Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)=O.[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][CH2:26][C:27]([CH3:29])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:32][O:31][C:24](=[O:30])[CH2:25][C:26]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:27]=1[CH3:29]
Reactant: Nc1sc2c(c1C(=O)c1ccc(OC(F)(F)F)cc1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Yield: 78.1 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-trifluoromethoxyphenyl)methanone (0.341 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.340 g (78%) of the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:44])[N:28]([CH2:42][OH:43])[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[N:17]=[C:18]([C:26]4[C:27](=[O:44])[N:28]([CH2:42][OH:43])[C:29](=[O:41])[C:30]=4[C:31]4[C:39]5[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Reaction time: 1.5 h

Procedure:
To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (500 mg, 0.842 mmol) in 1,2-dichloroethane (5 mL) was added TFA (1.44 g, 0.973 mL, 12.7 mmol) under argon at 0° C. The reaction mixture was stirred for 1 h under argon at 0° C. after which additional TFA (0.768 g, 0.52 mL, 6.74 mmol) was added. Stirring was continued for 1.5 h at 0° C. The reaction mixture was evaporated to dryness at reduced pressure and the crude product was crystallised from MeOH to afford the title compound as a red solid (TFA salt) as a dark red solid. 1H-NMR (400 MHz, DMSO-d6): 12.01 (d, 1H), 9.06 (bs, 2H), 8.11 (d, 1H), 7.71-7.66 (m, 2H), 7.51 (t, 1H), 7.27 (s, 1H), 7.14 (t, 1H), 6.77 (d, 1H), 6.45-6.39 (m, 2H), 5.92 (d, 1H), 5.00 (d, 2H), 3.84-3.54 (m, 6H), 2.39 (s, 3H), 0.96-0.67 (m, 4H). LCMS: [M+1]+=493.7, Rt(1)=1.84 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH:26]([CH3:28])[CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25].S(Cl)(Cl)=O.[NH3:34]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH:26]([CH3:28])[CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:20])[NH2:34])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1cc(C(=O)O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCc1cc(C(N)=O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reaction time: 1 h

Procedure:
A mixture comprising 168 mg of 4-chloro-5-[3-(2-n-butyl-4-carboxyphenoxy)propylamino]-2-i-propyl-3(2H) pyridazinone (Compound No. 112), 119 mg of thionyl chloride and 10 ml of dried tetrahydrofuran, was refluxed under stirring for 1 hour. The reaction mixture was subjected to distillation under reduced pressure. To the residue, 20 ml of dried benzene was added. The mixture was again subjected to distillation under reduced pressure to remove excess thionyl chloride by azeotropic distillation. The residual oily substance thereby obtained, was dissolved in 10 ml of dried tetrahydrofuran, and ammonia gas was introduced thereinto for 5 minutes under cooling with ice. Then, the reaction solution was further stirred for 15 minutes. The reaction mixture was subjected to distillation under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed sequentially with a 5% sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off, and a pale yellow oily substance thereby obtained was crystallized from methanol-ethyl ether to obtain 143 mg of the above identified compound as colorless crystals having a melting point of 172° to 174° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[F:22][C:23]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:22][C:23]1([F:29])[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH2:25][CH2:24]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC1(F)CCN(CCOc2ccccc2Br)CC1
Temperature: 60 °C

Procedure:
2-(2-Bromophenoxy)ethyl tosylate (1.86 g), 4,4-difluoropiperidine (0.73 g) and potassium carbonate (0.97 g) were mixed with dimethylformamide (30 ml) and heated to 60° C. for 18 h. The mixture was cooled and added to water (300 ml). The mixture was extracted with diethyl ether (×3), dried and evaporated. Purification was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures yielding, 4-difluoro-(2-(2-bromophenoxy)ethyl)piperidine (0.77 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 77.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-methoxy-propyl)-amide (91 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 3-methoxy-propylamine (24 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.42 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.78-7.63 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.38 (t, 2H), 3.34-3.27 (m, 2H), 3.24 (s, 3H), 1.82-1.71 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].[H-].[Na+].Br[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O>CN(C)C=O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CCBr
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)c(NCCC(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
1.03 g (2.54mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1) was dissolved in 20 mL of dimethylformamide under argon atmosphere, 308 mg (7.62 mmol) of sodium hydride (60% oil dispersion) and 0.77 mL (6.4 mmol) of 1-bromo-3-methylbutane were added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, the mixture was extracted once with ethyl acetate, the organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:n-hexane=3:1) to give 708 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-5-(3-methylbutylamino)-4H-1-benzopyran-4-one (yield: 59%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:23])=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:23])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.70 (m, 8H), 5.05-2.70 (m, 5H), 2.15-0.65 (m, 11H).
Reaction SMILES: [CH:1]([C:3]1([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2].C[Li].[C:28](=O)(O)[O-].[Na+]>C1COCC1.CCOCC>[OH:2][CH:1]([C:3]1([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CCO[Si](C)(C)C(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-formyl-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (6.3 g, 17 mmol) in THF (170 mL) at −70° C. was added 1.4M methyl lithium in ether (13.3 mL, 19 mmol). After 2 h, an additional amount of 1.4M methyl lithium in ether (2.5 mL) was added. After an additional 30 min, the reaction was poured into aq. sodium bicarbonate and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title product (6.6 g) which was used directly in the next step.
Reaction SMILES: C([NH:8][OH:9])(OC(C)(C)C)=O.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.Cl>C(OCC)C>[NH2:8][O:9][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(CON)cc1
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution was made of Boc hydroxylamine (2.0 g, 17.1 mmol) in dry TBF (60 ml). Sodium hydride (1.1 g of a 60% suspension in paraffin oil, 25.7 mmol) was then added and the suspension stirred. A catalytic amount of KI was then added to the reaction prior to the cautious addition of 4-methoxybenzyl chloride (3.2 g, 20.4 mmol). The reaction was then allowed to stir overnight before removal of solvent in vacuo. The residue was taken up with diethyl ether (100 ml) and HCl gas bubbled in for 20 minutes, causing the start of precipitation of the product. The flask was stoppered and left to stand overnight. The product was then filtered off as a off-white wax (39–52% yield according to varying batches).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[C:23]([CH3:24])=[CH:22][C@@H:21]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][C@@H:18]1[C:23]([CH3:24])=[CH:22][C@@H:21]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a solution of N-(allyloxy)-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-4-methyl-1,2,3,6-tetrahydropyridin-3-yl)-2-nitrobenzenesulfonamide (Intermediate 11, 11.58 g, 23.27 mmol) and potassium carbonate (16.08 g, 116.34 mmol) in acetonitrile (200 mL) at room temperature was added benzenethiol (11.95 mL, 116.34 mmol). After 3 hours, the reaction mixture was concentrated to dryness and DCM was added. The resulting solids were removed by filtration. The filtrate was concentrated onto silica gel. Silica gel chromatography (0%-100% ethyl acetate/hexanes) afforded the desired product (5.06 g, 69.6%) as an orange oil.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH:33]=O>CS(C)=O.O1CCCC1>[Cl:2][CH:3]=[CH:33][C:32]1[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:30]([O:29][CH3:28])[CH:31]=1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=CCl)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a suspension of 11.94 g of (chloromethyl)-triphenylphosphonium chloride in 85 ml of absolute dimethylsulfoxide and 170 ml of absolute tetrahydrofuran were added dropwise at 0° C., while stirring in an atmosphere of dry nitrogen, 21.5 ml of n-butyllithium solution. After stirring for 30 minutes a solution of 5.48 g of 3,4,5-trimethoxybenzaldehyde in 20 ml of absolute tetrahydrofuran was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then allowed to warm to room temperature. After about 4 hours the reaction mixture was worked up in the manner described in Example 5e. Column chromatography of the raw product with petroleum ether/ether (2:1) yielded 4.64 g of the title compound.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>C(O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:2]2[CH2:3][C:4](=[O:6])[NH:5][C:1]2=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C1C=CC(=O)N1
Solvent: CCO
Product: COc1ccc(SC2CC(=O)NC2=O)cc1

Procedure:
To a solution of maleimide (5.92 g, 61 mmol) in 200 ml of ethanol was added 4-methoxybenzenethiol (7.5 ml, 61 mmol), and after 18 hours at room temperature the solvent was removed to give 3-(4-methoxy-phenylsulfanyl)pyrrolidine-2,5-dione, mp 93-94° C. This compound (5.0 g, 21 mmol) was oxidized with hydrogen peroxide, 30% in acetic acid, 220 ml to give 3-(4-methoxybenzenesulfonyl)pyrrolidine-2,5-dione as a white solid, mp 144-146° C. This compound was reacted with 1-chloro-4-(5iodopent-1-ynyl)benzene in DMF using two equivalents of sodium bishexamethyldisilazide to give the title compound as colorless crystals, mp 160-162° C.; mass spectrum,(M—H) 444.2.
Reaction SMILES: Cl[P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1.[Si:8]([O:15][CH2:16][CH2:17][OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[Si:8]([O:15][CH2:16][CH2:17][O:18][P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1)([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:10])[CH3:9]
Reactant: O=P1(Cl)OCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCOP1(=O)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of freshly prepared 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.2 g, 0.1M) in dry dichloromethane (30 ml) was added, drop-wise, to a stirred mixture of 2-(tert-butyldimethylsilyloxy)ethanol (17.6 g, 0.1M), triethylamine (18.1 ml), 0.13M) in dry dichloromethane (30 ml) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to ambient temperature and was stirred for a further 2 hours. The mixture was filtered and the filtrand washed with n-hexane. The filtrate was evaporated in vacuo, diluted with n-hexane (30 ml) filtered and the filtrate evaporated in vacuo to give a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CN(C=O)C.CC#N>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(-c2ccncc2)nc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C1=C(c2ccccn2)CCN(Cc2ccccc2)C1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A Solution of 2 g (12.8 mmol) of 4-(2-pyridyl)pyridine (Aldrich) and 2.18 g (12.8 mmol) of benzylbromide in 15 mL of DMF and 15 mL of CH3CN was stirred at 95° C. for 4 h. The reaction mixture was then concentrated and redissolved in 20 mL of methanol. To the reaction mixture at 0° C. was added 0.95 g, (25.6 mmol) of NaBH4 and the reaction mixture was stirred for 1 h. The reaction was quenched with 6N HCl, and was partitioned between CH2Cl2 and 1N NaOH. The aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified chomatography [silica, CH2Cl2:ethyl acetate:(2M NH3 in MeOH), 100:100:2] to give 3.2 g of the title compound.
Reaction SMILES: O1CCCCC1O[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:9]=[CH2:10].[BrH:25]>C(OCC)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:8]=[CH:9][CH2:10][Br:25])=[CH:19][CH:20]=1
Reactant: C=CC(OC1CCCCO1)c1ccccc1Sc1ccc(F)cc1
Reactant: Br
Solvent: CCOCC
Product: Fc1ccc(Sc2ccccc2C=CCBr)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1-tetrahydropyranyloxy-1-[2-(4-fluorophenylthio)phenyl]prop-2-ene (2.71 g; 7.87 mmol) in 20 ml of diethyl ether under nitrogen cooled in an ice bath, was added concentrated HBr and the mixture stirred at 0° C. for one hour. The ice bath was removed and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with hexane. The organics were collected and washed with water and then brine and dried over MgSO4 and concentrated to afford the subtitle compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[O:17][C:18]([F:21])([F:20])[F:19])(=[O:9])=[O:8].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=2[F:29])=[CH:12][C:11]=1[O:17][C:18]([F:21])([F:20])[F:19])(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1OC(F)(F)F
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(F)cc2F)cc1OC(F)(F)F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-2-trifluoromethoxyphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white powder. δC (CDCl3, 62.9 MHz): 26.4, 29.5, 41.2, 62.1, 104.9 (t, J 26.0), 112.3 (dd, J 21.3, 2.9), 122.3 (dd, J 12.7, 3.9), 127.5, 131.3, 131.5, 131.5, 131.7 (d, J 2.0), 136.2, 140.6, 159.9 (dd, J 252.0, 11.7) and 163.3 (dd, J 252.0, 11.7).
Reaction SMILES: CC1(C)COB([C:8]2[CH:31]=[CH:30][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH:15]=[C:14]([C:20]2[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=2)[N:13]=4)OC1.Cl.N[OH:35].[OH-].[Na+]>O>[F:28][C:26]([F:27])([F:29])[CH2:25][N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:30]=[CH:31][C:8]([OH:35])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1
Reactant: NO
Reactant: CC1(C)COB(c2ccc3c(c2)OCCn2cc(-c4ncnn4CC(F)(F)F)nc2-3)OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a solution of 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (1.7 g, 3.8 mmol) in IMS was added hydroxylamine hydrochloride (1.58 g, 22.8 mmol) and sodium hydroxide (1.22 g, 30.4 mmol). The reaction mixture was stirred at RT for 18 h before being diluted with water (100 mL). The reaction mixture was concentrated in vacuo to remove the IMS. The solid which formed was collected by filtration and dried in vacuo to yield 468 as a beige solid (1.1 g, 85%). LCMS: RT=2.81 min, [M+H]+=352
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CN(C=O)C.C1C(=O)N([Br:25])C(=O)C1>O>[Br:25][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1])[NH2:6]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(Cl)c(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.2 %

Procedure:
The procedure of Mitchell and Williams, J. Org. Chem. 44:4733 (1979) was modified to obtain the title compound. A mixture of 4,5-dichloro-2-nitroaniline (1.59 g, 7.68 mmol, Aldrich), DMF (30 mL, dist. at reduced pressure) and NBS (1.51 g, 8.48 mmol, Aldrich) was stirred at room temperature (25° C.) for two days. The dark brown solution was poured into deionized water (200 mL) and allowed to set for 30 minuets. The mixture was filtered and the solids washed with deionized water giving 1.81 g (82.4%) of the crude bromide as a yellow powder. The powder was crystallized from ethanol/water (5:1) giving 1.74 g (79.2%) of the title compound as bright yellow needles, mp. 132°-4° C., pure by 1H NMR. 1H NMR (CDCl3) 6.82 (s, 2H), 8.32 (s, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=1)[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:31]3[CH:30]=[N:29][C:28]([CH2:26][CH3:27])=[CH:33][CH:32]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: CCc1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 153 mg (0.66 mmol) of 2-ethyl-5-iodo-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 62 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 1.6 min.