Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[OH:23][NH2:24].[OH-].[K+].Cl>C1(C)C=CC=CC=1.O.CN(C)C=O.O1CCCC1>[CH2:1]([S:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]([NH:24][OH:23])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(C(=O)O)c1SCc1ccccc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1ncc(C(=O)NO)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
In a suspension of 5-benzylthio-1-methylpyrazole-4-carboxylic acid (15.9 g, 64.0 mmol) in toluene (100 ml), thionyl chloride (11.4 g, 95.8 mmol) and N,N-dimethylformamide (0.1 g) were added, and refluxed for 4 hours. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (40 ml). On the other hand, in a solution of hydroxyamine hydrochloride (13.3 g, 191 mmol) in water (40 ml), a solution of 85% potassium hydroxide (12.6 g, 191 mmol) in water (40 ml) was added at 5-15° C., and stirred at room temperature for 15 minutes. Then, the above-mentioned tetrahydrofuran solution was added dropwise at 3-15° C. After further stirring at 3° C. for 1.5 hour, the mixture was adjusted to pH 3-4 by adding 35% hydrochloric acid (20 ml) and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified with silica gel column chromatography (developing solution: n-hexane/ethyl acetate=1/1) to obtain the aimed product (10.3 g). Resinous substance. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.42 (s, 3H), 3.95 (s, 2H), 6.93-7.01 (m, 2H), 7.20-7.28 (m, 3H), 8.04 (s, 1H), 9.76 (brs, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[C:6]([N+]([O-])=O)([C:11](O)=O)[CH:7]([C:8]([OH:10])=[O:9])[CH:2]1C=C2.[Cl-].[K+]>>[C:7]1([C:8]([OH:10])=[O:9])[C:6](=[CH2:11])[CH:5]=[CH:1][CH:2]=1
Reactant: O=C(O)C1C2C=CC(C2)C1(C(=O)O)[N+](=O)[O-]
Agent: [Cl-]
Agent: [K+]
Product: C=C1C=CC=C1C(=O)O

Procedure:
Mix the concentrated black liquor, lignin, humic acid, and sludge into slurry, with their mass percentage respectively being 50%, 35%, 10% and 5%. KCl is added. Then pulp spraying granulation is performed, with a nose temperature of 560° C., and a tail temperature of 52° C. Then a solid state fulvic acid fertilizer is obtained, with grain sizes of 3-5 mm, a hardness of 19.4N, a content of organic matter of 65%, a total content of N+P2O5+K2O of 5%, and a content of fulvic acid of 24%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br.[S:37]1[C:41]2[CH2:42][CH:43]([NH2:46])[CH2:44][CH2:45][C:40]=2[N:39]=[C:38]1[NH2:47]>>[NH2:47][C:38]1[S:37][C:41]2[CH2:42][CH:43]([NH:46][C:17]([C@@H:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:10](=[O:11])[C@H:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:18])[CH2:44][CH2:45][C:40]=2[N:39]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Agent: Br
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)NC1CCc2nc(N)sc2C1
Yield: 65 %

Procedure:
The title compound was prepared from (2S)-1-((2R)-2-{(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino}-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid and 4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine dihydrobromide according to the procedure of EXAMPLE 25, and was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[CH2:18][C:17]=2[CH:33]=1)=[O:12].[OH-].[Na+]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[CH2:18][C:17]=2[CH:33]=1)=[O:12]
Reactant: CCOC(=O)CC1Cc2ccc(C(=O)NCCNc3ccccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1Cc2ccc(C(=O)NCCNc3ccccn3)cc2Cc2ccccc21
Reaction time: 23 h
Yield: 51.2 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-[[[2-(2-pyridylamino)ethyl]amino]carbonyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (199.1 mg, 0.45 mmole) and 1.0 N NaOH (0.54 mL, 0.54 mmole) in absolute EtOH (4 mL) was warmed in an oil bath set at 45° C. After 23 hr, the reaction was concentrated and the residue was purified by ODS chromatography (gradient: 30% MeOH/H2O then 40% MeOH/H2O). Concentration and lyophilization gave the title compound (95.8 mg, 46%) as a nearly colorless powder: HPLC (PRP-1®, 30% CH3CN/H2O containing 0.1% TFA) K' =2.0; 1H NMR (400 MHz, CD3OD) δ 7.92 (app. d, J=4.2 Hz, 1 H), 7.61 (d, J=1.8 Hz, 1 H), 7.53 (dd, J=7.9, 1.8 Hz, 1 H), 7.38-7.47 (m, 1 H), 7.01-7.24 (m, 5 H), 6.56 (d, J=7.9 Hz, 1 H), 6.50-6.60 (m, 1 H), 4.34 (d, J=14.9 Hz, 1 H), 3.97 (d, J=14.9 Hz, 1 H), 3.78-3.89 (m, 1 H), 3.44-3.61 (m, 4 H), 3.39 (dd, J=15.4, 4.4 Hz, 1 H), 3.00 (dd, J=15.4, 10.2 Hz, 1 H), 2.61 (dd, J=14.9, 5.1 Hz, 1 H), 2.43 (dd, J=14.9, 9.5 Hz, 1 H); MS (ES) m/e 416 (M+H)+. Anal. Calcd for C25H24N3O3Na.1.33 H2O: C, 65.07; H, 5.82; N, 9.11. Found: C, 65.02; H, 5.62; N, 9.17.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:10]=[N:11][CH:12]=1)=[O:5])C.C(N(C(C)C)CC)(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[CH2:22][N:23]([C:38]([CH:35]2[CH2:37][CH2:36]2)=[O:39])[CH2:24][CH3:25])[CH:10]=[N:11][CH:12]=1)([OH:3])=[O:5]
Reactant: CCNCc1cc(C(=O)O)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(Cc1cc(C(=O)O)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(5-Ethoxycarbonylmethyl-pyridin-3-yl)-3-ethylaminomethyl-benzoic acid (0.347 g, 1.0 mmol) and diisopropylethylamine (0.44 mL, 2.5 mmol) were combined in CH2Cl2 (75 mL). Cyclopropanecarbonyl chloride (0.12 mL, 1.3 mmol) was added slowly, and the reaction was stirred at room temperature for 10 minutes. The mixture was quenched with H2O (100 mL), and the product was extracted with CH2Cl2. The combined organic layers were washed with brine and concentrated. The crude material was dissolved in MeOH (75 mL), 1N aqueous LiOH (5 mL) was added and stirred at room temperature for 3 hours. Additional 1N aqueous LiOH (1 mL) was added and the reaction was stirred at room temperature for 3 days. The mixture was quenched with 1N aqueous HCl (5 mL) and extracted with EtOAc. The combined organic layers were washed with H2O and brine, and then concentrated to give 4-(5-carboxymethyl-pyridin-3-yl)-3-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-benzoic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:12]=[CH:13][C:14](OCC)=[O:15].O.[OH-].[Na+]>C(OCC)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:12]=[CH:13][CH2:14][OH:15]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C=CCO)cc1OC

Procedure:
A solution of lithium aluminum hydride (0.02 mol) in diethyl ether (20 ml) was added dropwise to a solution of ethyl 3,4-dimethoxycinnamate (9.4 g, 0.04 mol) in diethyl ether (150 ml), and the mixture was heated under reflux for 1 hour. Water (15 ml) and 2.5N sodium hydroxide (5 ml) were added to the cooled solution, and the precipitate was filtered off and washed with ether. The combined filtrates were washed with water, dried, and evaporated to dryness. The crude product was put on a column of silica gel and eluted with hexane-ethyl acetate (1.5:1, v/v). 3,4-Dimethoxycinnamyl alcohol was isolated as a crystalline mass (5.0 g, 65%), m.p. 76°-76.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(Cl)cc2c1=O
Yield: 84.1 %

Procedure:
12 g (40 mmol) of the product from Example A in 100 ml of pyridine are heated with 17.2 g (0.2 mole) of piperazine under reflux for 5 hours. The mixture is concentrated in vacuo, the residue is stirred with 120 ml of water and the pH is adjusted to 5 with 2N hydrochloric acid. The precipitate is filtered off with suction, washed with water and methanol, boiled in 80 ml of methanol and dried. 12.3 g (84% of theory) 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro- 4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of melting point 295°-298° (with decomposition) are obtained.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1([CH2:6][O:7][C:8]2[C:29]([Cl:30])=[CH:28][C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([O:23]C)=O)=[CH:10][C:9]=2[Cl:31])[CH2:5][CH2:4]1>CN(C=O)C.CO.O>[CH:3]1([CH2:6][O:7][C:8]2[C:29]([Cl:30])=[CH:28][C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([NH:2][CH3:1])=[O:23])=[CH:10][C:9]=2[Cl:31])[CH2:5][CH2:4]1
Reactant: CN
Reactant: CO/N=C(/C(=O)OC)c1ccccc1COc1cc(Cl)c(OCC2CC2)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(Cl)c(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution of methylamine (0.8 ml) is added to a solution of methyl (E)-2-[2-(4-cyclopropylmethoxy-3,5-dichlorophenoxymethyl)-phenyl]-2-methoxyiminoacetate (compound nr.2; 0.88 g; 2 mmoles) in DMF (2 ml) and methanol (4 ml). The mixture is kept under stirring for 2 hours at room temperature, diluted with water (40 ml) and an extraction is effected with ethyl acetate (3×25 ml). The organic phases are joined, washed with water (2×20 ml), dried with sodium sulfate and concentrated at reduced pressure. 0.8 g of the product (thick oil) are obtained, which do not require further purification.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:19])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.C(O)C.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)Cl.CO>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([C:2]2[NH:3][C:4](=[O:19])[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=2)[CH2:32][CH2:31]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A high pressure reaction vial was charged with 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (50 mg, 175 μmol) and ethanol (460 μL). The reaction was treated with 1-(2-fluorophenyl)piperazine (63.1 mg, 55.3 μL, 350 μmol) and was sealed. The reaction was then heated to 100° C. where it stirred overnight. At this time, the reaction was allowed to cool to room temperature. It was then diluted with methylene chloride and methanol and concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 1-10% methylene chloride/methanol) afforded 2-(4-(2-fluorophenyl)piperazin-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one as a purple oil (31.5 mg, 40.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm −0.32-0.07 (m, 9H) 0.84 (t, J=8.01 Hz, 2H) 3.07 (br. s., 4H) 3.51 (t, J=8.01 Hz, 2H) 3.73 (br. s., 4H) 5.34 (s, 2H) 6.31 (d, J=3.52 Hz, 1H) 6.89 (d, J=3.52 Hz, 1H) 6.95-7.25 (m, 4H) 10.83-11.10 (m, 1H). LC-MS calcd. for C22H31FN5O2S [(M+H)+] 444, obsd. 444.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH:6]=[C:5]2[OH:15].BrC1C=CC(S(O[C@@H:27]2[CH2:31][N:30]([C:32](=[O:48])[C@@H:33]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C@H:29]([C:49]([O:51][CH3:52])=[O:50])[CH2:28]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH:6]=[C:5]2[O:15][C@H:27]1[CH2:31][N:30]([C:32](=[O:48])[C@@H:33]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C@H:29]([C:49]([O:51][CH3:52])=[O:50])[CH2:28]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: COc1cc2[nH]c(=O)cc(O)c2cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(=O)[nH]c3cc(OC)c(Br)cc23)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 60 °C

Procedure:
To a 0.27 M solution of hydroxyl-quinolinone from Step 3 (1 eq.) and brosylate from Step 2 (1 eq.) in N-methyl-2-pyrrolidinone was added cesium carbonate (1.5 eq.) and the resulting mixture was heated at 60° C. for 16 h. The mixture was cooled to RT and partitioned between water and EtOAc. The organic phase was washed with brine, dried (Na2SO4) and the volatiles were removed under reduced pressure. The residue was purified by SiO2 gel chromatography (eluting with 50% EtOAc/Hex and then 0-5% MeOH/DCM) to yield the title compound. MS (ES+) C29H38BrN3O8 requires: 637. Found: 636, 638 (M+H+).
Reaction SMILES: CO[C:3]1[CH:11]=[C:10](NC(C)=O)[C:9](S(C)=O)=[CH:8][C:4]=1[C:5](O)=[O:6].CC(C)=O.ClC(OCC(C)C)=O.C1([N:37]2CCCC2CN)CCCCC1>O.C(N(CC)CC)C>[C:5]([NH2:37])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:3]=1
Reactant: NCC1CCCN1C1CCCCC1
Reactant: COc1cc(NC(C)=O)c(S(C)=O)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116.9 %

Procedure:
81.3 g of 2-methoxy-4-acetamino-5-methylsulphinylbenzoic acid (0.30 mole), 600 ml of acetone, 120 ml of water and 41.7 ml of triethylamine with a density of 0.726 (0.30 mole) are placed in a 1 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The mixture is cooled to 0° C. and 40.8 g of isobutyl chloroformate (0.30 mole) is poured in drop by drop. It is agitated for 30 minutes with the cooling bath removed, cooled to 0° C. again and 54.6 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine (0.30 mole) is poured in drop by drop. The mixture is reacted for 1 hour at room temperature with agitation, and left to stand. The solution is evaporated to dryness. A paste is obtained and is dissolved in 200 ml of soda and 400 ml of water. It is heated to reflux for 2 hours, and 50 ml of a mixture distilling over at low temperature is distilled off then put back under reflux. The reaction medium is left to stand, then the suspension is extracted four times with 200 ml of methylene chloride. The organic phase is washed twice with 300 ml of 10% hydrochloric acid, the aqueous phase is filtered with carbon black and the filtrate is made alkaline with 300 ml of 40% soda. The suspension is extracted 3 times, each time with 300 ml of methylene chloride. The organic solution is washed with water and dried over magnesium sulphate. The solution is filtered and evaporated to dryness. 42.5 g (36%) of benzamide is obtained; this does not crystallise.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[N:32][CH:33]=2)=[O:19])=[CH:13][CH:12]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[N:32][CH:33]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2C(=O)Nc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2C(=O)Nc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.27 mL, 0.82 mmol) was added to a THF solution (0.9 mL) of ethyl 3-(5-(2-((2′,4′-dichloro-[1,1′-biphenyl]-4-yl)carbamoyl)-4,5-difluorophenyl)picolinamido)propanoate (100 mg, 0.17 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via HPLC to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.C1C(=O)N([I:19])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([C:9]([I:19])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Clc1cc(Br)c2ncc(I)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.2 g, 5.16 mmol) in chloroform (30 mL) were added NIS (1.161 g, 5.16 mmol) and TFA (0.795 mL, 10.32 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with NaHCO3. The organic layers were washed with brine and dried over Na2SO4. The crude product was purified by BIOTAGE® (100% CH2Cl2) to give the product (1.4 g, 76%). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (1H, s), 7.46 (1H, s); LC/MS: Rt=2.44 min. LC/MS (Condition A): 357.80/359.80/361.80.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15][C:16](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[C:38](C=O)=[C:37](Cl)[N:36]=[CH:35][N:34]=1.C1(C)C=CC=CC=1>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:37]3=[N:36][CH:35]=[N:34][C:33]([Cl:32])=[C:38]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A solution of 4-(tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 15; 1.80 g, 5.71 mmol), diisopropylethylamine (2.0 mL, 11.3 mmol), and 4,6-dichloropyrimidine-5-carbaldehyde (Intermediate 16; 1.00 g, 5.65 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. for 30 min, then it was warmed up to rt and stirred for 4 h. The solid was filtered. The filtrate was washed with brine (10 mL) and the aqueous layer was extracted with methyl tert-butyl ether (1×10 mL). The combined organic layers were washed with brine (1×10 mL) and concentrated to give an orange-red semi-solid. Toluene (10 mL) was added and the solution was heated to 110° C. for 6 h. The reaction mixture was cooled to room temperature and concentrated to give a semi-solid. This crude solid was dissolved in the minimum amount of dichloromethane and passed through a pad of silica gel, eluting with 9% ethyl acetate/hexanes. Concentration of fractions homogeneous for the product gave 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.33 g, 70%) as a cream white solid. 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.9-2.1 (m, 2H), 2.25 (qd, 2H, J=12.6, 4.5 Hz), 2.97 (t, 2H, J=12.0 Hz), 4.30 (br, 2H), 4.96 (tt, 1H, J=11.4, 4.2 Hz), 8.15 (s, 1H), 8.75 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.NN>[Ni].CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:16]
Reactant: COCCN(C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: COCCN(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-methoxy-ethyl)-methyl-(4-nitro-benzyl)-amine, from step 1, (56 mg, 0.25 mmol) is added methanol (1 mL), hydrazine (33 μL), and Raney-Nickel (10 mg). The reaction mixture is shaken at room temperature for 16 hours, then filtered and the solution concentrated to yield 4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenylamine, which is used as such for the subsequent reaction.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][CH2:7][C@H:8]([OH:36])[CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:25][N:24]=3)[O:20][N:19]=2)=[CH:13][C:12]=1[CH2:34][CH3:35]>C(O)C.[OH-].[Na+]>[CH2:34]([C:12]1[CH:13]=[C:14]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:25][N:24]=3)[O:20][N:19]=2)[CH:15]=[C:16]([CH3:17])[C:11]=1[O:10][CH2:9][C@@H:8]([OH:36])[CH2:7][NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])[CH3:35]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNCCC(=O)O
Yield: 45.9 %

Procedure:
A solution of the compound of Example 60 (53 mg, 101 μmol) in ethanol (1 mL) and 1 M aq. NaOH (1 mL) is stirred at rt for 18 h. The ethanol is evaporated, the remaining solution is neutralized by adding 1 N aq. HCl, and the mixture is separated by prep. HPLC to give the title compound (23 mg) as a white solid; LC-MS: tR=0.88 min, [M+H]+=497.08; 1H NMR (CDCl3): δ0.98 (d, J=6.5 Hz, 6H), 1.27 (t, J=7.3 Hz, 3H), 1.93 (hept, J=7.0 Hz, 1H), 2.34 (s, 3H), 2.44 (s, 3H), 2.60 (d, J=7.3 Hz, 2H), 2.65-2.83 (m, 4H), 3.18-3.40 (m, 4H), 3.82-3.96 (m, 2H), 4.52-4.61 (m, 1H), 7.88 (s, 1H), 7.92 (s, 1H), 8.06 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C:10]([CH3:23])([CH3:22])[CH2:11]/[CH:12]=[N:13]/[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27]([F:44])=[C:28](/[CH:32]=[C:33](/[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[F:43])\[C:34]#[N:35])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:18]([O:17][C:15]([CH:14]1[CH:32]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=2[F:44])[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[F:43])([C:34]#[N:35])[CH:12]([CH2:11][C:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])([CH3:23])[CH3:22])[NH:13]1)=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C(=O)OCc1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)C(=O)OCc2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 19 %

Procedure:
In a manner similar to the method described in Example 100b, 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid benzyl ester prepared in Example 103a (4.1 g, 12.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (1.55 g, 12.3 mmol), and triethylamine (2.5 g, 24 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (4 ml) in tert-butanol (40 mL) at 100° C. for 4 h to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (0.98 g, 19%).