Cc1cccc(N=C=S)c1
Product: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1NC(=S)Nc1cccc(C)c1
Yield: 48.6 %

Procedure:
Prepared according to the procedure described for Example 102 using 3-amino-N-(3,5-dimethylphenyl)4-methoxy-benzamide from Example 11 (0.542 g, 2.01 mmol) and 3-methylphenyl isothiocyanate (0.28 mL, 2.07 mmol) to afford the product (0.41 g); m.p. 188-189° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:34]1[CH:35]=[C:36]([CH:45]=[CH:46][CH:47]=1)[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:19]=[CH:20][C:21]([C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([C:37]([C:36]6[CH:45]=[CH:46][CH:47]=[CH:34][CH:35]=6)=[O:38])[CH:44]=5)=[CH:22][CH:23]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
In a sealed tube, a mixture of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (179 mg, 0.265 mmol), 3-bromobenzophenone (66 mg, 0.253 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.012 mmol) in 2M aq potassium carbonate (0.5 mL, 1.00 mmol) and 1,4-dioxane (1.5 mL) was stirred at 100° C. for 1 h. The reaction was cooled to room temperature and the reaction mixture was diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was acidified to pH˜5 using 1N aq HCl. The aqueous layer was then extracted with ethyl acetate (20 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-3% methanol/ethyl acetate) provided the title compound as an ivory solid (68 mg, 55%) after drying in the vacuum oven (70° C.) for 4 days. MS(ES)+ m/e 493.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of the title compound from Example 252 (0.19 grams) and glacial acetic acid (4 mL) was added a 0.7M bromine-acetic acid solution (0.7 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (0.18 grams, 71%, MH+ 526).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:40][N:24]2[C:25](=[O:39])[N:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:27][C@@H:23]2[CH2:22]1.C(Br)(Br)(Br)[Br:42]>C1COCC1>[Br:42][C@@H:21]1[CH2:40][N:24]2[C:25](=[O:39])[N:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:27][C@@H:23]2[CH2:22]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Br)CN12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Triphenylphosphine (1.7 g, 6.5 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (1.0 g, 3.3 mmol) and CBr4 (2.2 g, 6.6 mmol) in anhydrous THF (50 mL), the mixture was stirred at room temperature for 30 minutes under N2 protection. Then the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to give 1.15 g (95%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, 2H, J=9.3 Hz), 7.21 (d, 2H, J=8.4 Hz), 4.48-4.42 (m, 1H), 4.19 (dd, 1H, J1=13.2 Hz, J2=2.7 Hz), 4.11-4.02 (m, 2H), 3.92-3.88 (m, 1H), 3.53 (dd, 1H, J1=13.5 Hz, J2=5.4 Hz), 2.81-2.71 (m, 1H), 2.26-2.18 (m, 1H). LC-MS: 365.0 [M+1]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>ClCCl>[Cl:3][C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[C:12]([CH3:17])[N:13]=1
Reactant: Cc1cc(C(C)(C)C)cc[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 100 °C

Procedure:
Add phosphorus oxychloride (15 mL) to 4-tert-butyl-2-methyl-pyridine 1-oxide (2.00 g, 12.10 mmol) and heat to 100° C. for 36 hours. Evaporate off the excess phosphorus oxychloride. Treat the oil cautiously with ice and water with stirring and make basic by treatment with aqueous bicarbonate solution. Extract with dichloromethane (3×75 mL) and pool, desiccate, filter, and concentrated. Chromatograph the crude product on silica using a gradient of (0→5→8%) ethyl acetate in dichloromethane to afford the title compound (0.82 g, 4.46 mmol). MS (ESI), m/z 184 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OC)(C)(C)C>[CH3:23][S:24]([O:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5])(=[O:26])=[O:25]
Reactant: CCC[C@@H](O)c1ccc(C(=O)OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCC[C@@H](OS(C)(=O)=O)c1ccc(C(=O)OC)cc1

Procedure:
To a solution of (R)-methyl 4-(1-hydroxybutyl)benzoate, intermediate (26) (10 g, 48 mmol) in methyl t-butyl ether (80 mL) containing triethylamine (6.32 g, 62 mmol) was added methanesulfonyl chloride (6.05 g, 53 mmol) slowly at 20° C. The solution was filtered to remove triethylamine salts and the solution used in the next step without isolation.
Reaction SMILES: [F:1][C:2]1[C:3]([O:45][CH3:46])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40](O)=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1.[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[F:1][C:2]1[C:3]([O:45][CH3:46])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:38][CH:37]2[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]3[C:34]([C:40]([NH:53][S:50]([CH:47]4[CH2:49][CH2:48]4)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]2=[O:39])[CH2:33]3)[CH2:22]1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1F
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1F

Procedure:
The title compound was prepared from 17-[8-fluoro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid (73) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (56): m/z=754 (M+H)+. 1H NMR (CDCl3): 1H NMR (CDCl3): 0.75-1.52 (m, 15H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 4.07 (s, 3H), 4.60 (m, 1H), 5.05 (t, J=10.5 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.17 (s, 1H), 7.07 (s, 1H), 7.54 (s, 1H), 7.86 (m, 1H), 10.77 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:17]([O-])([O-])([O:19][CH3:20])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[N:1]=[C:17]([O:19][CH3:20])[CH3:18]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: COC(C)([O-])[O-]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(C)=Nc1ccccc1C(=O)c1ccccc1Cl

Procedure:
A solution of 20 parts of 2-amino-2'-chlorobenzophenone, 15 parts of methyl orthoacetate, 12 volume parts of acetic acid in 250 parts of benzene is refluxed for 5 hours. The mixture is washed with saturated aqueous sodium bicarbonate solution and water, and then dried over sodium sulfate. Evaporation of the solvent gives 2'-chloro-2-(1-methoxyethylideneamino) benzophenone as an oily substance in almost quantitative yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([F:11])[CH3:10])[CH:3]=1.C([Li])CCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C.Cl>C(OCC)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:3][C:4]=1[CH:9]([F:11])[CH3:10]
Reactant: CC(F)c1cc(Br)ccc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(F)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
4-Bromo-1-chloro-2-(1-fluoroethyl)benzene (2.55 g, 10.74 mmol) was dissolved in dry diethyl ether (50 mL) and cooled to −75° C. n-Butyllithium (4.72 mL, 11.81 mmol) was added dropwise keeping the temperature below −70° C. The reaction mixture was then stirred for 15 min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.197 g, 11.81 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then diluted with water and diethyl ether. The aqueous phase was acidified with 12N HCl and the product was then extracted with diethyl ether. The organic phase was dried and concentrated under vacuum to yield the title compound (1.55 g, 5.45 mmol, 50.7% yield) as a white solid: 1H NMR (CDCl3) δ 7.94 (d, 1H), 7.65 (m, 1H), 7.36 (m, 1H), 5.96 (dq, 1H), 1.64 (dd, 3H), 1.34 (s, 12H).