Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([NH:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN1CCOCC1.Cl.Cl.[NH:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][NH:34]/[C:33]/1=[N:42]\[C:43]([C:45]1[C:50]([NH2:51])=[N:49][C:48]([NH2:52])=[C:47]([Cl:53])[N:46]=1)=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:14]1([CH2:13][C@H:12]([NH:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])[C:20]([N:39]2[CH2:40][CH2:41][C:36]3([NH:32]/[C:33](=[N:42]/[C:43]([C:45]4[C:50]([NH2:51])=[N:49][C:48]([NH2:52])=[C:47]([Cl:53])[N:46]=4)=[O:44])/[NH:34][CH2:35]3)[CH2:37][CH2:38]2)=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of Tosyl-L-phenylalanine (1.0 g, 3.13 mmol) in DMF (25 ml) is added N-methyl morpholine (1.033 ml, 9.39 mmol) and 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (1.37 g, 3.44 mmol), followed by HATU (1.31 g, 3.44 mmol) and the resulting solution is stirred at room temperature for 20 minutes. The crude product is diluted with water (300 ml) and the resultant solid is isolated. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water−0.1% TFA) followed by catch and release resin (SCX-2) eluted with MeOH and 7M NH3 in MeOH yields a yellow solid which is triturated with MeOH and diethyl ether to give the title compound as a free base. The free base is stirred in 5M HCl at 100° C. for 30 minutes forming a gum. MeOH (5 ml) is added to the gum and then all solvent is removed in vacuo. The residue is triturated with MeOH and diethyl ether to give the title compound; [M+H]+ 626.4; 1H NMR (DMSO-d6): 1.12-1.71 (4H, m), 2.36-2.38 (3H, s), 2.59-2.83 (2H, m), 2.93-3.52 (4H, m), 3.41-3.60 (2H, m), 4.42 (1H, m), 7.12 (2H, d, J=6.9 Hz), 7.17-7.28 (3H, m), 7.35 (2H, d, J=7.7 Hz), 7.54-7.37 (2H, br), 7.57 (2H, d, J=7.7 Hz), 8.12 (1H, d, J=9.0 Hz), 7.70-8.26 (2H, br), 9.22 (1H, s), 9.95 (1H, s), 10.99 (1H, s).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:15](#[N:17])[CH3:16].O>CO.C(OCC)C>[O:9]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:15]#[N:17]
Reactant: CC#N
Reactant: CCOC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: N#CCC(=O)c1ccccc1
Temperature: 80 °C

Procedure:
Ethyl benzoate (20 g, 133 mmol) and NaOMe (133 mmol, from 3 g Na) in methanol was mixed and heated with stirring to 80° C. until a homogeneous gelatinous mass had formed. Acetonitrile (6.8 g, 165 mmol) was then added slowly under the surface of this mass over a period of 30 min. The temperature was raised to 120° C. and heated at reflux for 24 h, and the reaction mixture was then cooled on an ice bath and treated with water and diethyl ether until the solid material had dissolved. The aqueous layer was separated and acidified with 5% H2SO4, washed with NaHCO3 (aq; sat.), dried over sodium sulfate and concentrated. The crude product was used in the next reaction without any further purification. Yield: 7.3 g, 37.8%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH3:34])=[O:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:31]([O:33][CH3:34])=[O:32])([CH3:10])[CH3:9])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 850 mg of tert-butyl[2-(3-bromophenyl)propan-2-yl]carbamate in 8.5 ml of THF was added 4.1 ml of a 1.65 M n-butyllithium/hexane solution at −78° C., followed by stirring at the same temperature for 30 minutes. Then, 0.85 ml of methyl chloroformate was added dropwise thereto at −78° C., followed by stirring at the same temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 199 mg of methyl 3-{2-[(tert-butoxycarbonyl)amino]propan-2-yl}benzoate.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)([O:3]C)=[O:2].[OH-].[K+].CO>O1CCCC1.O>[C:1]([C:5]1[CH:13]=[C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)([OH:3])=[O:2]
Reactant: CCCCCCCCCC(=O)Nc1cc(C(=O)OC)c2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCC(=O)Nc1cc(C(=O)O)c2cc[nH]c2c1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
Five hundred-fifteen mg of 4-carbomethoxy-6-(N-decanoylamino)indole [prepared by the method of Wender et al., PNAS, 83: 4214-4218 (1986)] was dissolved in 60 mL of tetrahydrofuran. This solution was treated with 3 mL of a 1N KOH solution in water and also with 5 mL of methanol. The mixture was heated at 80° C. for 32 h. During this period another 2.5 mL of 1N KOH was added in two portions. After cooling the mixture was concentrated in vacuo. The mixture was then diluted with water and acidified with concentrated hydrochloric acid. The mixture was then extracted with methylene chloride. The organic layers were dried over sodium sulfate and concentrated to afford 300 mg of 4-carboxy-6-(N-decanoylamino)indole (60% yield), mp 248°-50° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][CH2:7][C:8](=[O:15])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[C:18]([CH:25]=O)=[CH:17]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:16]1[C:24]2=[N:23][CH:22]=[CH:21][CH:20]=[C:19]2[C:18]([CH:25]=[C:7]2[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]2=[O:15])=[CH:17]1
Reactant: CCOC(=O)C1=C(NC(C)C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NC(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of ethyl 2-(isopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.3 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.34 g, 2.3 mmol) in ethanol (15 mL), L-proline (0.027 g, 0.23 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.45 g, y. 56%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@:24]([OH:28])([CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][C@@:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:37]3[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][CH:38]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Reactant: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccnn2COCC[Si](C)(C)C)C1

Procedure:
(S)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 13.2, 60 mg, 0.130 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (85 mg, 0.261 mmol), Pd(PPh3)2Cl2 (10.98 mg, 0.016 mmol), Na2CO3 (55.3 mg, 0.521 mmol), DME (553 μL), water (158 μL) and EtOH (79 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 54.3 mg, 0.078 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc, from 10% to 60% EtOAc) to yield the title compound as a colorless oil. UPLC-MS (Condition 3) tR=1.26 min, m/z=578.3 [M+H]+, m/z=622.3 [M+formic acid-H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12](/[CH:14]=[C:15](/[N+:17]([O-:19])=[O:18])\[CH3:16])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].COC1C=C(C=C([N+]([O-])=O)C)C=CC=1OCC(O)=O.O.C(=O)(O)[O-].[Na+:44]>>[CH3:1][O:2][C:3]1[CH:13]=[C:12](/[CH:14]=[C:15](/[N+:17]([O-:19])=[O:18])\[CH3:16])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([O-:9])=[O:8].[Na+:44]
Reactant: COc1cc(/C=C(\C)[N+](=O)[O-])ccc1OCC(=O)O
Agent: COc1cc(C=C(C)[N+](=O)[O-])ccc1OCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(/C=C(\C)[N+](=O)[O-])ccc1OCC(=O)[O-]

Procedure:
One gram of (E) [2-methoxy-4-(2-nitro-1-propenyl) phenoxy]acetic acid is dissolved in 35.6 ml of 0.1N sodium bicarbonate and sufficient isotonic buffer to make a final volume of 100 ml. The water from all souces was pyrogen free. The solution is sterilized by filtration. This solution is 3.56 mM in active antisickling agent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]Br)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc(CBr)cc1C(C)(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1c(C(C)(C)C)cc(COc2ccc(C=O)cc2)cc1C(C)(C)C
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere 1,3-di(t-butyl)-2-methoxy-5-bromomethylbenzene (6.26 g, 20 mmol) is then reacted with 4-hydroxybenzaldehyde (2.44 g, 20 mmol) and potassium carbonate (3.04 g) in 140 ml of methyl ethyl ketone. The reaction mixture is heated to reflux and maintained at this temperature for about 18 hours at which time the reaction mixture is cooled. The inorganics are removed by filtration and the filtrate is concentrated in vacuo. The concentrated reaction products are purified by silica gel chromatography to yield 5.8 grams (81%) of 4-[[3,5-di(t-butyl)-4-methoxyphenyl]methoxy]benzaldehyde.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20]O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:26][C:25]([F:27])([F:28])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:1])[F:29])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20][N:35]2[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]2=[O:36])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)isochroman-1-yl)ethanol (100 mg, 0.230 mmol), phthalimide (50.8 mg, 0.345 mmol), and tetrahydrofuran (2 mL) at 0° C. was added diethylazodicarboxylate (0.055 mL, 0.345 mmol) dropwise. The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate (2×) which was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (8%-->12% EtOAc/Hex) gave 105 mg (81%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.55-7.80 (m, 7H), 7.12 (d, J=7.6 Hz, 1H), 7.01 (m, 3H), 4.66 (qAB, JAB=13.1 Hz, 2H), 4.03 (m, 2H), 3.74 (m, 2H), 3.72 (qAB, JAB=10.4 Hz, 2H), 3.02 (m, 1H), 2.66 (m, 1H), 2.30-2.50 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 168.2, 141.2, 136.6, 134.9, 133.7, 132.2, 131.7 (q, J=33.6 Hz), 129.2, 127.4, 126.8, 126.3, 125.5, 123.4 (q, J=273 Hz), 123.0, 121.5, 77.4, 76.1, 72.2, 60.4, 35.5, 33.5, 29.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[N:16][N:17]=[C:13]3[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][CH:4]=1)#[N:2].[Br:34]Br>C(Cl)(Cl)Cl>[Br:34][CH2:28][C:11]1[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:13]2[N:14]([N:15]=[N:16][N:17]=2)[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: BrBr
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (30 mg, 66.1 μmol; Example 70) was dissolved in chloroform (1 ml), and a solution of bromine (3×11.6 mg, 3×72.6 μmol, 3.3 eq.) in chloroform was added a little at a time at 0° C. The mixture was then stirred for 12 h, during which time it slowly warmed to RT. The mixture was then diluted with chloroform and washed with 10% strength sodium thiosulfate solution. The organic phase was separated off, dried over sodium sulfate and, after filtration, concentrated on a rotary evaporator. The crude product was reacted further without further purification (35.3 mg, 87% pure according to LC-MS, 87% of theory).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1ccc(Oc2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(4-fluorophenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(4-fluorophenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22](=[O:28])[NH:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:27][C:25]1[CH:26]=[C:21]2[C:22](=[N:23][CH:24]=1)[O:28][CH2:2][CH2:3][NH:4][C:5](=[O:6])[C:7]1=[C:11]3[N:12]=[C:13]([CH:14]=[CH:15][N:10]3[N:9]=[CH:8]1)[N:16]1[C@@H:17]2[CH2:18][CH2:19][CH2:20]1
Reactant: O=C(NCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 85 °C
Yield: 24.3 %

Procedure:
A suspension of (R)-N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (78 mg, 0.19 mmol) and Cs2CO3 (314 mg, 0.96 mmol) in DMF (5 mL) was heated at 85° C. for 30 minutes. After filtering through a GF/F paper the reaction was diluted with water (40 mL) and NH4Cl (saturated, 5 mL), then extracted with EtOAc (3×40 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system C-18 12+M column, 0 to 73% acetonitrile/water), to provide the title product as a white solid (17 mg, 24% yield). MS (apci) m/z=369.2 (M+H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[N+]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-])=O>CC1C=CC=CC=1C>[CH:1]([NH:4][C:15]1[C:14]2[C:13](=[O:23])[C:12]3[C:21](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:20](=[O:22])[C:19]=2[CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: CC(C)Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
384 g of isopropylamine and 1,390 g of o-xylene are initially introduced into a stainless steel autoclave, which has a capacity of 5 l and is fitted with a stirrer and steam jacket heating, and are heated to 165° C. A suspension of 543 g of 1-nitroanthraquinone with a purity of 98.4% by weight in 815 g of o-xylene is injected into the autoclave in the course of 20 minutes (molar ratio 3:1). During the addition the pressure rises from 10 to 40 bars and the temperature rises from 165 to 170° C. The reaction has ended after a further 30 minutes at 170° C. After cooling and letting-down, the residual solution is evaporated. 548 g of 1-isopropylaminoanthraquinone with a purity of more than 98% are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:34](O)=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][C:34]3[C:33]([F:36])=[C:32]([F:37])[C:31]([F:38])=[C:30]([F:39])[C:29]=3[F:28])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)co2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (315 mg), pentafluorophenol (0.10 mL) and triethylamine (0.23 mL) in DMF (4.1 mL) was added HATU (371 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:30])[C:21]4[C:26]([CH2:27]O)=[CH:25][C:24]([Cl:29])=[CH:23][N:22]=4)[CH:15]=[CH:16][C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2.COCCN(S(F)(F)F)CCOC.C(=O)(O)[O-]>C(Cl)Cl.C1COCC1>[NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([N:19]4[CH2:27][C:26]5[C:21](=[N:22][CH:23]=[C:24]([Cl:29])[CH:25]=5)[C:20]4=[O:30])[CH:15]=[CH:16][C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2
Reactant: NC1=N[C@@](c2cc(NC(=O)c3ncc(Cl)cc3CO)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC1=N[C@@](c2cc(N3Cc4cc(Cl)cnc4C3=O)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-3-(hydroxymethyl)picolinamide (Example 420, 60 mg, 0.136 mmol) in DCM (2 mL) was cooled 0° C. under nitrogen atmosphere. A solution of Deoxo-fluor, (50 w % in THF, 0.150 mL, 0.408 mmol) was added dropwise and the reaction mixture was allowed to stir at rt for 25 min. The reaction mixture was poured into aqueous saturated bicarbonate solution and extracted with EtOAc. The crude material was absorbed onto a plug of silica gel and purified by chromatography, eluting with a gradient of 20% to 100% EtOAc in hexane, to provide the title compound as white solid. MS m/z=423 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][C:33]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=4[O:31][CH3:30])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.1 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2,5-dimethoxybenzaldehyde (631 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (8042 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (290 mg) as yellow oil.