Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C.CCOCC>[CH2:12]([O:6][CH:3]([CH:2]([CH3:7])[CH3:1])[C:4]#[CH:5])[CH:11]=[CH2:10]
Reactant: C#CC(O)C(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(OCC=C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
A solution of 4-methylpent-1-yn-3-ol (2.00 g, 20.38 mmol) in DMF (30 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.992 g, 24.80 mmol). The reaction was stirred for 20 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (5.3 ml, 61.2 mmol) over 5 min. The reaction was stirred over the weekend. The reaction was diluted with Et2O (100 mL), washed with water (4×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give the product, 3-(allyloxy)-4-methylpent-1-yne (2.401 g, 13.03 mmol, 63.9% yield) as a pale yellow mobile oil. 1H NMR consistent with expected product; contains approx 4:1 product/SM. Used as-is without further purification. 1H NMR (CDCl3) δ: 5.86-5.99 (m, 1H), 5.32 (dq, J=17.2, 1.7 Hz, 1H), 5.16-5.25 (m, 1H), 4.28 (ddt, J=12.7, 5.0, 1.6 Hz, 1H), 4.19 (td, J=5.7, 2.1 Hz, 1H), 3.98 (ddt, J=12.7, 6.3, 1.3 Hz, 1H), 3.87 (dd, J=5.8, 2.0 Hz, 1H), 2.41 (d, J=2.0 Hz, 1H), 1.92-2.03 (m, 1H), 0.98-1.06 (m, 8H).
Reaction SMILES: CO.CN(C1CCN(C([C:21]2[CH:22]=[CH:23][C:24]([C:27](OC)=[O:28])=[N:25][CH:26]=2)=O)CC1)CCC1C=CC=CC=1.[BH4-].[Na+].[ClH:33]>C(O)C.C(O)(=O)C.O.C(O)(C)(C)C>[ClH:33].[ClH:33].[C:27](=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:26][NH:25]1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCC(N(C)CCc3ccccc3)CC2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C=C1CCCCN1
Reaction time: 0.08 h

Procedure:
1 ml of methanol was dropwise added, at about 80° C. to a mixture of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1(2-methoxycarbonylpyridin-5-yl)carbonylpiperidine, 0.12 g of sodium borohydride and 3.88 g of tert-butanol. (This gave rise to foaming.) In this state, the mixture was refluxed by heating, for 1.5 hours. The reaction mixture was returned to room temperature and mixed with 1 ml of water and 1 ml of acetic acid. The mixture was stirred for 5 minutes and then subjected to distillation to remove the solvent. The residue was mixed with water for dissolution. The solution was made basic with an aqueous sodium hydroxide solution and then extracted with chloroform. The extract was washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silical gel column chromatography (eluant:dichloromethane/methanol=45/1 to 25/1). The product was converted to a hydrochloride with 2 equivalents of 5N hydrochloric acid, in ethanol. The hydrochloride was crystallized from ethyl acetate-ethanol and recrystallized from ethanol-water to obtain 0.32 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-2-hydroxymethylpyridin-5-yl)carbonylpiperidine dihydrochloride as colorless prism-like crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:12][O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[C:3]([F:11])[C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Cl)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C=O
Temperature: 140 °C
Yield: 85.5 %

Procedure:
A mixture of 5-chloro-4-fluoro-2-hydroxy-benzaldehyde (0.8 g, 4.6 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.6 g, 9.2 mmol) and K2CO3 (2 g, 14.5 mmol) in DMF (40 mL) was placed in a sealed tube and heated by irradiation in microwave reactor at 140° C. for 12 min. After cooled to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over anhydrous Na2SO4 and concentrated to give the thitle compound as a brown solid (1.08 g).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
750 ml of water and 324 g of Na2S.9H2O are heated to 90°-95° C. in a cylindrical reaction vessel (1.5 l capacity, diameter 10 cm, height 20 cm) with a lid fitted with three tubes, which is provided with an anchor stirrer (diameter 9 cm, anchor height 12 cm) and thermometer, 81 g of finely sieved 1-nitro-anthraquinone (content 73.9%) is then stirred in at the same temperature in the course of one hour and finally the mixture is subsequently stirred at 90°-95° C. for 30 minutes. The reaction mixture is filtered and the residue is washed with hot water until neutral and dried at 60° C. in vacuo. 71.3 g of crude 1-amino-anthraquinone of the following composition are obtained: 72.5% of 1-amino-anthraquinone=98% of theory, 3.1% of 1,5-diamino-anthraquinone, 2.8% of 1,8-diamino-anthraquinone, 3.0% of 1,6-diamino-anthraquinone, 3.1 % of 1,7-diaminoanthraquinone, 2.3% of anthraquinone, 5.9% of 2-amino-anthraquinone and 0.1% of 2,6-+2,7-diamino-anthraquinone.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Nc1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCNc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluoroaniline (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by HPLC to give 7-(2-(2,4-difluorophenylamino)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=396.53).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5]O[C:3]=1[CH2:10][OH:11].[NH3:12]>>[CH3:1][CH:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][N:12]=[C:3]1[CH2:10][OH:11]
Reactant: N
Reactant: Cc1coc(CO)c(C)c1=O
Product: CC1=CN=C(CO)C(C)C1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
3,5-Dimethyl-2-hydroxymethyl-4-pyrone 4 (9.75 g, 63.3 mmol) was dissolved in 32% aqueous ammonia (0.880, 60 ml) in a 100 ml round bottom flask. The flask was sealed with a septum cap and made secure with wire. The solution was then stirred at 60° C. for 48 hours before being evaporated to dryness under reduced pressure to give 5 as an off-white solid (9.30 g, 60.8 mmol, 96% yield). Selected IR (cm-1, nujol) 3150-3500 (br, s), 1639 (s); 1H-NMR (DMSO-d6) δ 1.80 (s, 3H), 1.84 (s, 3H), 4.45 (s, 2H), 7.44 (s, 1H); Ms (APCI+) m/z (%) 154 (MH+, 100).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[NH2:8])=[C:4]([NH:10][C:11]([C@@H:13]2[CH2:17][CH:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][N:14]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:9])[NH:8][C:11]([C@@H:13]3[CH2:17][CH:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:15][N:14]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCCCC2)C[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCCCC2)C[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In the same manner as in Example 11, step A, tert-butyl(2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-piperidin-1-ylpyrrolidine-1-carboxylate was obtained as a pale-brown amorphous solid (132 mg) from 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D and 1-(tert-butoxycarbonyl)-4-piperidin-1-yl-L-proline (270 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (413 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.316 mL) and N,N-dimethylformamide (5.0 mL). To tert-butyl(2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-piperidin-1-ylpyrrolidine-1-carboxylate produced above were added 2M aqueous sodium hydroxide solution (0.52 mL) and ethanol (1.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. The mixture was extracted with ethyl acetate, and the mixture was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (63 mg) as a pale-brown amorphous solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19]O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][CH:18]1[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:9])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1cc(I)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1OCC1CCCN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 13 h
Yield: 77.8 %

Procedure:
To a stirred solution of 4-iodo-2-methylphenol (465 mg, 1.987 mmol), N-tert-butoxycarbonylprolinol (400 mg, 1.987 mmol), and Ph3P (625 mg, 2.384 mmol) in THF (7 mL) was added dropwise DIAD (0.5 mL, 2.404 mmol) at room temp, and the mixture was stirred for 13 hr at 70° C. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica-gel with n-hexane-EtOAc (9:1, v/v) as eluent to give 645.3 mg (78%) 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-1-iodo-3-methylbenzene as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.83–1.89 (m, 1H), 1.96–2.04 (m, 3H), 2.16 (s, 3H), 3.37–3.43 (br m, 2H), 3.81, 3.94 (br m each, 1H), 4.08–4.18 (m, 2H), 6.62 (br s, 1H), 7.42 (s, 2H); MS (FAB) m/z 418 (M++1).
Reaction SMILES: C(C1C(CC2C=CC(C)=CC=2)=CC2C(C)(C)CCC(C)(C)C=2C=1)=O.[CH3:25][C:26]1([CH3:59])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]2[CH:31]=[C:30](/[CH:38]=[CH:39]/[C:40]3[CH:50]=[CH:49][C:43]([C:44]([O:46]CC)=[O:45])=[CH:42][CH:41]=3)[C:29]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)=[CH:28][C:27]1=2>CCCCCC>[CH3:25][C:26]1([CH3:59])[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[C:32]2[CH:31]=[C:30](/[CH:38]=[CH:39]/[C:40]3[CH:50]=[CH:49][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=3)[C:29]([CH2:51][C:52]3[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=3)=[CH:28][C:27]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2Cc2ccc(C)cc2)C(C)(C)CCC3(C)C)cc1
Agent: Cc1ccc(Cc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Solvent: CCCCCC
Product: Cc1ccc(Cc2cc3c(cc2/C=C/c2ccc(C(=O)O)cc2)C(C)(C)CCC3(C)C)cc1
Yield: 64 %

Procedure:
Horner-Emmons olefination (following the procedure of Example) of 2-formyl-3-(4-methylbenzyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (210 mg, 0.65 mmol) followed by ester hydrolysis (following the procedure of Example) of ethyl 4-{(E)-2-[5,5,8,8-tetramethyl-3-(4-methylbenzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate gave 4-{(E)-2-[5,5,8,8-tetramethyl-3-(4-methylbenzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoic acid (185 mg, 64%) as a white crystalline solid (m.p. 216.3-217.3° C. (CH2CL2/hexane) 42.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@@:17]3([O:28][CH3:29])[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3)[CH:13]=[CH:14][C:15]=2[Cl:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(OC(=O)C)C>[CH3:39][C:38]1[CH:40]=[CH:41][C:35]([S:32]([O:27][CH2:26][C@@H:19]2[C@@H:20]([OH:25])[C@H:21]([OH:24])[C@@H:22]([OH:23])[C@@:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([CH2:9][C:8]4[CH:30]=[CH:31][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=4)[CH:11]=3)([O:28][CH3:29])[O:18]2)(=[O:34])=[O:33])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-(3-(4-(allyloxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1.2 g, 2.66 mmol) in leutidine (18.6 mL, 159.8 mmol), was added tosyl chloride (3.0 g, 15.98 mmol) at 0° C. The reaction mixture was stirred at r.t. for 12 h. After the completion of reaction as monitored by TLC, the reaction mixture was diluted with ethylacetate (50 mL) and washed with 5% HCl (3×10 mL). The organic layers were dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.7:9.3 MeOH:DCM) to provide title compound (1.42 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.BrC1C=C2C(Cl)=C(C(N)=O)C=NN2C=1.N[C@H]1[C@@H](CC)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:64][O:65][CH2:66][C:67]([NH:69][CH2:70][C:71]1[N:76]=[CH:75][C:74](B(O)O)=[CH:73][CH:72]=1)=[O:68].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:28]([C:8]1[CH:7]=[N:6][N:5]2[CH:31]=[C:2]([C:74]3[CH:75]=[N:76][C:71]([CH2:70][NH:69][C:67](=[O:68])[CH2:66][O:65][CH3:64])=[CH:72][CH:73]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12]1)(=[O:30])[NH2:29]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: COCC(=O)NCc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 93.8 %

Procedure:
A mixture of 180 mg (0.370 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and Intermediate 9 using the method described in Step 1 of Example 52), (6-((2-methoxyacetamido)methyl)pyridin-3-yl)boronic acid (332 mg, 1.480 mmol), potassium phosphate, tribasic, 2M (0.925 mL, 1.850 mmol) and PdCl2(dppf) (54.2 mg, 0.074 mmol) in DMA (2.5 mL) was stirred at 90° C. for 45 minutes. After cooling to rt, the reaction mixture was diluted with ˜40 ml of EtOAc. The resulting dark mixture was filtered through celite and the filtrate was washed with water (40 ml), 10% LiCl solution (2×40 ml) and brine (40 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a brown oil that was chromatographed on a 4 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient, followed by a 0-10% MeOH/CH2Cl2 gradient. The pure fractions were concentrated to afford a brown oil that was triturated with ethyl ether. Filtration and drying afforded (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (203 mg, 0.347 mmol, 94% yield) as a tan solid. The material will be used as is in the next step. MS (ES+) m/z: 586.3 (M+H); LC retention time: 2.388 min (analytical HPLC Method O).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(Cl)cccc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,6-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (32.5 mg) with purity >90%. MS (pos) m/z 395.1, 397.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.C(OCC)C>FC(F)(F)C(O)=O.CO.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([CH3:19])[OH:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CO
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)(C)O)CCCC3
Reaction time: 72 h
Yield: 69.1 %

Procedure:
Platinum (IV) oxide (0.3 g) was added to a suspension of 4-amino-2-butyl-α,α,-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1.0 g, 3.2 mmole) in trifluoroacetic acid (20 mL). The mixture was hydrogenated at 50 psi (3.44×105Pa) for 3 days. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The resulting residue was covered with water and aqueous sodium bicarbonate. A white solid was isolated by filtration then recrystallized for ethyl acetate. The reaction was repeated using 1.5 g of starting material. The combined products were taken up in dichloromethane, washed with 10% sodium hydroxide, dried over magnesium sulfate, then concentrated under vacuum. The material was recrystallized from ethyl acetate then from toluene to provide 1.15 g of crude product. This material was dissolved in methanol then combined first with one equivalent of hydrochloride acid then with diethyl ether. The resulting salt was converted back to the free base then purified by silica gel column chromatography diluting with 10% methanol in ethyl acetate. The resulting material was recrystallized from toluene then dried under vacuum at 110° C. to provide 0.7 g of 4-amino-2-butyl-α,α,-dimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol as a solid, m.p. 160°-161.5° C. Analysis: Calculated for C18H28N4O: % C, 68.32; % H, 8.92; % N, 17.70; % C, 67.96; % H, 89.95; % N, 17.48.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11].C(=O)(O)[O-].[Na+]>COCCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: OCc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: O=Cc1ccc(-c2ccccc2CO)cc1
Yield: 69.7 %

Procedure:
i)—To a solution of 2-bromo-benzylalcohol (5 g, 26.7 mmol) in 2-methoxyethanol/water (30 ml, 1/1) were added 4-formylphenylboronic acid (6 g, 40.0 mmol) and sodium bicarbonate (4.4 g, 52.4 mmol) under a nitrogen atmosphere. After (Ph3P)4Pd (1.54 g, 1.34 mmol) was added, the reaction mixture was heated under reflux for 17 h. After cooling, the mixture was filtered over dicalite and the residue was washed with water and ethyl acetate. The product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate concentrated under reduced pressure. Column chromatography afforded 2′-hydroxymethyl-biphenyl-4-carbaldehyde (3.95 g).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl[CH:9]([CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[SH:7][C:4]1[S:3][C:2]([S:1][CH:9]([CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][N:5]=1
Reactant: CCOC(=O)CCC(C)Cl
Reactant: Sc1nnc(S)s1
Product: CCOC(=O)CCC(C)Sc1nnc(S)s1
Yield: 15.3 %

Procedure:
By following the same procedure as Reference Example 6 using 6.9 g of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 4-chlorovalerate as the starting materials, 1.5 g of ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]valerate was obtained as an oily product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:8][C@H:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CCO[Si](C)(C)C(C)(C)C)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCC[C@H](CCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of aqueous HF (50%, 12 mL) was added to a mixture of compound 45 (6.3 g, 14.5 mmol) in acetonitrile (120 mL) and the mixture was stirred for 30 min. After completion of the reaction, the acid was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×150 mL) and the organic phase was separated, dried, concentrated, and the product was purified by flash chromatography to afford compound 46 as colorless oil (Rf 0.42, 25% ethyl acetate in hexane, 3.4 g, 74%).
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](O)[CH3:21]>>[Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:20][CH3:21])=[O:4]
Reactant: CCO
Reactant: CC(C)C(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(Br)C(C)C
Yield: 55 %

Procedure:
To a solution of 2-bromo-3-methylbutanoic acid (3 g, 16.5 mmol) in ethanol (200 ml), was added concentrated sulfuric acid (4 ml). After 36 h under reflux ebullition, the reaction medium, returned to ambient temperature, was neutralized with an aqueous saturated sodium carbonate solution. After distillation of the ethanol, the reaction medium was extracted with dichloromethane (100 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated to give ethyl 2-bromo-3-methylbutanoate (1.91 g, 55%).