Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.[H-].[Na+].[CH3:18]I.[OH-].[Na+]>CN(C)C=O.O.CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:18])[C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CI
Reactant: CCOC(=O)c1cc2cccc(Br)c2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(=O)O)cc2cccc(Br)c21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7.37 g ethyl 7-bromo-1H-indole-2-carboxylate are dissolved in 50 ml N,N-dimethylformamide, cooled to 0° C. and combined with 1.16 g sodium hydride (60% in mineral oil). The mixture is stirred for 20 minutes and then 1.78 ml methyl iodide are added dropwise. Then the mixture is allowed to come up to ambient temperature and stirred for 12 hours. Then 80 ml of methanol and 27.5 ml 2 N sodium hydroxide solution are added and the mixture is stirred for 3 hours at ambient temperature. The methanol is eliminated in vacuo, the residue is mixed with water and the precipitate is suction filtered. The filtrate is washed twice with ethyl acetate and the aqueous phase is combined with sufficient 2 N hydrochloric acid to give a pH of 2. The precipitated solid is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH2:28]([Mg]Cl)[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:20])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: CC(C)(C)C[Mg]Cl
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(CC(C)(C)C)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Neopentylmagnesium chloride (1.0 M, 0.55 mL, 0.55 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give 1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-3,3-dimethyl-1-(pyridin-2-yl)butan-1-ol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 4.0 M HCl/dioxane and heated to 65° C. for 2 hours, concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[NH2:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])=[C:14]([CH2:17][O:18][CH3:19])[CH2:15][S:16][C@H:11]12.C(N(CC)C1C=CC=CC=1)C>C(Cl)Cl>[Br:7][CH2:6][C:2]([CH2:3][C:4]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])=[O:21])=[C:14]([CH2:17][O:18][CH3:19])[CH2:15][S:16][C@H:11]12)=[O:5])=[O:1]
Reactant: C=C1CC(=O)O1
Reactant: BrBr
Reactant: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
168 mg of diketene were dissolved in 2 ml of methylene chloride and, whilst stirring the solution, it was cooled to -30° C. To the solution was then added dropwise a solution of 320 mg of bromine in 2 ml of methylene chloride, and the resulting mixture was added dropwise to a solution of 322 mg of pivaloyloxymethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate and 299 mg of N,N-diethylaniline in 5 ml of methylene chloride, which had been cooled to -5° C. The mixture was left to stand for 30 minutes, after which it was concentrated by evaporation under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, washed, in turn, with 5 ml each of water, 5% w/v aqueous hydrochloric acid and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulphate. The drying agent was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was chromatographed through a column containing 30 g of silica gel, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to give 288 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NC1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-piperidinylamine (5 g, 26.1 mmol), 2-(4-fluorophenyl)acetic acid (4 g, 26 mmol), 1-hydroxybenzotriazole monohydrate (3.89 g, 28.6 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (6 g, 31.2 mmol) and triethylamine (4.4 ml, 31.2 mmol) were stirred together for 18 hours in dichloromethane (250 ml). The mixture was evaporated under reduced pressure and the residue dissolved in ethyl acetate before washing with water (x3). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 9 g.
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][O:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[O:15]1[CH2:16][CH2:17][O:18][CH2:19][CH:14]1[C:13]1[C:7]2[S:6][C:5]([NH2:4])=[N:9][C:8]=2[C:10]([O:20][CH3:21])=[CH:11][CH:12]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc(C2COCCO2)c2sc(N)nc12
Temperature: 100 °C
Yield: 73.1 %

Procedure:
To a stirred solution of 1.10 g (3.39 mmol) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 50 ml dioxane and 50 ml ethylene glycol was added 100 ml of a 5 N aq. sodium hydroxide solution and the mixture was heated at 100° C. for 16 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulfate and concentrated in vacuo. Trituration in methanol afforded 0.66 g (73%) (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 267 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC=CC1C=CC=CC=1)[CH2:5]2.C(O)C>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CN(CC=Cc1ccccc1)C2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(c1)CNC2=O

Procedure:
5-Methyl-2-(phenyl-allyl)-2,3-dihydro-isoindol-1-one (3.64 g, 14.61 mmol) was taken up in a 50/50 mixture of ethanol-3M HCl (100 mL) and heated to 80EC for 12 h. The reaction mixture was cooled and the ethanol was removed under reduced pressure. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (1:1 hexane/ethyl acetate) Yield 1.40 g. 1H NMR (CDCl3, 300 MHz): δ 2.51 (s, 3H), 4.48 9s, 2H), 7.27-7.36 (m, 2H), 7.75 (d, J=8 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:19][C:20]1[C:21]([N:31]2[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]2)=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:25]2[CH:24]=[C:23]3[C:28]([CH:29]=[C:20]([O:19][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:21]([N:31]4[S:35](=[O:36])(=[O:37])[NH:34][C:33](=[O:38])[CH2:32]4)=[CH:22]3)=[CH:27][CH:26]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: NCc1cccc(B(O)O)c1
Product: NCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1

Procedure:
5-[7-(3-Aminomethylphenyl)-3-benzyloxynaphthalen-2-yl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one is prepared according to the general procedure outlined in Example 4, step A, starting with (3-aminomethylphenyl)boronic acid and 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one: (M−H)−=472.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][CH:6]1O)(=[O:3])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][CH:6]1[F:27])(=[O:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(F)[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
(2,3,4-Tri-O-acetyl)-L-fucopyranose (13.1 g) is dissolved in methylene chloride (100 ml), and thereto is added with stirring DAST (10.9 g) under ice-cooling, and the mixture is stirred for 4 hours under ice-cooling. The reaction mixture is poured into ice-water (200 g), and the mixture is separated. The organic layer is dried, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:4→1:2) to give (2,3,4-tri-O-acetyl)-L-fucopyranosyl fluoride (10.6 g) in the form of a mixture of α-anomer and β-anomer.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[CH3:21][C:20]1[C:16]([C:13]2[S:12][C:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][C:33](=[O:35])[CH3:34])[CH2:4]3)=[O:10])=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](N)C3)s2)noc1C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reaction time: 48 h
Yield: 82.2 %

Procedure:
A suspension of ((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (70 μL, 0.5 mmol) followed by acetyl chloride (22 μL, 0.3 mmol). The reaction mixture was allowed to stir 48 hr, evaporated and chromatographed on silica gel with EtOAc then MeOH/EtOAc (10%) as eluant to afford product as a colorless solid (66 mg, 83%). 1H NMR (CDCl3) 1.65 (m, 2 H), 1.81 (m, 1 H), 1.95 (s, 3 H), 2.00 (obs m, 1 H), 2.33 (d, J=1.3, 3 H), 3.30 (m, 2 H), 3.98 (m, 2 H), 4.10 (br d, J=11.0, 1 H), 6.10 (br d, J=6.6, 1 H), 7.43 (d, J=4.0, 1 H), 7.49 (br s, 1 H). 13C NMR 7.9, 23.5, 30.1, 46.5, 51.0 (br), 114.8, 118.7 (q, J=271), 128.3, 129.7, 131.7, 140.1, 155.2 (J=40), 157.9, 163.3, 170.3 19F NMR −63.1. LC/MS 5.72 min, [M+1]+ 402.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH:10]=[O:11])[CH:4]=[N:3]1.[OH-:12].[K+]>CO.[Ag-]=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=[N:3]1
Reactant: Cn1ncc(C=O)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: O=[Ag-]
Agent: [K+]
Solvent: CO
Product: Cn1ncc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 1-methyl-5-nitro-1H-pyrazole-4-carbaldehyde (0.42 g, 2.8 mmol) in methanol (5 mL) was treated with silver (I) oxide (1.29 g, 5.6 mmol) followed by 5N potassium hydroxide (1.5 mL) in 5 mL of methanol and then refluxed for 16 hours. The mixture was cooled to room temperature and quenched with concentrated HCl (8 mL) and ethyl acetate. The mixture was filtered through a layer of celite and concentrated to give crude 1-methyl-5-nitro-1H-pyrazole-4-carboxylic acid: 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 4.22 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=5)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:32][C:27]1[CH:26]=[C:25]([NH:24][C:23]2[N:22]=[CH:21][N:20]=[C:18]3[S:19][C:12]4[C:11]5[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[C:16]=5[CH2:15][CH2:14][C:13]=4[C:17]=23)[CH:30]=[CH:29][C:28]=1[F:31]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCN2CCNCC2)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl}ethyl methanesulfonate (80 mg, 0.1 mmol), piperazine (25.1 mg, 0.29 mmol) and diisopropylethylamine (25 mg, 0.19 mmol) were mixed in 2 mL DMF. The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was concentrated under reduced pressure and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product N-(3-chloro-4-fluorophenyl)-3-(2-piperazin-1-ylethyl)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (18.8 mg, 40%). 1H-NMR (DMSO-d6) δ 8.65 (broad s, 1H), 8.30 (s, 1H), 7.86 (dd, 1H), 7.60 (s, 1H), 7.56 (m, 1H), 7.35 (t, 1H), 4.19 (t, 2H), 4.34 (t, 2H), 3.20 (broad, 1H), 3.08 (t, 2H), 2.62 (m, 6H), 2.31 (m, 4H). LCMS RT=2.35 min, [M+H]+=484.1
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:6]([Cl:32])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH3:22])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[OH-].[Na+].CCOCC.Cl>C1COCC1>[Cl:32][C:6]1[C:5]([CH2:4][C:3]([OH:33])=[O:2])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH3:22])=[CH:17][CH:16]=2)[N:7]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc1N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(N(C)C(=O)c3ccc(Cl)cc3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
This crude methyl[4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]benzyl}-6-(dimethyl-amino)pyrimidin-5-yl]acetate was dissolved in THF (3 mL) and treated with 1N NaOH (2 mL) and stirred at room temperature for 24 hour. Et2O was added and the organic phase was siphoned off. The remaining aqueous layer was acidified with 6N HCl to pH˜5 and the separated solids were collected by suction and rinsed with water and diisopropyl ether. Drying under high vacuum at room temperature for 4 hours then gave [4-chloro-2-{4-[(4-chlorobenzoyl)(methyl)amino]-benzyl}-6-(dimethylamino)pyrimidin-5-yl]acetic acid (0.029 g, 27% yield) as a pale yellow powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 100 %

Procedure:
1-(tert-Butoxycarbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (14) (6.77 g; 14.1 mmol) is dissolved in methylene chloride (60 mL) at ambient temperature. Trifluoroacetic acid (40 mL) is added in a slow stream, and the solution is stirred for 1.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (300 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×100 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (5.34 g) as a white solid. ESMS: MH+ 379.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH2:17][CH2:18][CH3:19])[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)C(=O)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCc1c(-c2ccc(Cl)cc2)n[nH]c1-c1cccs1
Yield: 94.1 %

Procedure:
1-(4-Chlorophenyl)-2-propyl-3-(2-thienyl)-1,3-propanedione (1.4 g, 4.6 mM) was dissolved in ethanol (50 ml), and hydrazine hydrate (343 mg, 6.9 mM) was added thereto. This mixture was heated under reflux for 3 hours. After the mixture was allowed to cool, the solvent was distilled off under reduced pressure. The resulting precipitate was filtered while being washed with a solvent mixture composed of hexane and ether to obtain 1.3 g (4.3 mM) of 3-(4-chlorophenyl)-4-propyl-5-(2-thienyl)-1H-pyrazole, m.p. 129-132° C., in a 94% yield.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.COC([N:14]([C:29]1[C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]2[C:32]([CH:33]3[CH2:43][CH:34]3[CH2:35][O:36]2)=[CH:31][CH:30]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1/[CH:25]=[CH:26]\[CH2:27]O)(=[O:17])=[O:16])=O.[CH:44]([N:47](C(C)C)CC)(C)[CH3:45].C(N)C>C(Cl)Cl.O>[CH2:44]([NH:47][CH2:27]/[CH:26]=[CH:25]\[C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[S:15]([NH:14][C:29]1[C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]2[C:32]([CH:33]3[CH2:43][CH:34]3[CH2:35][O:36]2)=[CH:31][CH:30]=1)(=[O:17])=[O:16])[CH3:45]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: O
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reaction time: 2 h
Yield: 56.5 %

Procedure:
Methane sulfonic anhydride (0.09 g) was added to a stirred, cooled mixture of methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64, 0.17 g) and N,N-di-isopropyl-N-ethylamine (0.134 g) in DCM (10 mL) at 0° C. The temperature was allowed to rise to room temperature and the mixture was stirred for 2 hours. A solution of ethylamine (2M in toluene, 2 mL) was added and the resultant mixture was stirred at room temperature for 3 hours then diluted with water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give methyl (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.09 g) as a white solid.
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(F)ccc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cc(F)ccc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B79) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (304 mg) in DCM/DMF (15 ml/2 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and twice by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]2)=[CH:6][CH:5]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(-c2ccc(OC(F)(F)F)cc2)n1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 2-(4-(trifluoromethoxy)phenyl)-2H-1,2,3-triazole-4-carboxylate (127 mg, 422 μmol, Eq: 1.00) in THF (5 ml) and MeOH (1.00 ml) was added LiOH 1M (843 μl, 843 μmol, Eq: 2). The mixture was stirred overnight. To the residue was added water and 1 N HCl (pH:1), this aqueous phase was extracted two times with ethyl acetate, the resulting organic layers were combined and washed with brine, then dried over MgSO4, filtered and concentrated to give the desired compound (94 mg, 81.6%) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[CH3:9][C:10]1([CH3:24])[O:11][C:12](=[O:23])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:2]3[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=3)=[CH:16][C:15]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1ccc(Br)s1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)s3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile was prepared, according to the procedure of Example 5 using 5-bromo-2-thiophenecarbonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid, as an off-white solid: mp 264-266° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.97 (d, 1H, J=7.9 Hz), 7.60-7.66 (m, 3H), 6.96 (d, 1H, J=8.1 Hz), 1.65 (s, 6H); MS (APCI) m/z 285 (M+H)+, 302 (M+NH4)+. Anal. Calcd. For C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.01; H, 4.36; N, 9.39.