Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1([CH3:15])[C:9]([Br:10])=[C:8]([Br:11])[C:7](=[O:12])[C:6]([Br:13])=[C:5]1[Br:14])([O-])=O.BrC1C=C2C(=CC=1)C=C(O)C=C2>CCOCC>[Br:11][C:8]1[C:9]([Br:10])=[C:4]([CH3:15])[C:5]([Br:14])=[C:6]([Br:13])[C:7]=1[OH:12]
Reactant: CC1([N+](=O)[O-])C(Br)=C(Br)C(=O)C(Br)=C1Br
Agent: Oc1ccc2cc(Br)ccc2c1
Solvent: CCOCC
Product: Cc1c(Br)c(Br)c(O)c(Br)c1Br
Yield: 6.9 %

Procedure:
4-Nitro-4-methyl-2,3,5,6-tetrabromo-2,5-cyclohexadien-1-one (2.53 g, 4.95 mmol, purity: 82.6%) was added to 6-bromo-2-naphthol (1 g, 4.5 mmol) in 40 mL of dry ether. The reaction was allowed to react for 1.5 hr at room temperature. The solid was filtered to give 2,3,5,6-tetrabromo-4-methyl-phenol (144 mg). The solution was then evaporated under vacuum. The crude mixture was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4 and filtered and the solvent removed under vacuum. 2,3,5,6-tetrabromo-4-methyl-phenol (1.2 g) was separated by recrystallization of the crude product with ethyl acetate—hexane. The mother liquid was concentrated onto Florosil and purified on a silica column (15%-20% ethyl acetate-hexane) to yield 0.731 g (61%) of the title compound as a yellow solid: mp 111-113° C.; 1H NMR (DMDO-d6): δ 7.39 (1H, d, J=9.07 Hz), 7.54 (1H, d, J=9.05 Hz), 7.75 (1H, dd, J=9.05 Hz, J=1.70 Hz), 8.03 (1H, d, J=9.14 Hz), 8.29 (1H, d, J=1.84 Hz), 11.65 (1H, s); MS (ESI) m/z 266/268 (M−H)−; IR 1350 cm−1, 1490 cm−1.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C@H:16]([NH:29]C(=O)OC(C)(C)C)[CH2:17][N:18]([CH3:28])[C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOCC.CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CCO>[NH2:29][C@@H:16]([CH2:15][CH:12]1[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:14][CH2:13]1)[CH2:17][N:18]([CH3:28])[C:19](=[O:20])[O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CN(C[C@@H](N)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
(S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (1.9 g, 3.49 mmol) was dissolved into a minimal volume of Et2O (23.4 mL) and added to a solution of TsOH (0.66 g, 3.49 mmol) in absolute EtOH (5 mL). This solution was placed on a rotary evaporator and the Et2O was removed at ambient temperature. The flask was then lowed into the water bath (temperature: 60° C.) and the selective deprotection of the Boc group proceeded concurrent with removal of the remainder of solvent. The reaction was complete after 2 h and gave a pale yellow oil. The residue was dissolved into EtOAc (30 mL) and washed with 1 M aq NaOH (3×5 mL), brine (4×5 mL). The combined organic layers were dried and concentrated to provide (S)-2-(trimethylsilyl)ethyl 2-amino-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propyl(methyl)carbamate (1.15 g, 74%). MS (E/Z): 445 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1.[NH:29]1[CH2:39][CH2:38][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.C(O)(=O)C>[CH3:1][C:2]1[CH:28]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:11]([C:20]4[CH:21]=[CH:22][C:23]([CH2:24][N:29]5[CH2:30][CH2:31][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:38][CH2:39]5)=[CH:26][CH:27]=4)=[N:10][C:9]=3[N:4]2[N:3]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2n1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2ccc(-c3nc4c(cnc5cc(C)nn54)cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound (11-1) (1.28 g, 3.51 mmol, 1.0 eq) was dissolved in dioxane (38 mL, anhydrous). Ethyl isonipecotate (1.66 g, 10.5 mmol, 3.0 eq), glacial acetic acid (1.90 mL), and NaBH(OAc)3 (2.98 g, 14.1 mmol, 4.0 eq) were added and the reaction stirred at room temperature for 24 hours. The crude reaction was neutralized with NaHCO3 (aq.) and extracted with CHCl3 (×3). The combined organics were dried with brine and Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with a gradient of heptane and EtOAc (20% to 100% EtOAc) to afford Compound (13-1).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:14][C:13]2[CH2:12][CH2:11][S:10][CH2:9][C:8]=2[CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[S:14]1[C:13]2[CH2:12][CH2:11][S:10][CH2:9][C:8]=2[CH:7]=[C:6]1[CH:4]=[O:3]
Reactant: CCOC(=O)c1cc2c(s1)CCSC2
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cc2c(s1)CCSC2
Reaction time: 0.17 h
Yield: 36.2 %

Procedure:
The 1.1 gram (4.8 mmol) 6,7-Dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid ethyl ester was dissolved in 100 ml THF and LAH (40 ml, 0.5M in DMG) was injected and the reaction was left at 23° C. for 10 minutes. Then it was refluxed for 18 hrs. Quenched at 23° C. with water (10 ml). The organic layer decanted and the remaining was washed with 20 ml DCM. The combined organic layers dried over sodium sulfate. Filter, concentrate and flash column chromatograph with 10–20% ethyl acetate produced 940 mg crude product. This crude material was dissolved in DCM (40 ml) and manganese dioxide (2 gram was added). The reaction was carried on at 23° C. for half an hour. The material was then filtered through a pad of celite concentrated. Flash column chromatography gave 320 mg (36%) product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[NH:23][C:24]([C@@H:26]([NH2:34])[CH2:27][CH2:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[NH:23][C:24]([C@@H:26]([NH:34][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH2:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](CCc2nnn[nH]2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]([CH3:16])[CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[F:34].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:20]2[CH2:19][CH2:18][N:17]([CH:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:23])[CH:14]([CH3:16])[CH3:15])[CH2:22][CH2:21]2)=[O:30])=[CH:27][C:26]=1[F:34]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of N-tert-butyl-3-(2-methyl-1-(piperazin-1-yl)propyl)benzamide (13.6 mg, 0.043 mmol), 4-amino-3-fluorobenzoic acid (10 mg, 0.065 mmol), N-ethyl-N-isopropylpropan-2-amine (11 mg, 0.086 mmol) and 1-propanephosphonic acid cyclic anhydride (55 mg, 0.086 mmol, 50% solution in ethyl acetate) in dichloromethane (2.0 mL) was stirred at room temperature for 2 hours. The mixture was treated with strong cation exchange column chromatography and purified with silica column chromatography (eluting with 33% ethyl acetate in heptane then 66% ethyl acetate in heptane) to afford the title compound (11.8 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[N:18]=[C:17]([NH:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:16]2[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=2[CH2:10]1.[CH3:29][O:30][C:31]1[N:36]=[C:35](B2OCCN(C3C=CC=CC=3)CCO2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]2[N:18]=[C:17]([NH:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:16]3[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=3[CH2:10]2)=[C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[N:36]=2)[CH:7]=1
Reactant: Cc1nc(N)nc2c1C(NOC1CCCCO1)=N[C@@H](c1ccc(F)cc1Br)C2
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3C(NOC3CCCCO3)=N2)n1
Temperature: 85 °C
Yield: 124.7 %

Procedure:
(7R)-7-(2-bromo-4-fluorophenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine (0.838 g, 1.86 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.33 g, 4.47 mmol), sodium carbonate 2M solution (3.72 mL, 7.44 mmol) were combined in N,N-Dimethylacetamide (12 mL) and then the mixture was purged with nitrogen for 5 minutes. 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.136 g, 0.186 mmol) was then added and the reaction was heated in 85° C. oil bath overnight. Next day, the reaction was diluted with ethyl acetate 80 mL, washed with brine (80 mL), dried over sodium sulfate, and concentrated to a crude product which was then purified by flash column chromatography, SiO2, gradient 20-100% ethyl acetate/hexane to give a white solid, 1.11 g of product, contaminated with the impurity of mass 182 (byproduct from the boronic ester, compound 6). MS (ES) [M+H] calc'd for C25H27FN6O3, 479. found, 479.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:7]([O:28][CH3:29])=[C:8]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:9]=1)[CH:5]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C([BH3-])#N.[Na+].FC(F)(F)C(O)=O.C1COCC1.Cl.O>C1COCC1>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([CH2:5][N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:7]([O:28][CH3:29])=[C:8]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[CH:9]=1
Reactant: C1COCCN1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1CN1CCOCC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A mixture of 3-chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzaldehyde (10 mg, 0.023 mmol), in THF (0.95 mL) was stirred at 40° C. for 1 hour. Sodium triacetoxyborohydride (15 mg, 0.069 mmol) and acetic acid (50 μL, 0.88 mmol) were added and the mixture was stirred at 40° C. overnight. Morpholine (20 μL, 0.23 mmol) and sodium cyanoborohydride (14 mg, 0.23 mmol) were added and the mixture was heated at 40° C. for 1 hour. The solvents were stripped down and few drops of trifluoroacetic acid/THF solution (1:1) were added and the mixture stirred for 30 minutes. The mixture was treated with 6.0 M HCl in water (0.5 mL, 3 mmol) for 30 minutes. Purification by preparative LCMS (pH 10) gave the desired compound (3.4 mg, 35%). LCMS calculated for C19H23ClFN6O2 (M+H)+: m/z=421.2. found: 421.1. 1H NMR (DMSO-d6, 500 MHz) δ 12.91 (1H, br s), 8.17 (2H, m), 7.72 (1H, m), 5.89 (1H, br s), 4.05 (3H, s), 3.50 (7H, m), 2.41 (4H, m), 1.42 (3H, m).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:30]=[CH:31][C:24]([CH3:23])=[C:25]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][N:34]=3)[CH:26]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2ccccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-benzohydrazonoyl chloride (1.1 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.50 g of desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12]1([CH:18]([CH3:22])[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:22])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Product: CCOC(=O)c1cc(C(=O)C(C)c2ccccc2)c(C)[nH]1

Procedure:
5-Methyl-4-(2-phenyl-propionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (138) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and 2-phenyl-propionyl chloride following the procedure described in Example 32. Reaction conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 86%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([O:14]CC)=[CH2:13])=[CH:7][CH:6]=2>O1CCOCC1.Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=2
Reactant: C=C(OCC)c1ccc2cnc(Cl)cc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc2cnc(Cl)cc2c1
Yield: 89 %

Procedure:
A solution of 3-chloro-6-(1-ethoxy-vinyl)-isoquinoline (934 mg, 4 mmol) in 1,4-dioxane (10 mL) and hydrochloric acid (2 M, 5 mL) was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extracts were combined, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 4:1 to afford the title compound (732 mg, 89%) as a white solid. 1H NMR (300 MHz, CDCl3) δ2.77 (s, 3H), 7.88 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.15 (dd, J=8.5, 1.4 Hz, 1H), 8.37 (br s, H), 9.17 (s, 1H). LCMS (m/z) 206/208 [M+H], Tr=4.40 min.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]([O:32]C)=[O:31]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:20]=[C:21]([Br:27])[C:22]([O:26][CH2:29][C:30]([OH:32])=[O:31])=[C:23]([Br:25])[CH:24]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(Br)c(O)c(Br)c1)c1c(Cc2ccccc2)sc2ccccc12
Reactant: COC(=O)CBr
Product: O=C(O)COc1c(Br)cc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1Br

Procedure:
This compound was prepared from (2-benzyl-benzo[b]thiophen-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone and methyl bromoacetate in substantially the same manner, as described in Example 20, and was obtained as an off-white solid, mp 162-163° C., MS m/e 558 (M)+; Analysis for: C24H16Br2O4S Calc'd: C, 51.45; H, 2.88 Found: C, 51.15; H, 2.71
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[SH:24])[CH3:2].Br[CH2:26][CH2:27][Cl:28]>C(#N)C>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[S:24][CH2:26][CH2:27][Cl:28])[CH3:2]
Reactant: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Reactant: ClCCBr
Solvent: CC#N
Product: CCOCn1c(SCCCl)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
A mixture of (R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-8-mercapto-3-methylxanthine (0.19 g, 0.533 mmol) potassium carbonate (0.15 g, 10.7 mmol) and 1-bromo-2-chloroethane (114 mg, 0.80 mmol) in acetonitrile (10 ml) was stirred at 65° C. for 1.5 hours. After concentrating under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-7-ethoxymethyl-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (150 mg, 67% yield) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH2:11](O)[CH:12]=C>C1(C)C=CC=CC=1.[Zn]>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: COC(=O)C1CCCC1=O
Reactant: C=CCO
Agent: [Zn]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1CCCC1=O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A stirred solution of methyl 2-oxocyclopentanecarboxylate (4.26 g, 30 mmol) and allyl alcohol (10.2 mL, 150 mmol) in anhydrous toluene (25 mL) was treated with powdered zinc (0.40 g, 6 mmol), refluxed for 48 h, and cooled to room temperature. The suspension was filtered, the filter cake rinsed with toluene, and the filtrate concentrated to afford allyl 2-oxocyclopentanecarboxylate (5.01 g, 99%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 5.89 (ddt, J1=15.9 Hz, J2=10.5 Hz, J3=4.8 Hz, 1 H), 5.33 (dtd, J1=15.9 Hz, J2=2.7 Hz, J3=1.4 Hz, 1 H), 5.23 (dtd, J1=10.5 Hz, J2=2.7 Hz, J3=1.4 Hz, 1 H), 4.83-4.75 (m, 1 H), 3.18 (t, J=9.0 Hz, 1 H), 2.41-2.23 (m, 4 H), 2.22-2.07 (m, 1 H), 1.94-1.80 (m, 1 H); MS (+CI): m/z for C9H12O3: expected 168.1; found 169.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19]3)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:20]1[CH2:21][CH2:22][N:18]([C:14]2[N:13]=[C:12]([NH:11][C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:3]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:19]1
Reactant: OB(O)c1ccccc1
Reactant: CC1CCN(c2cccc(Nc3cc(Cl)nn4ccnc34)n2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC1CCN(c2cccc(Nc3cc(-c4ccccc4)nn4ccnc34)n2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
A mixture of 6-chloro-N-(6-(3-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (296 mg, 0.9 mmol), phenylboronic acid (165 mg, 1.35 mmol), Pd2(dba)3 (52 mg, 0.09 mmol), X-phos (172 mg, 0.36 mmol) and Na2CO3 (287 mg, 2.7 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 16 h under N2. The solution was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=5:1) to give N-(6-(3-methylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (134 mg, 40%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.82 (s, 1H), 8.06-7.93 (m, 3H), 7.93-7.39 (m, 5H), 6.20 (d, 1H, J=7.8 Hz), 5.98 (d, 1H, J=8.1 Hz), 3.86-3.80 (m, 1H), 3.67-3.62 (m, 1H), 3.55-3.46 (m, 1H), 3.14 (t, 1H, J=9.3 Hz), 2.47-2.37 (m, 1H), 2.23-2.14 (m, 1H), 1.75-1.62 (m, 1H), 1.19 (d, 3H, J=6.6 Hz). LC-MS: [M+H]+, 371, tR=2.057 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=4.787 min.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.O.C[NH:13][CH:14]1[CH2:26][C:25]2[C:24]3C(=CC(C)=CC=3)N[C:17]=2[CH2:16][CH2:15]1>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:8][C:7]2[C:26]3[C:14](=[CH:15][CH:16]=[CH:17][C:25]=3[CH3:24])[NH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CNC1CCC(=O)CC1
Reactant: CNC1CCc2[nH]c3cc(C)ccc3c2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC1CCc2[nH]c3cccc(C)c3c2C1

Procedure:
A solution of 15 g. of 4-methylaminocyclohexanone and 18.4 g. of 3-methylhydrazine hydrochloride in 200 ml. of absolute ethyl alcohol and 50 ml. of 4-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for six hours, cooled, and filtered to give 12.3 g. of solids which were slurried in 50 ml. of water. The slurry was cooled, the solids were collected by filtration, suspended in ether-chloroform, and the suspension was treated with dilute potassium hydroxide. The ether-chloroform extract was evaporated to dryness under pressure to give 7.6 g. of 3-(methylamino)-7-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 163°-166° C. The alcoholic reaction mixture filtrate was evaporated to dryness under reduced pressure, the residue was boiled in isopropyl alcohol, and the insoluble material was collected by filtration, dissolved in water and the resulting solution was made alkaline with dilute potassium hydroxide. The resulting solids were collected by filtration to give, after recrystallization from ethyl acetate, 3.6 g. of 3-(methylamino)-5-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 187°-190° C., which contained about 6% of the 7-methyl isomer as determined by gas chromatographic analysis.