Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:16][C:17](C)([O-:19])C.[K+].C([O-])(O)=O.[Na+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([O:19][CH2:17][CH3:16])[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1F
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.3 %

Procedure:
tert-Butyl 6-amino-2-fluoropyridine-3-carboxylate (0.7 g, 0.0033 mol) in EtOH (25 ml) was treated with potassium tert-butoxide (0.39 g, 0.0035mol) and the mixture was heated under reflux overnight. After cooling to room temperature, saturated NaHCO3 solution was added and the precipitated solid was collected by filtration and dried/n vacuo to give tert-butyl 6-amino-2-ethoxypyridine-3-carboxylate(0.6 g).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:36])=[C:7]([CH3:35])[C:8]2[O:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([NH:30][CH2:31][CH3:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)=[O:17])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:33]=1[CH3:34])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[OH:4][C:5]1[C:6]([CH3:36])=[C:7]([CH3:35])[C:8]2[O:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([NH:30][CH2:31][CH3:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)=[O:17])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:33]=1[CH3:34]
Reactant: CCNc1cccnc1N1CCN(C(=O)CC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cccnc1N1CCN(C(=O)CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)CC1
Reaction time: 3.5 h

Procedure:
A solution of 1-[[6-(acetyloxy)-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]acetyl]-4-[3-(ethylamino)-2-pyridinyl]-piperazine (EXAMPLE 68, 0.80 g) in methanol (20 ml) is mixed with potassium carbonate (10% aqueous, 1.5 ml) and stirred for 3.5 hr at 20°-25° under a nitrogen atmosphere. Then acetic acid (0.2 ml) is added and the solution is concentrated. The residue is partitioned between methylene chloride and potassium bicarbonate (1N). The organic extracts are combined and washed with water, dried over magnesium sulfate and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH:24]=[CH2:25]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH:24]=[CH2:23])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(NC2CCNCC2)cc1
Reactant: C=CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CCC(Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred mixture of 15 parts of N-(4-chlorophenyl)-4-piperidinamine, 12 parts of N,N-diethylethanamine in 130 parts of benzene is added dropwise a solution of 10.3 parts of 3-bromo-1-propene in 70 parts of benzene. Upon completion, the whole is stirred first for 20h.30 at room temperature and further for 40 minutes at reflux. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1,1'-oxybisethane and treated with activated charcoal. The latter is filtered off and the 1,1'-oxybisethane is evaporated again, yielding 2.9 parts of N-(4-chlorophenyl)-1-(2-propenyl)-4-piperidinamine; mp. 90° C.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:3]([O:5]CC)=[O:4].[OH-].[Na+:25].O.CO>C(OCC)(=O)C>[F:1][C:2]([F:23])([CH2:8][CH2:9][C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])[C:3]([O-:5])=[O:4].[Na+:25]
Reactant: CCOC(=O)C(F)(F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C([O-])C(F)(F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A mixture of ethyl 2,2,5,5,6,6,7,7,8,8,8-undecafluorooctanoate (46.4 g, 0.125 mol), sodium hydroxide (5.11 g, 0.128 mol), water (80 mL) and methanol (80 mL) was stirred at ambient temperature for 2 hr and at 50° C. for 2 hr. After cooling, ethyl acetate was added to extract the product. The organic layer was washed with brine and dried over magnesium sulfate, and then the solvent was removed in vacuo. After drying overnight under high vacuum, 44 g (96% yield) of sodium 2,2,5,5,6,6,7,7,8,8,8-undecafluorooctanoate was obtained as a white solid having a melting point of 155°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2.C(Cl)Cl.[I:20]I>C(OC(F)(F)F)(=O)C.[Ag].O>[I:20][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:11]2
Reactant: II
Reactant: COc1cccc2c1CC(NC(C)=O)CC2
Agent: [Ag]
Agent: CC(=O)OC(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(I)c2c1CC(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.19 g. (0.01 mol.) of N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl) acetamide and 2.21 g (0.01 mole) of silver trifluoromethyl acetate in 80 ml. of methylene chloride was added dropwise a solution of iodine (2.52 g.; 0.02 mole) in 80 ml. of methylene chloride. The reaction mixture was stirred for one hour at room temperature, filtered and evaporated to leave an oil to which 100 ml. of water was added. After 30 minutes the oil solidified. The crystals were collected, dried and recrystallized from ethanol to give N-(1,2,3,4-tetrahydro-5-iodo-8-methoxy-2-naphthalenyl) acetamide as a white solid m.p. 202°-3°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=[O:18])[C:8]=2[CH:19]=1)([O-])=O>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[NH:10][C:9](=[O:18])[C:8]=2[CH:19]=1
Reactant: O=C1Nc2ccccc2Sc2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)Nc1ccccc1S2
Yield: 65.8 %

Procedure:
2-Nitro-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.82 g) was dissolved in warm acetic acid (100 ml) and the resulting solution hydrogenated over Adam's catalyst (80 mg) for 3 hours at atmospheric pressure. The catalyst was filtered off and the solution evaporated to dryness. Recrystallisation of the residue from methanol gave the product as a greenish powder (0.48 g, m/s. M- =242).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([C:26]([OH:28])=[O:27])[C:7](=[O:25])[NH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14]([C@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)=[CH:13]2)[CH3:3].[C:29]([O-])(O)=O.[Na+].C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CC(O)=O>[CH2:2]([C:4]1[CH:5]=[C:6]([C:26]([OH:28])=[O:27])[C:7](=[O:25])[NH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14]([C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH3:29])=[CH:13]2)[CH3:3]
Reactant: O=C([O-])O
Reactant: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)cc([C@H]1CCCN1)n2C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)cc([C@H]1CCCN1C)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a suspension of (R)-5-ethyl-6-(1-methyl-2-(pyrrolidin-2-yl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride (59.1 mg, 0.15 mmol) in dichloroethane (2.0 mL) was added aqueous NaHCO3 (0.20 mL). Reaction mixture was stirred at room temperature for 10 min before solution of HCHO (37% aqueous, 50 μL, 0.67 mmol) was added followed by AcOH (˜0.20 mL) to pH˜3-4. Upon addition of NaBH(OAc)3 (150 mg, 0.70 mmol) reaction was stirred at room temperature for 1 h. Complete consumption of starting material was observed. Mixture was quenched with addition of solution of NaHCO3 (aqueous saturated, 2 mL) and product was extracted with DCM (3×5 mL). Organic phase was dried over Na2SO4 and solvent was concentrated. Residue was triturated with Et2O and solid was collected by filtration to afford (R)-5-ethyl-6-(1-methyl-2-(1-methylpyrrolidin-2-yl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (40.0 mg, 72%) as yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a solution of 1.0 g (4.4 mmol) of 1-Boc-4-(2-amino-phenyl)-piperazine and 1.1 mL (6.6 mmol) of triethylamine in 12 mL of DCM was added 0.63 mL (6.6 mmol) of ethanesulfonyl chloride, and the mixture was stirred at r.t. for about 16 hours. The mixture was diluted with ethyl acetate and washed once with 10% aqueous sodium bisulfate and then once with saturated aqueous sodium bicarbonate. The organic portion was dried (Na2SO4), filtered and concentrated in vacuo. Silica gel chromatography (3iotage, 40% ethyl acetate/hexanes) of the residue afforded about 0.73 g (45%) of the title compound. LRMS (ESI−): 368 (M−1)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[CH3:35])[CH:19]=[C:20]([C:25](=[O:27])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[CH3:35])[CH:19]=[C:20]([C:25](=[O:27])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12]1
Reactant: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CCN(C(=O)OCc3ccccc3)CC2)cc1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CCNCC2)cc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.5 %

Procedure:
5 ml of methanol was carefully added to 0.06 g of 5% by weight palladium carbon under ice cooling, and this mixture was stirred under a hydrogen atomosphere at room temperature for 20 minutes, followed by addition of a solution of 0.4 g of methyl 6-(1-benzyloxycarbonyl-4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate in 2 ml of methanol, and the mixture was subjected to hydrogenation under atmospheric pressure for 4 hours. After completion of the reaction, the palladium carbon was removed by filtration and the solvent was removed by distillation under reduced pressure to obtain 0.24 g of methyl 6-(4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 226°-228° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16]1)[CH3:2]>[Pt]>[CH2:1]([C:3]1[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16]2)=[CH:5][C:6]([O:12][CH2:13][CH3:14])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1N
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To 1-[2-ethyl-5-(ethyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (0.22 g, 0.57 mmol) in EtOAC (30 mL) was added platinum on carbon (sulfided) (0.11 g, 0.029 mmol). The mixture was stirred under H2 (1 atm) overnight. Filtering the mixture through Celite® and concentrating provided the title compound of Step C (0.21 g, 0.56 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ 6.55 (s, 1H), 6.44 (s, 1H), 4.29 (br. s., 2H), 3.91 (q, J=7.1 Hz, 2H), 3.02-3.21 (m, 2H), 2.94 (s, 3H), 2.78 (d, J=11.2 Hz, 2H), 2.37-2.59 (m, 6H), 1.57-1.77 (m, 3H), 1.34-1.49 (m, 1H), 1.18-1.34 (m, 4H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)[OH:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[N:24]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH:23]=1.O>O1CCCC1.C(#N)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:28]2[CH:29]=[C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH3:14])=[CH:23][N:24]([S:40]([C:43]4[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=4)(=[O:42])=[O:41])[C:25]3=[N:26][CH:27]=2)[N:7]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)C(O)c1cccc(Br)n1
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(O)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
In a microwave vial (6-bromo-pyridin-2-yl)-hydroxy-acetic acid methyl ester (430.9 mg, 1.75 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 1.75 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (20 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (143.0 mg, 0.18 mmol) was added and the vial sealed. This reaction mixture was heated to 80° C. for 30 minutes in a microwave reactor. 100 ml water was added and this mixture was extracted with ethyl acetate (3×) the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to yield hydroxy-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid methyl ester as a white solid (312 mg, 32% yield). MS: m/z 544.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[F:41])[NH2:37].C(N(CC)CC)C>ClCCCl.ClCCl.CN(C=O)C>[Br:33][C:34]1[CH:35]=[C:36]([NH:37][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:18])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(F)c(Br)c4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (0.214 g, 0.569 mmol) was dissolved in 1,2-dichloroethane (2 ml) and a drop of DMF was added. To the mixture was added oxalyl chloride (2M in dichloromethane) (0.313 ml, 0.626 mmol). Gas evolution was observed. The mixture was stirred for 2 hours at ambient temperature. A solution of 3-bromo-4-fluoroaniline (0.113 g, 0.597 mmol) and triethylamine (0.158 ml, 1.138 mmol) in dichloromethane (1 ml) was added to the acid chloride solution. The mixture was stirred for 0.5 hour and the crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 0.2656 g of the title compound as a white solid (85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH2:15][OH:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:15]=[O:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: COc1ncc(-c2ccncc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ncc(-c2ccncc2)cc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 103.5 %

Procedure:
321 mg of 5-(4-pyridinyl)-2-methoxy-3-pyridinemethanol was dissolved in 10 ml of chloroform, 1.6 g of manganese dioxide was added thereto, and the mixture was stirred at room temperature for 14 hours. After filtering through Celite, the filtrate was evaporated. The crude product was purified by silica gel chromatography (toluene:ethyl acetate=3:1), to give 329 mg of the title compound as a white powder.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:18]([CH3:19])=[CH:17][C:16](O)=[C:15]([C:21]#[N:22])[C:14]1=[O:23].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:3][C:16]1[CH:17]=[C:18]([CH3:19])[N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[Cl:6])[C:14](=[O:23])[C:15]=1[C:21]#[N:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C#N)c(=O)n1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (2.59 mL) was slowly added to N,N-dimethylformamide (17.8 mL) under ice-cooling, and the mixture was stirred for 15 min. To the reaction mixture was added a solution of 1-(2-chlorophenyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D (2.90 g) in N,N-dimethylformamide (4.50 mL) under ice-cooling, and the reaction mixture was heated overnight at 80° C. The reaction mixture was cooled to room temperature, and poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (2.50 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:9]([CH:22]([CH3:24])[CH3:23])[CH:8]=1)(=O)=O.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:10]1[CH:11]=[CH:12][C:7]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:8][C:9]=1[CH:22]([CH3:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 95 °C
Yield: 23.6 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 150, 970.0 mg, 2.35 mmols) in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15 minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09 mmol). The resulting reaction mixture was heated to 95° C. for 20 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound (200.0 mg, 78%) was isolated by chromatography (0-25% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl-].[CH:58]1[C:70]2[CH:69]([CH2:71][O:72][C:73]([NH:75][C@@H:76]3[C@@H:81]([NH3+:82])[C:80]([F:84])([F:83])[CH2:79][CH2:78][CH2:77]3)=[O:74])[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]=2[CH:61]=[CH:60][CH:59]=1>CN(C=O)C.O>[CH:58]1[C:70]2[CH:69]([CH2:71][O:72][C:73](=[O:74])[NH:75][C@H:76]3[CH2:77][CH2:78][CH2:79][C:80]([F:84])([F:83])[C@@H:81]3[NH:82][C:8]([C:6]3[S:7][C:3]([CH:2]([F:1])[F:20])=[C:4]([C:11]4[N:15]5[N:16]=[CH:17][CH:18]=[CH:19][C:14]5=[N:13][CH:12]=4)[CH:5]=3)=[O:10])[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]=2[CH:61]=[CH:60][CH:59]=1
Reactant: O=C(O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Reactant: [NH3+][C@@H]1[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.08 h

Procedure:
To 5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acid (26 mg, 0.088 mmol) in DMF (0.4 mL) were added BOP (58 mg, 0.13 mmol) and DIEA (0.062 mL, 0.35 mmol). The mixture was left to stir for 5 min, treated with (1R,6S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-difluorocyclohexanaminium chloride (36 mg, 0.088 mmol), and left to stir for 2 h. The mixture was diluted with water and extracted with EtOAc (×3). The combined organics were dried (sodium sulfate), concentrated, and purified by flash chromatography to afford 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate. LRMS (APCI) calc'd for (C33H28F4N5O3S) [M+H]+, 650.2. found 650.2.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[N:14][NH:15][CH:16]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[NH:14]1[CH:13]=[C:12]([C:11]2[C:5]3[C:6](=[N:7][CH:8]=[C:3]([OH:2])[CH:4]=3)[NH:9][CH:10]=2)[CH:16]=[N:15]1
Reactant: COc1cnc2[nH]cc(-c3cn[nH]c3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cnc2[nH]cc(-c3cn[nH]c3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a suspension of 35 (25 mg, 0.12 mmol) in CH2Cl2 (2.0 mL), cooled to 0° C., was added a 1M solution of BBr3 (467 μL, 0.48 mmol) in CH2Cl2 and the reaction mixture stirred for 2 h at room temperature. More CH2Cl2 (2.0 mL) and BBr3 (467 μL) was added at r.t. and the stirring continued for 65 h. The reaction mixture was partitioned between AcOEt and saturated aqueous NaHCO3 and the layers separated. The aqueous phase was extracted with more AcOEt (4×), the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give 36 as a white solid (9.1 mg, 39%); 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.90 (s, 2H), 9.05-9.20 (bs, 1H), 11.32 (bs, NH).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(F)cc2F)cc1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A mixture of 4-bromo-2-hydroxybenzaldehyde (7.5 g), (2,4-difluorophenyl)boronic acid (8.84 g), tris(dibenzylideneacetone)dipalladium (0) (1.367 g), 2M aqueous sodium carbonate solution (56.0 mL) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.53 g) in toluene (70 mL) was stirred at 100° C. under nitrogen atmosphere overnight. The mixture was diluted with ethyl acetate and water. The organic layer was separated and concentrated in vacuo. The residue was passed through a silica gel pad and concentrated in vacuo. The residue was crystallized from methanol-water (80 mL-20 mL) to give the title compound (8.50 g).