Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Ca+2].[C:6]1([C:12]2([CH2:17]C3SCCCS3)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C.O.C(OCC)(=O)C>[C:6]1([C:12]2([CH2:17][CH:1]=[O:4])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(C2(CC3SCCCS3)CCCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=CCC1(c2ccccc2)CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
263 mg (0.969 mmol) of mercuric chloride and 129 mg (1.29 mmol) of calcium carbonate were added to a suspension of 90 mg (0.323 mmol) of 2-(1-phenylcyclopentyl)methyl-1,3-dithiane [prepared as described in step (iv) above] in a mixture of 4 ml of acetonitrile and 0.6 ml of water, and the resulting mixture was stirred for 3 hours at 90° C. At the end of this time, the reaction mixture was cooled and then diluted with ethyl acetate. The insoluble materials were filtered off from the diluted mixture with the help of Celite (trade mark) filter aid. The filtrate was then washed with a 1M aqueous solution of sodium acetate, with a saturated aqueous solution of ammonium chloride and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 5 g of silica gel, using methylene chloride as the eluent, to give 58.4 mg (yield 96%) of the title compound as a foam-like material.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].C(N(CC)CC)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:19]1([C:18]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC1CCCCNC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1NCCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 125 g of α-amino-ε-caprolactam, 118 g of triethylamine and 600 ml of chloroform, 288 g of chlorotriphenylmethane was added under ice-cooling. The mixture was further stirred for an hour under the same conditions, followed by 2 hours' stirring at room temperature. Thus resulting precipitates were collected by filtration, washed thoroughly with acetone and dried to provide 330 g of α-triphenylmethylamino-ε-caprolactam, m.p. 240-241° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]=[CH:11][C:10]([C:13]([NH:22][C:23](=O)OC(C)(C)C)([CH3:21])[C:14](=O)[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1.O.[F-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[C:7]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:12]=[CH:11][C:10]([C:13]([NH:22][CH3:23])([CH3:21])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C(=O)N1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(C)(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
LAH (447 mg, 11.8 mmol) was added to a solution of 1,1-dimethylethyl [1-(4-biphenylyl)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]carbamate (580 mg, 1.47 mmol) in THF (20 ml) at 0° C. under argon. The resulting mixture was then refluxed for 2.5 h. The reaction mixture was then cooled in and ice bath and diluted with toluene (20 ml). Water (847 ul, 47 mmol) was added followed by NaF (1.48 g, 35.3 mmol) and the mixture was stirred at 0° C. for 30 min, filtered and the filter pad was washed with THF. The combined filtrates were concentrated to give 417 mg (96%) as a light brown oil. MS (ES) m/e 295.4 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[N+:36]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N+:48]([O-:50])=[O:49])[CH:47]=1)[C:42](Cl)=[O:43])([O-:38])=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[N+:36]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N+:48]([O-:50])=[O:49])[CH:47]=1)[C:42]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:43])([O-:38])=[O:37]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5cc([N+](=O)[O-])cc([N+](=O)[O-])c5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
20.00 g (51.7 mmol) of cholesterol, 2.88 g (25.75 mmol) of 4-dimethylaminopyridine, 6.27 g (62.04 mmol) of triethylamine are dissolved in 100 mL of dichloromethane. 11.92 g (51.7 mmol) of commercial 3,5-dinitrobenzoylchloride dissolved in 50 mL of dichloromethane are added at 0° C. The solution is stirred for 2 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallization from ethyl acetate:hexane mixture yielded 16.94 g (56%) of (3-β)-cholest-5-en-3-yl 3,5-dinitrobenzoate as yellowish crystals.
Reaction SMILES: [CH2:1]=O.[NH2:3][C@H:4]([C:15]([OH:17])=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+].Cl>O>[CH2:1]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Formaldehyde (37% aq. solution, 39.7 mL, 490 mmol) was added to a stirred solution of L-tryptophan (100.0 g, 490 mmol) in aqueous sodium hydroxide solution (19.6 g in 200 mL of H2O, 490 mmol) and stirred for 2 hr. The mixture was heated to reflux and stirred for 3.5 hr. The mixture was cooled to 50° C. and carefully acidified to pH 5-6 with 6.0 M HCl(aq) solution. The mixture was diluted with water (200 mL). The flask was removed from heat and cooled to room temperature. The precipitates filtered off and washed with water. The solids were resuspended in THF (800 mL), stirred at RT for 1 hr, and filtered to afford compound 1 (101.3 g, 95%) as beige solid. 1H NMR (300 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.88 (br s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.02 (t, 1H), 6.97 (t, 1H), 4.18 (q, 2H), 3.61-3.56 (m, 1H), 3.12 (dd, 1H), 2.83-2.75 (m, 1H); LC-MS [M+H+ 217].
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][N:38]([CH3:53])[CH2:39][CH2:40][N:41]([CH3:52])[C:42]1[S:43][C:44]2[CH:50]=[C:49]([NH2:51])[CH:48]=[CH:47][C:45]=2[N:46]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:37][N:38]([CH3:53])[CH2:39][CH2:40][N:41]([CH3:52])[C:42]1[S:43][C:44]2[CH:50]=[C:49]([NH:51][C:8](=[O:10])[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH:48]=[CH:47][C:45]=2[N:46]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)C=Cc3ccc(F)cc3)cc2s1
Yield: 11.3 %

Procedure:
Prepare according to Method A, using 4-fluorocinnamic acid (100 mg, 0.602 mmol), HATU (228 mg, 0.600 mmol), N2-(2-dimethylamino-ethyl)-N2-methyl-benzothiazole-2,6-diamine (100 mg, 0.400 mmol), DIEA (260 μL, 1.49 mmol), and a chromatography gradient of MeOH in CH2Cl2 (8-20%) to yield the title compound (18 mg, 11%). mass spectrum (m/e): 399.0 [M+H]. 1H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 8.30 (d, 1H, J=1.8 Hz), 7.72-7.66 (m, 2H), 7.57 (d, 1H, J=15.8 Hz), 7.50 (dd, 1H, J=8.8, 2.2 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.32-7.25 (m, 2H), 6.84 (d, 1H, J=15.8 Hz), 3.95 (dd, 2H, J=6.4, 6.4 Hz), 3.39-3.33 (m, 2H), 3.13 (s, 3H), 2.83 (s, 6H).
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:19])[C:10]([C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([CH3:19])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)C(C)C(=O)c1cccnc1F
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)[nH]c(-c2cccnc2F)c1C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of ethyl 2-cyano-4-(2-fluoropyridin-3-yl)-3-methyl-4-oxobutanoate (19.4 g) in ethyl acetate (20 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (90 mL), and the mixture was stirred for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as yellow crystals (yield 14.3 g, 69%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([O:22]C1CCCCO1)[CH2:17][CH2:16]2)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2].C(O)(=O)C.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([OH:22])[CH2:17][CH2:16]2)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2O
Temperature: 70 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
1.8 g of 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethane was added to 30 ml of a 4:2:1 mixed solution of acetic acid, tetrahydrofuran and water. The resulting mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled and added to a mixture of 100 ml of water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1) to obtain 1.0 g of oily 1-acetoxy-1-[(1-hydroxy)indan-5-yl]-2-[2-(N,N-dimethylamino)ethoxy]ethane (compound No. 296).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.CC1(O)CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C:24]([CH3:28])([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1(O)CCNC1
Agent: Cl
Product: CC1(O)CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methylpyrrolidin-3-ol hydrochloride and isolated as white solid (14.1 mg, 75%). MS(m/e): 401.4 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:28][C@@H:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH3:27])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(Cl)cc1
Temperature: 200 °C
Yield: 87.2 %

Procedure:
Two 20 mL microwave vials were charged with a half portion of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.50 g, 13.5 mmol), (R)-1-(4-chloro-phenyl)-ethylamine (4.20 g, 27.0 mmol), N,N-diisopropylethylamine (4.7 mL, 27 mmol) and acetonitrile (20 mL); and the mixture was heated in a microwave at 200° C. for 2.5 h. The mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL) and ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL), dried (Na2SO4), and concentrated. The residue was purified on silica gel column (0-5% MeOH/CH2Cl2) to give a pale yellow foam (4.46 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]([CH3:10])=[O:9])[CH2:3][CH2:2]1>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([CH3:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(=O)C=C1CCOCC1
Solvent: CCOC(C)=O
Product: CC(=O)CC1CCOCC1
Yield: 93.8 %

Procedure:
A solution of 1-tetrahydro-4H-pyran-4-ylideneacetone (4.0 g, 28.5 mmol) in ethyl acetate was added to a Parr vessel. The vessel was purged with nitrogen, and 10% palladium on carbon (400 mg) was added. The vessel was shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for approximately ten minutes, and the reaction mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was dried under a stream of nitrogen to provide 3.80 g of 1-tetrahydro-2H-pyran-4-ylacetone as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O.CCOC(C)=O>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:8][CH:7]=2)[CH:10]=1)=[O:22]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCN(C)CC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 5 %

Procedure:
To a stirred solution of 6-(4-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in dry DMF, 1-methylpiperazine (5 equiv.) was added at 0° C. and reaction mixture was stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography/preparative HPLC to give the desired compound (5% yield). LCMS: 528.25 (M+1)+; HPLC: 98.21% (@ 254 nm) (Rt; 4.802); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.94 (bs, 1H), 8.36 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.46 (d, J=7.6 Hz, 2H), 5.89 (s, 1H), 5.33-5.30 (m, 1H), 4.41 (d, J=4 Hz, 2H), 3.52 (s, 3H), 2.30-2.45 (m, 7H), 2.21 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.54 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([CH2:15][O:16]COC)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.O.C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCOCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: OCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
3-(3-Chloro-4-fluoro-phenyl)-5-methoxymethoxymethyl-pyridazine (0.06 g, 0.21 mmol) was dissolved in dioxane (2 ml) and treated with 1N HCl (0.2 ml, 0.2 mmol). The reaction mixture was refluxed for 1.5 hours then cooled to room temperature. Water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 1:1 then 2:8) to provide [6-(3-chloro-4-fluoro-phenyl)-pyridazin-4-yl]-methanol (13 mg, 26%) as a light yellow solid, MS: m/e=239.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=1[NH2:27])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CC(OC)(C)C>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=1[NH2:27])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: C=CCOC(=O)c1ccc(SC[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: C=CCOC(=O)c1ccc(SC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(N)c1
Reaction time: 48.5 h
Yield: 94.2 %

Procedure:
6.4 g (15.658 mmol) of N-tert-butoxycarbonyl-3-(4-alloxycarbonyl-2-aminophenylthio)-L-alanine methyl ester (99%) was dissolved in 480 ml TBME and emulsified in 1.5 L buffer solution (0.1M sodium chloride; 160 mM sodium phosphate pH 7.5) under vigorous stirring. 12.0 ml Alcalase 2.4 L [a subtilisin Carlsberg from Novo Nordisk] was added and the pH maintained at 7.5 under vigorous stirring by the controlled addition (pH-static) of 1.0N sodium hydroxide solution. After 48.5 h, 16.6 ml of 1.0N sodium hydroxide solution was consumed and the conversion degree was >97% (HPLC analysis). After phase separation, the aqueous phase was extracted once with 1 L TBME. The combined TBME phases were extracted with 2×0.4 L 0.1 M potassium phosphate buffer pH 7.6. The combined aqueous phases were acidified to pH 2 with 32% hydrochloric acid and extracted with 3×0.5 L ethyl acetate. In case a stabile emulsion was formed, the phase separation was achieved by filtration on Dicalite. The combined ethyl acetate phases were dried on anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane, evaporated and dried at HV to give 5.85 g N-tert-butoxycarbonyl-3-(4-alloxycarbonyl-2-aminophenylthio)-L-alanine as a yellow highly viscous oil (yield: 94.6%). Analytical data: 1H-NMR (DMSO, 400 MHz) 1.338 (s, 9H, OC(CH3)); 3.077 (dd, 1H, SCH2, J=12.8 Hz, J=6.8 Hz); 3.238 (dd, 1H, SCH2, J=13.8 Hz, J=4.6 Hz); 3.867 (m, 1H, COCHNH); 4.753 (d, 2H, COOCH2, J=5.2 Hz); 5.526 (d, 1H, CH═CH2, J=10 Hz); 5.538 (d, 1H, CH=CH2, J=17.6 Hz); 5.595 (m, 2H, NH2); 6.018(ddtr, 1H, CH2CH═CH2, J=16.6 Hz, J=10.6 Hz, J=5.6 Hz); 6.519 (m, 1H, CONHCH); 6.876 (d, 1H, arom. CSCH, J=8.4 Hz); 7.330 (d, 1H, arom. CSCHCH, J=8.4 Hz); 7.338 (s, 1H, arom. CHCNH2). IR (ATR-IR) 3420 and 3355 cm−1 (—NH, —NH2); 2980 and 2935 cm−1 broad (—COOH); 1705 cm−1 (COOH —C═O, carbamate —C═O); 1510 cm−1 (amide —CO—NH); 1486 cm−1 aromate; 1229 and 1160 cm−1 (COOH); 982 and 932 cm−1 (vinyl, —C═CH2). MS (ESI-positive ionisation) m/z=397.1 [M+H+]; m/z=419.4 [M+Na+]. OR [α]D=+16.16° (CHCl3; c=1.0). HPLC analysis: column: ABZ+plus; mobile phase: A: 0.1% TFA in H20; B: MeCN; gradient B: 30–80% 0–15 min, 80–30% 15–16 min, 30% 16–19.5 min; flow; 1 ml/min; pressure:50–80 bar; detection: UV, 300 nm; retention times: 11.2 min (product-acid); 12.7 min (substrate-ester).
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1>N.CO.[Ni]>[CH3:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2ccc(C)cc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc2c(c1)C(N)CCO2

Procedure:
A solution of Example 7A (4.24 g) in 20% ammonia in methanol (50 mL) was treated with Raney Nickel, 40 g, under hydrogen (60 psi) for 4 hours at ambient temperature. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue dissolved in diethyl ether which was washed sequentially with water and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.78-1.88 (m, 1H), 2.10-2.21 (m, 1H), 2.27 (s, 3H), 4.01 (m, 1H), 4.22 (m, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 7.11 (s, 1H). MS (DCI) m/z 164 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]([F:40])[C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH:33]([F:40])[C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36])[CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C(O)C(F)(F)C(F)Br
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4C(F)C(F)(F)C(=O)O)c3)no2)cc1Cl
Temperature: 140 °C
Reaction time: 10 h
Yield: 4.4 %

Procedure:
D5 (200 mg), Cs2CO3 (552 mg) and DMF (2.8 ml) were stirred at RT and treated with 3-bromo-2,2,3-trifluoropropanoic acid (175 mg). This mixture was heated at 140° C. for 1 hour in a microwave reactor. 2 further equivalents of Cs2CO3 (368 mg) were added and heating continued at 140° C. for 10 hours. The reaction mixture was then evaporated, treated with H2O, shaken and filtered to give a brown solid residue. This was purified by MDAP to give the title compound (12 mg) as a white solid. δH (methanol-d4, 400 MHz): 1.42 (6H, d), 4.83 (1H, septet), 6.87 (1H, d), 7.29 (1H, d), 7.45 (1H, d), 7.54 (1H, d), 7.61 (1H, d), 7.80 (1H, d), 8.06 (1H, d), 8.11 (1H, d), 8.19-8.22 (1H, m), 8.44 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[S:5][C:4]2[O:11][CH:12]=[CH:13][C:3]1=2.[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:8]([C:6]1[S:5][C:4]2[O:11][CH:12]=[CH:13][C:3]=2[C:2](=[O:1])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc(=O)c2ccoc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(=O)c2ccoc2s1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-oxo-4H-furano[2,3-b]thiopyran-6-carboxylic acid (9.9 g, 0.05 mol) in tetrahydrofuran (50 ml) was added carbonyldimidazole (8.9 g, 0.055 mol). The mixture was stirred at ambient temperature for 3/4 hr. Anhydrous dimethylamine was bubbled into the reaction mixture at 0° C. The reaction was stirred at 0° C. for 3/4 hr. and the solvents were evaporated in vacuo. The residue was treated with H2O (150 ml) and the solid that separated was collected and dried in vacuo.