Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:7]=1.C(O)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.[Pd].C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C#CCCn2ccnn2)nn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: OCc1ccccc1
Product: Clc1ccc(CCCCn2ccnn2)nn1

Procedure:
3-Chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine (2.50 g, 10.7 mmol) is dissolved in ethyl acetate (450 ml) and hydrogenated for 3.5 h at r.t. in the presence of palladium on charcoal (10%, 2.50 g). The reaction mixture is filtered and concentrated in vacuo. The residue was dissolved in THF (10 ml) and added to a solution of benzyl alcohol (0.94 ml, 9.0 mmol) and sodium tert-butoxide (NaOtBu) (0.842 g, 8.76 mmol) in THF (80 ml). After stirring for 2 h ethyl acetate (100 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over Na2SO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate) 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is obtained as a colorless solid. Yield 1.14 g (45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[Cl:17].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:37][C:31]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:29][C:30]2[CH:40]=[CH:39][C:38]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:37][C:31]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])=[CH:10][C:9]=1[Cl:17]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1N
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2Cl)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Reaction time: 0.17 h

Procedure:
A solution of 1B (200 mg, 0.62 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. and treated with several drops of DMF. Oxalyl chloride was added dropwise over 10 minutes. The resulting solution was stirred for 10 minutes, and then concentrated to dryness. The resulting solid was dissolved in CH2Cl2 (10 mL) and treated with ethyl 2-amino-5-phenoxybenzoate (144 mg, 0.56 mmol) and diisopropylethylamine (130 μL, 0.74 mmol). The reaction was stirred at room temperature for 3 hours and then concentrated to afford 1C as a white solid.
Reaction SMILES: Br.[F:2][C:3]1[C:4]([CH3:14])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([OH:13])[CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23][O:24][CH3:25].O>CN1C(=O)CCC1.C1(C)C=CC=CC=1>[F:2][C:3]1[C:4]([CH3:14])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH2:22][CH2:23][O:24][CH3:25])[CH:7]=2
Reactant: Cc1nc2cc(O)ccc2cc1F
Reactant: COCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCOc1ccc2cc(F)c(C)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a suspension of 3-fluoro-2-methylquinolin-7-ol hydrobromide (0.37 g, 1.43 mmol) and Cs2CO3 (1.08 g, 3.31 mmol) in NMP (6 mL) was added 1-bromo-2-methoxyethane (0.230 g, 1.66 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. Water (10 mL) and toluene (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (2:1 hexane/ethyl acetate) to give 3-fluoro-7-(2-methoxyethoxy)-2-methylquinoline (0.234 g, 0.995 mmol, 90.1% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:53](Cl)(=[O:55])[CH3:54].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]([C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[C:53](=[O:55])[CH3:54])[CH3:2]
Reactant: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: CC(=O)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(C)=O)c1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-(3-(Ethylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 2, Step 2; 680 mg, 1.198 mmol) was dissolved in DCM (20 mL), charged with DIEA (0.42 mL, 2.396 mmol), and cooled to 0° C. Acetyl chloride (0.095 mL, 1.318 mmol) was added drop-wise and the reaction was warmed to room temperature and stirred for 1 h. The reaction was charged with TFA (2.3 mL, 30.0 mmol) and triethylsilane (0.20 mL, 1.198 mmol) and stirred for 1 h at room temperature. The solvents were removed in vacuo and the residue was treated with DCM (3 mL) and triethylamine (1 mL) and stirred for 15 min. The residue was purified by flash chromatography (2-10% MeOH/DCM w/NH3) to afford (R)—N-ethyl-N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. for C19H22N6O2 [M+1]+ 366. found 366.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(F)c1F
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(F)c1F
Reaction time: 8 h
Yield: 57.4 %

Procedure:
2-Aminobenzenesulfonamide (26 mg, 0.15 mmol) was dissolved in pyridine (1 ml) and 2,3-difluorophenylsulfonyl chloride (19 μl, 0.15 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (30 mg, 58%).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=3)[C:3]=2[O:15][CH2:16][O:17][CH3:18])=[CH:24][CH:25]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2ccc(F)cc2)c(C)cc2cc(OC)ccc12
Temperature: 160 °C
Yield: 84.2 %

Procedure:
2-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (2.00 g, 6.44 mmol), 3-fluorobenzeneboronic acid (1.80 g, 12.88 mmol), tetrakis(triphenylphosphino)palladium (0) (0.74 g, 0.64 mmol), 2 M sodium carbonate (60 mL) and ethylene glycol dimethyl ether (60 mL) were combined and heated in a sealed tube at 160° C. for 75 min. The reaction was cooled to room temperature and filtered through a celite pad with 100 mL each diethyl ether and water. The organic layer was washed with brine (100 mL), dried (Na2SO4) and concentrated to an orange viscous oil. The crude product was purified by column chromatography with 10% EtOAc/hexane to afford 1.77 g (84%) of the title compound, 283 as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 2.14 (s, 3H), 3.02 (s, 3H), 3.86 (s, 3H), 4.71 (s, 3H), 7.12-7.23 (m, 4H), 7.25 (d, J=2.5 Hz, 1H), 7.46-7.52 (m, 1H), 7.53 (s, 1H), 7.93 (d, J=9.2 Hz, 1H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=[O:16])[C:10]([OH:12])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=[O:16])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NC[C@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 83.3 %

Procedure:
To a mixture of 2-(S)-tert-butoxycarbonylamino-3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid (90 mg, 0.18 mmol) in CH2Cl2 (2 mL) was added TFA (0.5 mL). The resultant mixture was stirred at room temperature for 4 h. Reaction mixture was concentrated and residue was treated with water (80 mL). The pH value was adjusted to 9-10 by 1 N NaOH aq. Solution. Then it was acidified by 1 N HCl to pH=4-5. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 57 mg (0.15 mmol) in 81% yield. LC-MS ESI−: 391.08 (M−1)−.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Cl:15])O1.[Cl:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1I>>[Cl:17][C:18]1[C:19]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Cl:15])=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH2:24])[N:23]=1
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Reactant: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Product: Nc1nc(Cl)c(-c2ccncc2Cl)cc1[N+](=O)[O-]
Yield: 22 %

Procedure:
Following the same procedure as in Intermediate 1 (step a), but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-chloropyridine, 6-chloro-5-iodo-3-nitropyridin-2-amine (Intermediate 5—step a) was transformed into the title compound as a white solid (205 mg, 22%).
Reaction SMILES: C(O)(=[O:3])C.FC(F)(F)C(O)=O.[F:12][C:13]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:14]=1[C:15]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])=[O:28])=[CH:23][C:22]=1[F:35])=[O:19])=[O:16].OO>O>[F:12][C:13]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:14]=1[C:15]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])(=[O:3])=[O:28])=[CH:23][C:22]=1[F:35])=[O:19])=[O:16]
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F
Temperature: 90 °C

Procedure:
In a mixed solution consisting of 5 ml of acetic acid and 10 ml of trifluoroacetic acid was dissolved under heating 0.6 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)phenyl]urea, and 1.5 ml of 30% hydrogen peroxide aqueous solution was added to the solution, followed by heating at 90° C. for 2 hours. The reaction mixture was diluted with water, and the crystals which separated out were recovered by filtration, and washed with water and ethanol successively to give 0.6 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl]urea (Compound No. 6), m.p. of 176°-177° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([N:43](C)[C:44](=O)OC(C)(C)C)[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([NH:43][CH3:44])[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
TFA (0.5 mL, 6.49 mmol, Eq: 145) was added to a solution of tert-butyl (S)-(2S)-1-((2S)-1-(2-(2-benzoylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (28 mg, 44.6 μmol, Eq: 1.00) in DCM (0.5 mL) and the resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (1×10 mL) and the organic layer was concentrated in vacuo. The crude residue was treated with MeOH/DCM/ether to give (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-benzoyl-phenyl)-amide as an off-white solid (21 mg), m/z=528 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[C:16]([CH:18]3[CH2:20][CH:19]3B3OC(C)(C)C(C)(C)O3)[N:15]=[C:14]([CH3:30])[N:13]=2)[N:10]=[C:9]([CH3:31])[N:8]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][N:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[C:16]([CH:18]3[CH2:20][CH:19]3[C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][N:39]=3)[N:15]=[C:14]([CH3:30])[N:13]=2)[N:10]=[C:9]([CH3:31])[N:8]=1
Reactant: COc1ccc(Cc2nc(C)nn2-c2cc(C3CC3B3OC(C)(C)C(C)(C)O3)nc(C)n2)cc1OC
Reactant: Cc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cc2nc(C)nn2-c2cc(C3CC3c3ccc(C)cn3)nc(C)n2)cc1OC

Procedure:
A slurry of crude 4-(5-(3,4-dimethoxybenzyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyrimidine (3-2, 88 mg, 0.179 mmol, 1.0 eq), 2-bromo-5-methylpyridine (92 mg, 0.537 mmol, 3.0 eq.), cesium carbonate (233 mg, 0.716 mmol, 4.0 eq.), palladium(II) acetate (4.02 mg, 0.018 mmol, 0.10 eq.), and butyldi-1-adamantylphosphine (19.26 mg, 0.054 mmol, 0.30 eq.) in toluene (1 ml) and water (300 μL) was heated at 100° C. for 16 hours. The solvent was removed by roto-evaporation and the resulting oil was purified by reverse phase liquid chromatography (H2OCH3CN gradient w/ 0.1% NH4OH present) to afford 4-(5-(3,4-dimethoxybenzyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-(2-(5-methylpyridin-2-yl)cyclopropyl)pyrimidine (3-3) as slightly yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, 1H, J=2.0 Hz), 7.53 (s, 1H), 7.36 (dd, 1H, J=7.8, 2.2 Hz), 6.89 (d, 1H, J=2.0 Hz), 6.85 (dd, 1H, J=8.1, 2.2 Hz), 6.76 (d, 1H, J=8.1 Hz), 4.71 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 2.67 (bs, 4H), 2.62 (m, 1H), 2.42 (s, 3H), 2.29 (s, 3H), 1.84 (m, 2H). HRMS m/z (M+H) 495.1925 found, 495.1905 required.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[CH3:34][CH:35]([CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:36](O)=[O:37].C1(N=C=NC2CCCCC2)CCCCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>C(Cl)Cl.C1CCCCC1.C(Cl)Cl.C(OCC)C.C(OCC)C.C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:36](=[O:37])[CH:35]([CH3:34])[CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CCN1CCCCC1)C(=O)O
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)C(C)CCN3CCCCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reaction time: 16 h

Procedure:
2.0 g. (5.05 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine are combined with 1.12 g. (5.05 mm.) of α-methyl-γ-piperidino butyric acid hydrochloride and 1.08 g. (5.25 mm.) of dicyclohexylcarbodiimide in 110 ml. of methylene chloride and the mixture is stirred at room temperature for 16 hours. After cooling for 4 hours, the by-product of dicyclohexylurea is removed by suction filtration. The mother liquor is evaporated to give a colorless foamy residue which is dissolved in a methylene chloride/cyclohexane mixture and stored for 16 hours in the cold. A small amount of solid is separated by gravity filtration, and the solvents are removed using a rotary evaporator. The residue is dried to give a colorless solid which is dissolved in a mixture of methylene chloride/diethyl ether and converted to the dihydrochloride by the addition of a solution of hydrogen chloride is diethyl ether. The solvents are decanted, and the gummy residue crystallized upon trituration with diethyl ether. The solid is filtered and recrystallized from 20 ml. of methylene chloride/20 ml. diethyl ether to give the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C[O:10][C:11](=O)[C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:11](=[O:10])[C:12]([OH:25])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCC[C@H]1CO
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COC(=O)C(O)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
((S)-1-Methyl-pyrrolidin-2-yl)-methanol (2.38 ml, 20 mmol) and hydroxy-diphenyl-acetic acid methyl ester (7.27 g, 30 mmol) are suspended in toluene (20 ml). Molecular sieve 4A (3 g) is added and the suspension is heated under stirring to 80° C. Sodium (0.46 g, 20 mmol) is added and the reaction mixture stirred at 80° C. for 3 hours. The reaction mixture is cooled to room temperature, solid filtered off, and washed with toluene. The filtrate is washed once with saturated aqueous NaHCO3 solution (50 ml) and twice with aqueous HCl 1M (30 ml each). The combined acidic aqueous layers are adjusted to pH 8 with saturated aqueous NaHCO3 solution. The emulsion is extracted with ethyl acetate (50 ml). The combined ethyl acetate layers are dried over sodium sulphate, filtered off and evaporated to dryness to give the product as a yellow oil that crystallises on standing. (M+H)+:326.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[O:30]CC=C)=[C:11]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=3[S:16][C:12]2=[N:13][C:14]=1[CH3:15])[O:6][CH2:7][CH3:8])[CH3:2].CN1C(=O)CC(=O)N(C)C1=O>ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([O:6][CH2:7][CH3:8])[C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[OH:30])=[C:11]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=3[S:16][C:12]2=[N:13][C:14]=1[CH3:15])[CH3:2]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(OCC)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Yield: 95 %

Procedure:
To a stirred solution of [4-(2-Allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-ethoxy-acetic acid ethyl ester (22 mg, 46 μmols) in dichloromethane (3 mL) was added 1,3-dimethylbarbituric acid (38 mg, 240 μmols, 5 eq), and the reaction was evacuated and filled with nitrogen. Palladium tetrakis(triphenylphosphine) (1.2 mg, 2 mol %) was added and the reaction was heated to reflux for 16 hours. The reaction was concentrated in vacuo. The residue was purified using ISCO Companion with a Redisep silica gel 4 g cartridge and a gradient of heptane and ethyl acetate (0% to 40%). Fractions containing desired product were combined and concentrated in vacuo to give ethoxy-[4-(2-hydroxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-acetic acid ethyl ester as a pale yellow oil, 20 mg (95% yield). LC-MS (12 min acidic) 6.40 mins 58-69% pure by UV, ES+/APCI+ 440, ES−/APCI− 438; 6.66 mins 27-31% pure by UV, ES+/APCI+ 440, ES−/APCI− 438.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:16])[C:13](Cl)=[O:14])[CH3:10].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1)=[O:14])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
37.5 g (0.3 mol) of Thioanisol and 41.4 g (0.3 mol) of chloro-oxo-acetic acid ethyl ester dissolved in 200 ml of dichloromethane are added dropwise to a suspension of 60 g (0.45 mol) of aluminum trichloride in 350 ml of dichloromethane at 0° C. The solution is stirred overnight at room temperature and then heated to reflux for two hours. After cooling to room temperature, the reaction mixture is poured on a mixture of 100 ml conc. HCl and ice/water. After extraction with dichloromethane, the organic phase is washed with water and sodium bicarbonate and dried over magnesium sulfate. The salt is filtered off and the solvent distilled to give 52.3 g (78%) of (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester as a yellow oil. This oil is used for the next step without further purification. The structure is confirmed by the 1H-NMR spectrum (in CDCl3). δ[ppm]: 7.87 (d,2H), 7.24 (d,2H), 4.39 (q,2H), 2.48 (s,2H), 1.37 (t,3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[N:6][N:5]2[C:12]=1[S:13]([N:16]=CN(CC(C)C)CC(C)C)(=[O:15])=[O:14].O.N>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[N:6][N:5]2[C:12]=1[S:13]([NH2:16])(=[O:14])=[O:15]
Reactant: C#Cc1ccc2nc(Cl)c(S(=O)(=O)N=CN(CC(C)C)CC(C)C)n2n1
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: C#Cc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
N′-(2-Chloro-6-ethynylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine (792 mg, 2.00 mmol) was suspended in dioxane (10.0 mL), and 28% ammonia water (4.00 g, 65.8 mmol) was added dropwise to the suspension under stirring at room temperature. The mixture was stirred at room temperature for 3 days, then concentrated to remove ammonia, and adjusted to pH 1 with conc. hydrochloric acid. The reaction solution was diluted with water and extracted with ethyl acetate, and the extract was dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues were purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound as pale yellow crystals. The yield was 71 mg (13.8%).