Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:19]=3)=[N:11][C:12]([C:15](O)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:42][C:43]1([C:49]([O:51][CH3:52])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[ClH:1].[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH:19]=3)=[N:11][C:12]([C:15]([NH:42][C:43]3([C:49]([O:51][CH3:52])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)C1(N)CCCCC1
Reactant: Cc1cnc(-c2ccc(C(=O)O)nc2-c2ccc(Cl)c(OCCCN(C)C)c2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1(NC(=O)c2ccc(-c3ncc(C)cc3Cl)c(-c3ccc(Cl)c(OCCCN(C)C)c3)n2)CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a suspension of 134 mg (0.29 mmol) of 3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-methyl-2,3′-bipyridine-6′-carboxylic acid in 5 mL of anhydrous acetonitrile are successively added 0.18 mL (1.02 mmol) of DIEA and 56 mg (0.29 mmol) of methyl 1-aminocyclohexanecarboxylate hydrochloride. The mixture is cooled to 0° C. and 112 mg (0.35 mmol) of TBTU are added. After stirring for 18 hours between 0 and 10° C., the reaction medium is concentrated under reduced pressure and then taken up in 20 mL of a 1/1 EtOAc/ether mixture. After washing with 10 mL of water and 10 mL of saturated aqueous NaHCO3 solution, the organic phase is dried over Na2SO4 and concentrated under reduced pressure. 0.2 mL (0.1 mmol) of a 2N solution of HCl in ether and then 20 mL of anhydrous ether are added to the residue, taken up in 5 mL of DCM, which allows precipitation of 139 mg of methyl 1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-methyl-2,3′-bipyridin-6′-yl)-carbonyl]amino}cyclohexanecarboxylate hydrochloride in the form of a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1>CN(C)P(N(C)C)(N(C)C)=O.O>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCOc2ccc(Cl)cc2Cl)cc1

Procedure:
A solution of 22.8 g of β-bromo-2,4-dichlorophenetole and 29.8 g of ethyl 4-aminobenzoate in 100 ml of hexamethylphosphoramide is heated at 125° C. for 16 hours. The solution is chilled, diluted with water (80 ml) and filtered. The solid is washed with 50% ethanol to give the product. Recrystallization from ethanol gives crystals, mp 111°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:36])[CH2:17][OH:16])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]=1[CH3:26]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine (compound 341) (95 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, the mixture was stirred at 0° C. for 30 min, and the mixture was then stirred at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (63 mg, yield 64%).
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:5][CH:4]1[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1>CO>[OH:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:5][NH:2][CH3:1]
Reactant: NS(=O)(=O)c1ccc(C2CO2)cc1
Reactant: CN
Solvent: CO
Product: CNCC(O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of methyl amine (20 mL, 40 mmol, 2.0 M in methanol) was added 4-oxiran-2-ylbenzenesulfonamide (Preparation 49)(0.52 g, 2.6 mmol) at 0° C. The clear solution was warmed to room temperature and stirred overnight. The solvent and excess of methyl amine was evaporated to yield an oil. The crude oil was dissolved in methanol (5 mL), and stirred with resin (BioRad 50W×2, 1 g) for 4 hours. The resin was collected by filtration and washed with methanol (3×15 mL). The product on the resin was washed off with NH4OH/CH3OH (20 mL, 10% ammonium hydroxide aqueous solution (Aldrich, 29.4% NH3) in methanol). The solution was concentrated to dryness, and treated with high vacuum to give the title compound (0.19 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:11]=[N+:12]=[N-:13].[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[N:11]([CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:12]=[N-:13]
Reactant: CCOC(=O)C[C@@H](O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](O)CN=[N+]=[N-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
In a 200 ml four-necked flask were charged 20.0 g (0.12 mol) of ethyl (R)-4-chloro-3-hydroxybutyrate, 15.6 g (0.24 mol) of sodium azide and 80 ml of DMF, and the reaction mixture was stirred for 24 hours at a reaction temperature of about 100° C. After cooling the reaction mixture, the reaction mixture was diluted with 100 ml of toluene, washed with 50 ml of water, and concentrated to give 16.5 g (79%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>C1(C)C=CC=CC=1>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([CH:17]3[CH:16]1[C:15](=[O:18])[CH:14]=[CH:13][C:12]3=[O:19])[C:4]([Cl:9])=[C:5]2[Cl:8]
Reactant: O=C1C=CC(=O)C=C1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Yield: 64 %

Procedure:
A mixtures of 54.6 g. (0.2 mole) of hexachlorocyclopentadiene, 21.6 g. (0.2 mole) of p-benzoquinone, and 10 ml. of toluene were placed in a 125 ml. round bottom flask and heated for three hours so that the toluene refluexed gently. At the end of this period the reaction mixture suddenly solidified completely, indicating completion of the reaction. The crude product was bright yellow. The damp material was transferred to a Buchner funnel, rinsed with absolute ethanol, dried on the funnel, and crystallized from ehtnaol. 49 g. of bright yellow dense crystals were obtained, m.p. 189°-193° C (reported 188° C). The yield was 64%.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[S:33][CH:34]=[C:35]([C:37](O)=[O:38])[N:36]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:37]([C:35]2[N:36]=[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[S:33][CH:34]=2)=[O:38])[CH2:6][CH2:7]1
Reactant: O=C(O)c1csc(-c2ccccn2)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccn3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(pyridin-2-yl)thiazole-4-carboxylic acid (see Tetrahedron 2011, 67, 267) gave 326. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.70-8.65 (m, 1H), 8.50 (s, 1H), 8.35-8.30 (m, 1H), 8.04-7.97 (m, 1H), 7.87 (s, 1H), 7.59-7.53 (m, 1H), 4.94-4.88 (m, 1H), 4.84-4.67 (m, 1H), 4.48-4.34 (m, 1H), 4.24-4.07 (m, 1H), 3.80 (s, 3H), 3.60-3.47 (m, 1H), 2.17-2.09 (m, 1H), 1.96-1.78 (m, 3H). LCMS (ES+) m/z 417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:22])[CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN1C(C)(C)CC(Nc2ccc(Cl)nn2)CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)nn1)C1CC(C)(C)N(C)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-5, (4.0 g, 14.1 mmol) in DMF (140 mL) cooled to 0° C. was added 60% wt NaH (735 mg, 18.39 mmol) portionwise. The reaction was warmed to RT and stirred for 60 minutes. After 60 minutes methyl iodide (0.88 mL, 14.1 mmol) was added and the reaction was stirred an additional 3 h, then slowly quenched with water at room temperature. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 6-chloro-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-4 (3.98 g). The crude material was carried on without further purification. LCMS Rt=1.16 min (condition B), MS (M+1)=297.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 (d, J=9.6 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 4.79-5.00 (m, 1H), 2.86 (s, 3H), 2.22 (s, 3H), 1.61-1.73 (m, 2H), 1.48-1.57 (m, 2H), 1.14 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: Cl.[CH3:2][NH:3]C.C[Al](C)C.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:14]([C:23]2[N:27]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]3[CH:32]=[CH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=4)=[CH:35][C:25]=3[N:24]=2)[CH:13]=1.O>C1(C)C=CC=CC=1>[NH2:42][C:39]1[N:38]=[CH:37][C:36]([C:34]2[CH:33]=[CH:32][C:26]3[N:27]([C:28]([CH3:29])([CH3:30])[CH3:31])[C:23]([C:14]4[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=4[N:18]4[CH:22]=[N:21][CH:20]=[N:19]4)[C:11]([NH:3][CH3:2])=[O:10])=[N:24][C:25]=3[CH:35]=2)=[CH:41][N:40]=1
Reactant: COC(=O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of dimethlyamine hydrochloride (20 mg, 0.3 mmol) in dry toluene (8 mL) is added AlMe3 (0.22 mL, 0.45 mmol) at room temperature. The solution is stirred at the same temperature for 15 minutes. 3-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-4-[1,2,4]triazol-1-yl-benzoic acid methyl ester (example 7) (70 mg, 0.15 mmol) is added to the solution and it is heated to 90° C. for 12 hours. The mixture is cooled down to room temperature and water (10 mL) is added. The mixture is extracted with EtOAc (3×10 mL) and the combined organic layer is dried by Mg2SO4 (300 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (17 mg, 25%). LCMS (ESMS): m/z 468.20 (M++1)
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[CH:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][C:24]#[CH:25])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1I.CCN(CC)CC>C1COCC1.[Cu]I>[CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][C:24]#[C:25][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)C(O)[C@@H]1O
Reactant: Fc1ccccc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O[C@@H]1[C@H](O)[C@@H](CC#Cc2ccccc2F)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4S,2R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-prop-2-ynyloxolane-3,4-diol (0.017 g, 0.05 mmol) and 1-fluoro-2-iodobenzene (0.02 mL, 0.13 mmol) in THF (3.50 mL) under an atmosphere of N2 was added catalytic amount of dichlorobis(triphenylphosphine) palladium (II) and copper (I) iodide. Et3N (0.20 mL) was then added. The resulting mixture was stirred under N2 at 75° C. for 2 days. The solvent was removed under reduced pressure, and the residue was purified by preparative thin layer chromatography to give (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[3-(2-fluorophenyl)prop-2-ynyl]oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:24](O)([C:26](F)(F)F)=[O:25]>C(Cl)Cl>[OH:25][CH:24]([CH3:26])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:23][CH:22]=2)=[O:8])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)CN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Yield: 31.4 %

Procedure:
In an analagous manner to 23, tert-butyl 4-(4-formylbenzoyl)piperazine-1-carboxylate 26 (500 mg, 1.57 mmol) in DCM (10 mL) was reacted with TFA (1.17 mL, 15.72 mmol) to afford product as white sticky solid. Yield: 31.4%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].[CH3:17][O-:18].[Na+]>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[C:2]([O:18][CH3:17])[CH:7]=1
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nnc1Oc1ccccc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
In methanol (60 mL) was dissolved 3.00 g (11.8 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2), 1.00 g (17.6 mmol) of 95% sodium methoxide was added to the solution at room temperature and the mixture was stirred at 60° C. for 4 hours. Moreover, 1.00 g (17.6 mmol) of 95% sodium methoxide was further added and after stirring the mixture at 60° C. for 1 hour, it was allowed to stand at room temperature overnight. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was successively washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=4:1) to obtain 2.75 g (11.0 mmol, Yield: 93.2%) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:11][CH:10]1[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1)[CH3:13]
Reactant: Oc1cccc(O)c1O
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC1Oc2cccc(O)c2O1
Yield: 92.9 %

Procedure:
Pyrogallol (0.50 g, 3.96 mmol), triethyl orthoformate (0.80 cm3, 4.81 mmol) and amberlyst-IR-120(plus), (0.11 g, 5% weight alcohol) were combined in dried toluene (40 cm3) and heated to reflux under nitrogen for 28 hours. Any low boiling solvents were removed by distillation through a 10 cm Vigreux column, and the reaction vessel was recharged with toluene as required. The cooled solution was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure. The residue was filtered through a pad of silica with ethyl acetate (20% in heptane), and the filtrate was evaporated under reduced pressure to give the protected pyrogallol, (0.67 g, 92%) as clear oil.
Reaction SMILES: C[O:2][C:3]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[C:16]([O:23]C)=[C:15]([CH3:25])[C:4]=1[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:22][O:21][C:17]1[C:16](=[O:23])[C:15]([CH3:25])=[C:4]([CH2:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:18]=1[O:19][CH3:20]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
The compound (116 mg, 0.34 mmol) obtained in Step 4 was dissolved in a mixture of acetonitrile (2.2 ml) and water (0.81 ml), to which was added CAN (447 mg, 0.82 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with methylene chloride. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by a silica gel column chromatography (methylene chloride:methanol=8:1) to yield the title compound (92 mg, 0.29 mmol, yield 85%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:13]([C:15]2[CH:16]=[CH:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:14]=1>>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[C:13]([C:15]2[CH:16]=[CH:17][C:18](=[S:21])[NH:19][N:20]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NCC(O)COc1ccc(N)cc1-c1ccc(=S)[nH]n1
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=S)[nH]n2)c1

Procedure:
Addition of acetic anhydride to a stirred suspension of 6-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(3H)-pyridazinethione in an aqueous buffer solution at pH 5.5 gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2[CH:36]=[CH:37][CH:38]=[N:39]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:38]1([NH:39][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:23])[CH2:36][CH2:37]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reaction time: 43 h
Yield: 77.1 %

Procedure:
To a solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 30.0 mg, 0.092 mmol) and HATU (52.1 mg, 0.137 mmol) in dry DMF (0.5 mL) was added cyclopropylamine (10.5 mg, 0.183 mmol) followed by diisopropylethylamine (35.5 mg, 0.275 mmol). The mixture was stirred under an atmosphere of N2 for 43 hours. The crude mixture was purified by reverse phase chromatography eluting with 0-50% acetonitrile/water to yield the title compound as a white solid (26 mg, 78% yield). MS (apci) m/z=367.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]2[CH2:15][CH:16]([CH3:18])[O:17][C:13]=2[C:12]([Cl:19])=[CH:11][CH:10]=1.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>O1CCOCC1>[Cl:19][C:12]1[C:13]2[O:17][CH:16]([CH3:18])[CH2:15][C:14]=2[C:9]([N:8]=[C:21]=[O:22])=[CH:10][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1Cc2c(N)ccc(Cl)c2O1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1Cc2c(N=C=O)ccc(Cl)c2O1

Procedure:
6.07 g of triethylamine was added to a mixture of 9.18 g of 32A, 11.87 g of trichloromethyl chloroformate and 250 mL of dioxane, and the mixture was refluxed for 6 hours. The mixture was cooled, filtered, and the filtrate was stripped of solvent, to give 7-chloro-2,3-dihydro-4-isocyanato-2-methylbenzofuran (34A), as a brown liquid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:29])([F:28])[C:12]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][C@H:20]([C:25]([OH:27])=O)[CH2:19][CH2:18][C:17]=2[N:16]=1)([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:55][C@@H:56]([C:58]1[C:63]([F:64])=[CH:62][C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([CH3:70])[CH:59]=1)[CH3:57]>CN1CCCC1=O>[F:64][C:63]1[CH:62]=[C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[C:60]([CH3:70])=[CH:59][C:58]=1[C@H:56]([NH:55][C:25]([C@@H:20]1[CH2:19][CH2:18][C:17]2[N:16]=[C:15]([C:12]([CH3:14])([CH3:13])[C:11]([F:29])([F:10])[F:28])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:27])[CH3:57]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)[C@@H]2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 60.6 %

Procedure:
N-methylpyrrolidinone (1.2 mL) and N,N-diisopropylethylamine (87 uL, 0.50 mmol) were added to (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (47 mg, 0.16 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (75 mg, 0.20 mmol) in a 4 mL vial, and the mixture stirred at room temperature for 10 min, before a solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (55 mg, 0.19 mmol) in N-methylpyrrolidinone (0.5 mL) was added. After 30 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (50 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (br s, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.06 (d, J=11.7 Hz, 1H), 5.10 (app pentet, J=7.2 Hz, 1H), 3.00 (s, 3H), 2.93-2.76 (m, 4H), 2.68-2.59 (m, 1H), 2.25, (s, 3H), 2.09-2.03 (m, 1H), 1.88-1.76 (m, 1H), 1.54 (s, 3H), 1.35 (d, J=7.0 Hz, 3H); m/z=515.8 (M+H)+.