Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47](OC)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[N:20]1)[CH3:18].O>O1CCCC1>[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47]([C:2]4[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=4)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:25])=[O:26])[CH:21]=[N:20]1)[CH3:18]
Reactant: CCn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)OC)C2)cn1
Reactant: FC(F)(F)c1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3cc(C(F)(F)F)ccn3)C2)cn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 8.5 %

Procedure:
2-Bromo-4-(trifluoromethyl)pyridine (171 μl, 1.382 mmol) in dry tetrahydrofuran (1 mL) was added to butyllithium (2.5 M in Hexanes) (885 μl, 1.416 mmol) in dry tetrahydrofuran (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes, then a solution of (R)-methyl 6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (220 mg, 0.453 mmol) in dry tetrahydrofuran (2 mL) was added dropwise and the reaction mixture stirred for 1 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (2×15 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) and preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-70% acetonitrile in water) to afford (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (23 mg) as a white solid. LCMS (Method F, ES-API): RT 3.00 min, m+H=601.2; 1H NMR (400 MHz, CDCl3): δ 8.88-8.87 (1H, m), 8.15 (1H, m), 7.71-7.69 (2H, m), 7.67 (1H, d, J=0.6 Hz), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.44 (1H, dd, J=12.0, 2.0 Hz), 4.22-4.16 (3H, m), 3.80-3.76 (1H, m), 2.94 (1H, d, J=16.9 Hz), 2.88-2.79 (1H, m), 2.67 (1H, d, J=12.3 Hz), 2.52-2.40 (2H, m), 1.51 (3H, t, J=7.3 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][N:5]2[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18].C1(C(N2C3C(=CC([C:38]4[CH:39]=[N:40][NH:41][CH:42]=4)=CC=3)N(C(OC(C)C)=O)C[C@@H]2C)=O)CC1>>[CH3:16][C@H:7]1[CH2:6][N:5]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[CH:3]=2)[N:8]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Product: COC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
4-Isopropyl 1-methyl (S)-2-methyl-6-(1H-pyrazol-4-yl)-2,3-dihydroquinoxaline-1,4-dicarboxylate was synthesized from 4-isopropyl 1-methyl (S)-6-bromo-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate according to the procedure outlined above for (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 359 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1.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>CN(C=O)C>[Br:17][C:13]1[CH:12]=[C:11]([CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:18]([N:26]([C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH3:27])=[O:20])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Reactant: CNc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H](Cc1cccc(Br)c1)NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Boc-L-3-BromoPhe (5 g, 14.5 mmol) was dissolved in 50 mL of DMF and to it were added 4-chloro-N-methylaniline (2.1 mL, 17.4 mmol) and N,N-diisopropylethylamine (7.6 mL, 43.5 mmol). The reaction mixture was cooled to 0° C. and to it was added HATU portion wise (6.6 g, 17.4 mmol). The reaction mixture was allowed to stir at ambient temperature overnight and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl, saturated aqueous NaHCO3 and brine. The mixture was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 5.6 g of (S)-tert-butyl 3-(3-bromophenyl)-1-((4-chlorophenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate as a white solid. MS (m/z): 469.1 [M+H]+; HPLC retention time 4.39 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:11]=[N:12][C:13]([Br:16])=[CH:14][CH:15]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[N:12]=[CH:11][C:10]([CH:8]2[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 70318 %

Procedure:
5-(6-bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (650.0 mg, 1.7 mmol) prepared in Step 2 and a solution of potassium hydroxide (185.0 mg, 3.3 mmol) in distilled water (10.0 mL) were added to methanol (10.0 mL). The reaction mixture was stirred at 70° C. for 2 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 455.0 g of the titled compound as a pale yellow solid.
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Br)(Br)[Br:19]>C1C=CC=CC=1>[Br:19][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)C(O)c1ccc(OC)c(OC)c1
Solvent: c1ccccc1
Product: CCOC(=O)C(Br)c1ccc(OC)c(OC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of ethyl 2-hydroxy-2-(3,4-dimethoxyphenyl)acetate (19.5 g) in benzene (200 ml) was added phosphorus tribromide (8.18) dropwise at 50° C. and the mixture was stirred at 60° C. for one hour. The reaction mixture was then washed successively with water, saturated aqueous solution of NaHCO3 and water and dried (MgSO4). The benzene was distilled off and the residue was subjected to silica gel chromatography. From the fraction eluted by ethyl acetate-hexane (1:3, v/v), ethyl 2-bromo-2-(3,4-dimethoxyphenyl)acetate (18.5 g, yield 75%) was obtained as an oil.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:19]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:20]=1[CH:21]=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[I:27][C:24]1[CH:23]=[C:20]2[C:19](=[CH:26][CH:25]=1)[N:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)[N:2]=[CH:21]2
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
4-Hydrazinobenzoic acid (11.32 g, 60 mmol) and cesiumcarbonate (58.65 g, 180 mmol) are added to 2-fluoro-5-iodobenzaldehyde (15 g, 60 mmol) in 300 mL N-methylpyrrolidon. After 1 h stirring at r.t., the reaction is heated for 4 h at 150° C. The reaction mixture is allowed to cool off and poured on 1 L ice water. The reaction mixture is acidified with citric acid and vigorously stirred at r.t. for 30 min. The precipitate is filtered off and given in ethyl acetate. The slurry is vigorously stirred for 1 h and sucked off. The filter residue (few material) is discarded and the filtrate evaporated. This residue which is contaminated with N-methylpyrrolidine is treated with 300 mL of a mixture of ethyl acetate/hexane (1:3) and stirred overnight. The precipitated crystals are sucked off and dried. 17.11 g (78.32%) of 4-(5-iodoindazole-1-yl)-benzoic acid are obtained.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1)[NH2:2].C(O[CH:18]=[CH:19][C:20](=O)[C:21]([F:24])([F:23])[F:22])C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[CH3:14][C:5]1[CH:4]=[C:3]([N:1]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[N:2]2)[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Cc1cc(NN)c2cccc(O)c2n1
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2nccc2C(F)(F)F)c2cccc(O)c2n1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 4-hydrazino-2-methyl-quinolin-8-ol (21 mg, 0.11 mmol) and 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (16 μL, 0.11 mmol) in ethanol (0.5 mL) was heated to 75° C. for 30 min. The solvent was than removed in vacuo and the residue was redissolved in acetic acid (0.5 mL). After the addition of concentrated H2SO4 (20 μL) and stirring for 1 h at 100° C., the reaction mixture was cooled to room temperature and a mixture of Na2CO3 (0.40 mg, 3.8 mmol) in water (1 mL) was added. The reaction mixture was then concentrated in vacuo and the residue was partitioned between DCM (10 mL) and water (5 mL). The pH of the aqueous layer was adjusted to 10 by the addition of saturated aqueous NH3 solution and the aqueous layer was extracted with DCM (1×320 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS (m/z): 294.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([CH:20](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:33][S-:34].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([S:34][CH3:33])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C[S-]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A mixture of compound tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (200 mg, 0.43 mmol) in N,N-dimethyl formamide (2 mL) was added sodium methanethiolate (994 mg, 1.44 mmol). The reaction mixture was stirred at 110° C. for 4 hours. The reaction was quenched by adding water (6 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3), and the organic layer was concentrated. The crude product was purified by preparative TLC (elute: petroleum/ethyl acetate: 5:1) to give product tert-butyl 2-methyl-1-(3-(methylthio)butan-2-yl)-1H-indole-3-carboxylate (100 mg, yield: 68%). LRMS (M+H+) m/z: calc'd 333.18. found 334.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH:58][C:57]3[CH:59]=[CH:60][C:54]([Cl:53])=[CH:55][CH:56]=3)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(C(=O)O)cc2)COC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1C(c2ccc(C(=O)Nc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 102.5 %

Procedure:
To a stirred suspension of (RS)-4-(4-carboxy-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (80 mg) in THF (4 ml) were added sequentially N-methylmorpholine (0.11 ml), TBTU (160 mg) and 4-chloro-aniline (48 mg) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-[4-(4-chloro-phenylcarbamoyl)-phenyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (110 mg, quant.) as a light yellow solid. MS (ISP): 455.2 ([{37Cl}M+Na]+), 453.2 ([{35Cl}M+Na]+), 433.3 ([{37Cl}M+H]+), 431.4 ([{35Cl}M+H]+), 377.3 ([{37Cl}M+H—C4H8]+), 375.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@@H:14]1[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@@H:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Yield: 88.1 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.07 g, 10.0 mmol) was stirred in refluxing absolute ethanol (40 mL) under nitrogen to achieve partial dissolution. To this stirred mixture was added a solution of freshly prepared (1S,4R)-4-amino-2-cyclopentene-1-methanol (PCT Application 9204015.3, 1.57 g, 12.5 mmol as 90%) in ethanol (15 mL) followed by triethylamine (3.5 mL, 25 mmol, freshly distilled from calcium hydride). After 14 hours of reflux, the resulting dark solution was cooled and 1 N sodium hydroxide (10 mL) was added. The volatiles were evaporated in vacuo. The residual tan solid foam was dissolved in 5% methanol-ethyl acetate, and the solution was washed through a silica gel pad to give the title compound as an off-white solid (2.50 g, 88%), after evaporation of solvents. Recrystallization of the solid from ethyl acetate-methanol (20:1) gave the title compound (VIa) as fine white crystals (2.29 g, 81%), m.p. 177-178° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6)δ: 8.99 and 8.58 (s and d, J=11.1 Hz, total 1, amide NH), 8.11 and 7.80 (s and d, J=11.1 Hz, total 1, amide CH), 6.77 and 6.61 (two d, J=8.0 Hz) overlapping 6.60 and 6.48 (two br s, total 3, NH and NH2), 5.85 and 5.70 (two m, 1 each, CH=CH), 5.15-5.00 (m, 1, NCH), 4.71 (t, J=5.1, 1, OH), 3.45-3.30 (m overlapping H2O, OCH2), 2.80-2.65 (m, 1, CH), 2.45-2.25 and 1.45-1.30 (both m, 1 each, CH2); [α]20 589+21.2°, [α]20 578+22.2°, [α]20546+25.2°, [α]20436+41.4°, [α]20365+48.3° (c 0.50, methanol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(C(O)=O)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: COc1ccc(CCBr)cc1
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Temperature: 25 °C

Procedure:
Mix (2-benzothiazolyl)(4-piperidinyl)methanone.CF3CO2H (331 g, 9.19 mmol), 2-(4-methoxyphenyl)ethyl bromide (2.07 g, 9.64 mmol), potassium carbonate (3.33 g, 24.mmol and dimethylformamide (35 mL) and heat at 90° C. overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (30% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound as a tan powder; mp 119°-20° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17]N(C)C)[C:12]2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:28]([NH2:31])(=[NH:30])[CH3:29].C(OCC)(=O)C>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11]3[CH:17]=[N:30][C:28]([CH3:29])=[N:31][C:12]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncc2c(n1)C1CC2CN(Cc2ccccc2)C1

Procedure:
To a solution of 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one (1.42 mmol) in ethanol was added potassium carbonate (3.8 mmol) and acetamidine hydrochloride (1.6 mmol). The reaction mixture was heated under reflux overnight. After cooling the solvents were removed and dichloromethane and aqueous sodium bicarbonate solution were added. The dichloromethane layer was separated and dried to and oil. Purification by flash chromatography on silica gel eluted with ethyl acetate yielded product (0.23 mmol). 1H NMR (CD3OD, 400 MHz) δ 8.25 (s, 1H), 7.18 (br s, 3H), 6.85 (br s, 2H), 3.60–3.40 (m, 2H), 3.10 (s, 1H), 3.00 (m, 2H), 2.79 (m, 1H), 2.70 (s, 3H), 2.5 (m, 1H), 2.45 (m, 1H), 2.25 (m, 1H), 1.70 (m, 1H); APCl MS m/z 266.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:17])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Br)cc1C=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
5-Bromo-2-methoxy-phenol was synthesized by dissolving 5-bromo-2-methoxy-benzaldehyde (50 g, 233 mmol), in CH2Cl2 (150 mL) was cooled with an ice bath to 0° C., and subsequently, 3-chloroperoxybenzoic acid (70-75% purity) (68.1 g, 276 mmol) in CH2Cl2 (500 mL) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 72 h. The colorless solid was filtered off, and the filtrate was stirred for 2 h with a 2 N Na2SO3 solution (200 mL). The organic layer was evaporated and the remainder dissolved in diethyl ether and washed with 1 N Na2SO3 and a half saturated NaHCO3 solution. The organic phase was extracted with a 2 N aqueous NaOH solution. The combined basic extract was acidified (pH ˜3-4) with concentrated HCl and then extracted with diethyl ether. The combined organic extracts were dried over MgSO4, filtered, and the solvent evaporated to afford intermediate 5-bromo-2-methoxy-phenol (43.5 g, 90%). 1H NMR (CDCl3) 7.06 (d, J=2.3, 1H), 6.96 (dd, J=8.6, 2.3, 1H), 6.70 (d, J=8.6, 1H), 5.67 (s, 1H), 3.86 (s, 3H).
Reaction SMILES: CC(O[C:6](=[O:18])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH:15]=[O:16])[C:9]1=[O:17])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:43][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:49][C:50]([NH2:54])=[N:51]2)=[CH:46][CH:45]=1>>[NH2:54][C:50]1[CH:49]=[C:48]([N:55]2[CH2:56][CH2:57][N:58]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH:15]=[O:16])[C:9]3=[O:17])=[O:18])[CH2:59][CH2:60]2)[C:47]2[C:52](=[CH:53][C:44]([Cl:43])=[CH:45][CH:46]=2)[N:51]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C=O)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C=O)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3R)-1-formylhexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 445 (M++1). 1H NMR (CDCl3): δ 1.30 (m, 1H), 1.65 (m, 1H), 1.80˜2.30 (m, 4H), 3.09 (dd, 1H), 3.14 (m, 4H), 3.68 (m, 4H), 4.62 (br.dd, 1H), 4.82 (ddd, 1H), 4.90 (br.s, 2H), 5.84 (d, 1H), 6.16 (s, 1H), 7.18 (dd, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 9.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccc(O)cc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and tyramine in DME. ES-MS m/e (%): 400 ([M+OAc]−, 20), 340 ([M—H]−, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](Cl)=[O:26])[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])[CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4)nc23)CC1
Yield: 93.2 %

Procedure:
Beginning with 0.078 gm (0.339 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.127 gm (0.712 mMol) 3-pyridinecarbonyl chloride hydrochloride, 0.106 gm (82%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Br:10])[CH:9]=1.[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: COCCl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(Br)cc(Br)c1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
A flask was charged with sodium hydride (953 mg, 23.8 mmol, 60% in oil), in dry DMF (30 ml) and cooled to 0° C. (ice bath) under nitrogen atmosphere. 3,5-Dibromophenol (5 g, 19.9 mmol) was added in 4 equal portions over 10 minutes. After complete addition the cooling bath was removed and the mixture allowed to warm to ambient temperature over 20 minutes. Chloromethyl methyl ether (1.8 ml, 21.8 mmol) was added slowly, via syringe over about 5 minutes. The mixture was stirred over night. The material was quenched via the addition of saturated aqueous NH4Cl (20 ml) and all volatiles were stripped (rotovap/mechanical pump). The remainder was taken up in water (80 ml) and ethyl acetate (80 ml) and the material shaken in a separtatory funnel. The ethyl acetate phase was collected and washed with an equal volume of brine solution. The aqueous phases were back extracted with ethyl acetate (2×50 ml), the organics combined, dried (MgSO4), filtered and stripped to provide a crude oil. The oil was purified by silica gel chromatography using 4%-6% EtOAc in hexanes as eluant to provide 5.74 g of 1,3-dibromo-5-methoxymethoxy-benzene as a light yellow oil.