Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C@H:32]([CH3:48])[C@@H:33]([O:39][C:40]([O:42][CH2:43][C:44]([Cl:47])([Cl:46])[Cl:45])=[O:41])[C@@H:34]([CH3:38])[CH2:35][CH:36]=[CH2:37])[C:3]([CH3:31])([CH3:30])[C@@H:4]([O:22][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[C@H:5]([CH3:21])[C:6](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:7].OO.[OH-].[Li+].S([O-])([O-])=[O:54].[Na+].[Na+]>C1COCC1.O.O>[O:1]=[C:2]([C@H:32]([CH3:48])[C@@H:33]([O:39][C:40]([O:42][CH2:43][C:44]([Cl:47])([Cl:46])[Cl:45])=[O:41])[C@@H:34]([CH3:38])[CH2:35][CH:36]=[CH2:37])[C:3]([CH3:30])([CH3:31])[C@@H:4]([O:22][Si:23]([CH2:28][CH3:29])([CH2:24][CH3:25])[CH2:26][CH3:27])[C@H:5]([CH3:21])[C:6]([OH:7])=[O:54]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)O
Reaction time: 1 h

Procedure:
A solution of (4S)-3 -[(2S,3S,6R,7S,8S)-5-oxo-3-(triethylsilyloxy)-2,4,4,6,8-pentamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoyl]-4-benzyloxazolidinone (21.5 g) in 125 mL of 4:1 THF/water is cooled on ice and treated with 10.2 mL of 30% H2O2 followed by a solution of lithium hydroxide (0.96 g) in 50 mL of water. After 1 hour, a solution of sodium sulfite (12.6 g) in 75 mL of water is added, and the mixture is adjusted to pH 3 and concentrated under vacuum. The resulting slurry is extracted with ethyl acetate. The extract is washed with brine, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:14][C:15]([C:17]1[C:18]([OH:34])=[C:19]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[C:20](=[O:24])[O:21][C:22]=1[CH3:23])=[O:16])[CH3:13]>C(OCC)(=O)C>[C:8]([O:34][C:18]1[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:22]([CH3:23])[O:21][C:20](=[O:24])[C:19]=1[C:25]1[C:26]([CH3:33])=[CH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31])(=[O:10])[CH3:9]
Reactant: CCOC(=O)c1c(C)oc(=O)c(-c2c(C)cc(C)cc2C)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)oc(=O)c(-c2c(C)cc(C)cc2C)c1OC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
1.0 g (10 mmol) of triethylamine and then 0.8 g (10 mmol) of acetyl chloride are added dropwise at 0° C. to 3.2 g (10 mmol) of 5-ethoxycarbonyl-4-hydroxy-6-methyl-3-(2,4,6-trimethylphenyl)pyrone in ml of ethyl acetate. The mixture is stirred for 20 hours at 20° C. and filtered, the organic phase is washed with semi-concentrated sodium chloride solution and dried over sodium sulphate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35-70 μm) using toluene/acetone (40:1 parts by volume). 2.9 g of 4-acetoxy-5-ethoxycarbonyl-6-methyl-3-(2,4,6-trimethylphenyl)pyrone are obtained (yield: 81% of theory). M.p.=107° to 109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][N:8]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ccccn2)cn1
Yield: 118.8 %

Procedure:
6-Methoxy-3-pyridylboronic acid (105 g), 2-bromopyridine (90 g), palladium acetate (3.21 g), triphenylphosphine (15 g), potassium carbonate (237 g), 1,2-dimethoxyethane (900 mL) and water (900 mL) were heated under reflux for 5 hours and 40 minutes under stirring. After cooling the reaction solution, ethyl acetate (1 L) was added thereto to extract. The organic layer was washed with 1 L of 10% aqueous solution of ammonium chloride, 1 L of 10% aqueous ammonia and 1 L of 10% saline, and then evaporated, to give 126 g (87%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[OH:21][CH:22]1[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]1.CC([O-])(C)C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:21][CH:22]2[CH2:25][CH:24]([C:26]#[N:27])[CH2:23]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: N#CC1CC(O)C1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CC(C#N)C3)nc(Cl)nc21
Temperature: 70 °C
Yield: 77 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 3-hydroxycyclobutanecarbonitrile (1.1 equiv), sodium 2-methylpropan-2-olate (1.2 equiv) and 1,4-dioxane (0.14 M) were combined in a sealable vessel with a stir bar. The resulting mixture was put under nitrogen atmosphere, sealed, stirred vigorously, and heated at 70° C. for 16 h. After cooling to room temperature, the reaction mixture was purified using silica gel chromatography (0 to 50% ethyl acetate in hexane) to give the title compound (77% yield). MS (ESI) m/z 505.0 [M+H]+.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9](Br)=[CH:8][CH:7]=[CH:6][C:5]=12.C([O:13][B:14](OCC)[O:15]CC)C.[Li]CCCC.[Cl-].[NH4+]>O1CCCC1.CCCCC>[N:1]1[O:2][N:3]=[C:4]2[C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOB(OCC)OCC
Reactant: Brc1cccc2nonc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2nonc12
Reaction time: 0.08 h
Yield: 32 %

Procedure:
To a solution of 4-benzo[c]furazanyl bromide (4 g, 0.020 mol) in tetrahydrofurane (80 ml) and n-pentane (20 ml) is added triethylborate (3.8 ml, 0.022 mol) and N,N,N,N-tetraethylendiamine (3 ml, 0.02 mol). Then, n-BuLi (8.8 ml, 2.5N in hexane, 0.022 mol) is added dropwise at -100° C. and the solution is stirred for 5 minutes more. The reaction mixture is poured into an aqueous solution of saturated ammonium chloride and the water phase is extracted with ethyl acetate. The organic solvent is removed and the crude product is taken up in dichloromethan/n-hexane (5:6). The suspension is filtered to yield the title compound (1.05 g) which is used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]3)=[CH:25][CH:26]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2c1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 6-bromo-2-naphthoate (150 mg, 0.57 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg, 0.68 mmol), and 2.0 M Na2CO3 (1.10 mL, aq) in dimethoxyethane (5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (14 mg, 0.02 mmol) and the mixture stirred at 70° C. for 20 min. The mixture was diluted with 25 mL of EtOAc then filtered through a plug of Celite and silica gel. The filtrate was washed with H2O, then brine, dried over Na2SO4, then concentrated and purified by silica gel chromatography (40 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give methyl 6-(4-hydroxyphenyl)-2-naphthoate as a beige solid (55 mg, 35%.) 1H NMR (DMSO-d6): 9.67 (s, 1H), 8.60 (s, 1 H), 8.17-8.13 (m, 2 H), 8.02 (d, J=9 Hz, 1 H), 7.95 (d, J=9 Hz, 1 H), 7.87 (d, J=9 Hz, 1H), 7.67 (d, J=8 Hz, 2H), 6.89 (d, J=8 Hz, 2H), 3.89 (s, 3H). ESI-LCMS m/z 279 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[S:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:9][CH2:8][C:7]2=[C:6]3[C:13](=[CH:12][CH:11]=[CH:10]2)[C:17]2[CH2:16][S:15][CH2:20][CH2:19][C:18]=2[N:5]3[CH2:4][CH2:3]1
Reactant: O=C1CCSCC1
Reactant: CN1CCc2ccccc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: O
Product: CN1CCc2cccc3c4c(n(c23)CC1)CCSC4
Temperature: 25 °C
Yield: 23.6 %

Procedure:
To a solution of 4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.50 g, 8.1 mmole) in 1-propanol (100 mL) was added tetrahydro-thiopyran-4-one (5.0 g, 43 mmole), followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole), and the resulting reaction mixture was refluxed for 40 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL), saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.52 g of the title compound as an off-white solid, mp 123-125° C., with a trace of ethyl acetate. MS (ESI) m/z 273 ([M+H]+).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30](O)([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with ethyl [4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (81%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.19 (m, 3H), 6.75 (d, 1H), 6.50-6.45 (m, 1H), 5.08 (s, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H), 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 433.3 (M+1).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=1[C:19]=34)[CH2:9]2)(=O)C.Cl.O.O1C2C=CC(C(O)=O)=CC=2C=CN1>C(O)C>[NH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=1[C:19]=34)[CH2:9]2
Reactant: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Agent: Cl
Agent: O=C(O)c1ccc2c(c1)C=CNO2
Solvent: CCO
Solvent: O
Product: CC1COc2c(N3Cc4ccc(CN)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
315 mg of 10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6carboxylic acid was added to a mixed solution of 12 ml of concentrated HCl, 2.5 ml of water, and 5 ml of ethanol, and the mixture was heated under reflux for 15 hours. After the mixture was concentrated under reduced pressure, the residue was recrystallized from ethanol to obtain 170 mg of 10-(5-aminomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4]-benzoxazine-6-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.S([O-])(O)(=O)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=CSc1ccc(OC)cc1)C(=O)OCC
Temperature: 166 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzenethiol (X-1; 5 g, 0.0357 mol), diethyl ethoxymethylene malonate (7.3 ml) and sodium hydrogen sulfate monohydrate (100 mg) were heated with stirring in an oil bath at 166° C. for 2 h. After cooling, ice water was added to the reaction mixture and extracted with ether. The crude product was purified by silica gel (250 g) and ethyl acetate/hexane (1:4) to give compound (XI-1) (5.7 g, 51%) as an oil. NMR(CDCl3):1.29(3H,t, J=7.1), 1.38(3H, t, J=7.1), 3.83(3H, s), 4.23(2H, q, J=7.1), 4.35(2H, q, J=7.1), 6.93, 7.45(4H, AB, J=8.8), 8.30(1H,s)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][N:21]=[C:22]2[N:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-c2ccncc2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccncc4)n3)cnc2n1
Yield: 46.7 %

Procedure:
6-Bromo-2,4′-bipyridine (0.34 g, 1.44 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-100%) and trituration with isohexane gave 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,4′-bipyridine (180 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.43 (1H, d, J 7), 7.77 (1H, d, J 8), 7.88-7.91 (3H, m), 7.98 (1H, dd, J 8 and 8), 8.59 (1H, s), 8.80-8.85 (1H, m), 10.51 (1H, d, J 7); m/z (ES+) 342 (M++M).
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[C:7](Cl)[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].C1(O)C=CC=CC=1.[OH-].[Na+]>[Pd].[H][H].O.C1(C)C=CC=CC=1.[Ta]>[Cl:9][C:8]1[CH:2]=[C:3]([CH:5]=[C:6]([Cl:11])[CH:7]=1)[NH2:4]
Reactant: [H][H]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Pd]
Agent: [Ta]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1

Procedure:
40 parts of 2,3,4,5-tetrachloroaniline, 150 parts of phenol and 12 g of a moist palladium/charcoal catalyst already used for this reaction (1% strength, 8 g dry) are mixed, and the mixture is stirred in a tantalum autoclave for 6 hours after forcing in hydrogen up to a total pressure of from 16 to a maximum of 18 bar at 165° C. After the pressurised vessel has been cooled and the pressure released, the reaction mixture is diluted with water, toluene is added, and the mixture is rendered alkaline with sodium hydroxide solution. The catalyst is separated off by filtering under suction. The toluene phase is distilled, and 27.7 parts (=99% of yield) of 98.5% strength 3,5-dichloroaniline are obtained.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2[C:15]3[C:16]([S:42][C:11]=2[CH2:10]1)=[N:17][C:18]([CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[C:19]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:20]=3[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>>[CH2:40]([N:37]([CH2:36][C:18]1[N:17]=[C:16]2[S:42][C:11]3[CH2:10][NH:9][CH2:14][CH2:13][C:12]=3[C:15]2=[C:20]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:19]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:38][CH3:39])[CH3:41]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)c1ccccc1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 69.5 %

Procedure:
A mixture of the compound obtained in Example 1A (4.02 g) and 3N HCl (12 ml) was stirred at 80° C. for 13.5 hours. After the reaction mixture was alkalinized with 1N NaOH, it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno-[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (2.30 g, 70%) as an amorphous solid having a melting point of 72 to 75° C.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:10]([OH:12])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1(N=C=N)CCCCC1.OC1C2N=NNC=2C=CC=1.[NH2:41][CH:42]1[CH:47]([OH:48])[CH2:46][CH2:45][CH2:44][CH:43]1[OH:49].C(O)C(N)(CO)CO>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:10](=[O:12])[NH:41][CH:42]2[CH:47]([OH:48])[CH2:46][CH2:45][CH2:44][CH:43]2[OH:49])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: NC1C(O)CCCC1O
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1
Agent: N=C=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C(NC1C(O)CCCC1O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
A mixture of (R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-amino]-propionic acid (0.352 g, 1.1 mmol) and N-cyclohexylcarbodiimide N′-methylpolystyrene (1.93 mmol/g, 1.03 g) in DCM (10 mL) was treated with hydroxybenzotriazole (0.27 g, 2 mmol). After stirring at room temperature for 5 minutes the mixture was treated with 2-amino-cyclohexane-1,3-diol (0.0.13 g, 1 mmol) and stirring was continued for a further 2 days. The reaction mixture was treated with PS Trisamine (3.75 mmol/g, 1.3 g) and after stirring at room temperature for 2 hours the resin was filtered off and washed with DCM. The combined filtrate plus washings were evaporated under reduced pressure to give morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-ethyl]-amide (0.32 g) as pale yellow thick oil. MS: 434 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[CH:7]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:25]([NH:24][CH:20]1[CH:21]([OH:23])[CH2:22][N:18]([C:11]2[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[CH:13][C:12]=2[F:17])[CH2:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C(NCc5ccccc5)C4)nc32)c(OC)c1
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 244A (0.049 g) in tetrahydrofuran (3 mL) at 25° C. was treated with a solution of lithium hydroxide monohydrate (0.048 g) in water (3 mL), stirred for 18 hours, concentrated, acidified with HCl (2N in diethyl ether), and filtered.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][N:20]=[C:19]([CH:31]([NH2:33])[CH3:32])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:33]([CH:31]([C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][N:20]=3)[CH3:32])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCC(F)(F)C(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)C(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (490 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.65 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (500 mg, 1.65 mmol, Amine-72, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[C:30]([OH:35])(=[O:34])[C:31]([CH3:33])=[O:32]>C(O)C.[Pd]>[C:30]([OH:35])(=[O:34])[C:31]([CH3:33])=[O:32].[C:30]([CH:31]([NH:11][C@H:12]([C:14]([N:16]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])[CH3:33])([OH:35])=[O:34]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2
Agent: [Pd]
Agent: CC(=O)C(=O)O
Solvent: CCO
Product: CC(N[C@@H](C)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of N-carbobenzoxy-L-alanyl-N-(5-indanyl)glycine (3.8 g, 9.59 mmol) and pyruvic acid (4.2 g, 47.9 mmol) in 200 ml ethanol was added 10% palladium on carbon (9.5 g). The mixture was hydrogenated at 50 psi for 4 h, filtered and concentrated in vacuo. The residue was dissolved in H2O and ethyl acetate. The aqueous layer was washed twice with ethyl acetate, once with ether, and lyophilized to provide the crystalline (m.p. 140° C. dec.) product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH3:15][C@@H:16]1[CH2:21][NH:20][C@@H:19]([CH3:22])[CH2:18][N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][C@@H:16]1[CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[C@@H:19]([CH3:22])[CH2:18][N:17]1[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 76 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.45 g, 20 mmol), (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (5.14, 24 mmol) and DIPEA (5.14 mL, 30.00 mmol) in DMF (40.0 mL) was heated at 125° C. for 2.5 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by MPLC silica chromatography, eluting with EtOAc. Product fractions were evaporated and triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford (2R,5S)-tert-butyl 2,5-dimethyl-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (6.09 g, 76%) as a white crystalline solid.