Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH:22]=[CH:21][N:20]=[N:19]3)[N:13]=2)[CH:3]=1.[C@@H:23]1([NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:29]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[NH2:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:30][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH:22]=[CH:21][N:20]=[N:19]3)[N:13]=2)[CH:3]=1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2ccnn2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2ccnn2)n1
Temperature: 150 °C
Yield: 23.7 %

Procedure:
6-Chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (44 mg, 0.139 mmol) was dissolved in N-methylpyrrolidinone (0.9 mL). cis-Cyclohexane-1,2-diamine (95 mg, 0.834 mmol) was added and the mixture was warmed to 150° C. After 16 h the mixture was cooled and concentrated in vacuo. The residue obtained was diluted with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, 0:0:10 to 0.1:1:10 ammonium hydroxide:methanol:dichloromethane) gave 6-(cis-2-amino-cyclohexylamino)-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (13 mg, 23%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H) 9.13 (d, J=8.3 Hz, 1H) 8.84 (d, J=1.1 Hz, 1H) 8.16-8.26 (m, 1H) 8.03 (d, J=0.8 Hz, 1H) 7.96 (d, J=7.9 Hz, 1H) 7.67 (s, 1H) 7.51-7.57 (m, 1H) 7.51-7.57 (m, 1H) 7.43-7.50 (m, 1H) 3.60 (br. s., 1H) 2.96-3.03 (m, 1H) 1.21-1.64 (m, 8H); MS (EI/CI) m/z: 395 [M+H].
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([S:4]([CH3:6])=[O:5])[S:2][CH3:1])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSC(Cc1ccc(Br)cc1)S(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
1.182 g of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice 229 mg (1.0 equivalent) of sodium hydride was added. The mixture was stirred for one hour. 1.91 g of p-bromobenzyl bromide (0.8 equivalent) was added, and the mixture was further stirred for 13 hours at room temperature. 50 ml. of methylene chloride was added, and the resulting precipitate was filtered. The filtrate was concentrated at reduced pressure, and subjected to column chromatography (silica gel, methylene chloride) to give 698 mg of methyl 2-(p-bromophenyl)-1-methylthioethyl sulfoxide in a yield of 36.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:18].[OH-]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([NH2:18])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)CCNC(=O)OCc1ccccc1

Procedure:
Crude 2-(N-benzyloxycarbonylamino)ethanesulfonyl chloride was dissolved in acetonitrile (10 mL). The resulting solution was cooled on an ice/water bath and a solution 1:1 of 28% NH4OH (5 mL) and acetonitrile (5 mL) was dropped therein. After stirring for 30′, the solvents were evaporated off under vacuum and the crude residue was recrystallised with methanol to give 2-(N-benzyloxycarbonylamino)ethanesulfonamide as white powder (0.51 g; 1.96 mmol).
Reaction SMILES: ClC1C=CC(N2N=CC=N2)=C(C=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[N:50]1([C:55]2[C:56](C(O)=O)=[N:57][CH:58]=[CH:59][CH:60]=2)[CH:54]=[CH:53][CH:52]=[N:51]1>>[N:50]1([C:55]2[C:56]([C:7]([NH:9][C@H:10]3[CH2:14][CH2:13][CH2:12][C@@H:11]3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=3)=[O:8])=[N:57][CH:58]=[CH:59][CH:60]=2)[CH:54]=[CH:53][CH:52]=[N:51]1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Reactant: O=C(O)c1ncccc1-n1cccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ncccc1-n1cccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3-(1H-pyrazol-1-yl)pyridine-2-carboxylic acid (CAS number 1521232-19-8; 38 mg, 0.20 mmol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=CC(S(Cl)(=O)=O)=C[CH:21]=1.C(O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:20]([CH3:30])([CH3:25])[CH3:21])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To 4-chloro-2-nitrobenzoic acid (262 g) in a pyridine (1.3 liter) solution, p-toluenesulfonyl chloride (272.6 g) was slowly added at room temperature, and the mixture was stirred at that temperature for 15 minutes. To the reaction solution, tert-butyl alcohol (249 ml) was added dropwise, then the mixture was stirred for 5 hours. To the reaction mixture toluene (1 liter) was added, and the mixture was stirred for 1.5 hours, then the precipitate were removed by filtration. The filtrate was concentrated, ethyl acetate (1.3 liter) was added to the residue, the mixture was successively washed with water, saturated aqueous potassium hydrogensulfate solution, aqueous saturated sodium hydrogencarbonate solution, and brine, then the organic layer was dried over anhydrous sodium sulfate, then concentrated. Methanol (470 ml) was added to the residue, and after the precipitation of the crystals was confirmed, water (142 ml) was added. The mixture was stirred under ice cooling for 1.5 hours, then the crystals were collected by filtration. The same recrystallization procedure as the above was performed again to obtain the title compound (297 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[C:18]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:26]1([C:25]2[C:18]3[C:17]([NH:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:22][CH:21]=[N:20][C:19]=3[O:23][C:24]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2oc3ncnc(NCCN4CCNCC4)c3c2-c2ccccc2)cc1

Procedure:
A mixture of 69 (0.2 g, 0.57 mmol), 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 1.13 mmol) and DIEA (0.20 mL, 1.14 mmol) in 1-butanol (5 mL) was heated to 120° C. for 1.5 h. After concentration, the residue was purified by silica gel chromatography using 2-5% MeOH/DCM, to give 4-[2-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-ylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester 71 (0.20 g). Compound 71 was subjected to 20 mL of 20% TFA/DCM at rt for 2 h, then the reaction was concentrated almost to dryness under reduced pressure, and purified by silica gel column chromatography using 0.1% MeOH/DCM containing 1 mL ammonium hydroxide, to give 72 (0.15 g). MS: 400.2(M+1). 1HNMR (DMSO-d6) ppm 8.36 (s, 1H), 7.61-7.33 (m, 10H), 5.49 (t, 1H, J=4.48 Hz), 3.45 (dd, 2H, J1=5.10 Hz, J2=5.84 Hz), 2.33 (t, 2H, J=5.80 Hz), 2.13 (br, 4H), 1.95 (br, 1H) (note: some peaks overlapped with water peak in DMSO-d6). 1HNMR (CCl3-d) ppm 8.43 (s, 1H), 7.60-7.50 (m, 6H), 7.50-7.26 (m, 4H), 5.39 (t, 1H), 3.54 (dd, 2H, J1=5.05 Hz, J2=6.20 Hz), 2.73 (t, 4H, J=4.71 Hz), 2.44 (t 2H, J=5.91 Hz), 2.28 (br, 4H), 1,87 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][N:19](C(OCC5C=CC=CC=5)=O)[CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[C:4]([N:38]2[C:42]([CH3:43])=[N:41][CH:40]=[N:39]2)[CH:3]=1.Br.Br.CC(O)=O>O1CCOCC1.CC(O)=O>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][NH:19][CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[C:4]([N:38]2[C:42]([CH3:43])=[N:41][CH:40]=[N:39]2)[CH:3]=1
Reactant: Cc1ncnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCOC21CCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1ncnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCOC21CCNC1
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a stirred solution of Example 37 (1.1358 g, 1.9265 mmol) in 1,4-dioxane (10 mL) was added 33 wt % HBr in AcOH (2 mL) at room temperature. Immediately upon addition of HBr/AcOH to the reaction, solids precipitated out of the reaction mixture. So, 3 mL of anhydrous MeOH was added and stirred for 2 h. Then, the reaction mixture was purified by preparative HPLC using water/MeOH containing 0.1% TFA to afford desired product (0.448 g, 41%) as white solid. 1H NMR (500 MHz, DMSO-d6) δ: 1205 (1H, s), 9.35-9.28 (1H, br s), 9.27-9.19 (1H, br s), 9.14 (1H, t, J=6.1 Hz), 8.12 (1H, s), 7.57-7.53 (2H, m), 7.48-7.44 (1H, m), 4.27 (2H, d, J=6.1 Hz), 4.09-4.05 (2H, m), 3.91-3.86 (2H, m), 3.70-3.49 (3H, m), 3.42-3.34 (1H, m), 2.66-2.59 (1H, m), 2.45-2.39 (1H, m), 2.33 (3H, s). HRMS (M+H) calcd for C21H23N7O4F: 456.1796; found: 456.1805.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:6]1[CH:5]=[C:4]([CH:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74 mmol), Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (375 mg) as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:13][CH2:14]3)[C:6]=2[N:7]=1
Reactant: Cc1nn(C2CC2)c2nc(Cl)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C2CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-chloro-1-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (297 mg, 1.180 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (289 mg, 1.534 mmol), 1-hydroxy-7-azabenzotriazole (321 mg, 2.360 mmol), EDC (452 mg, 2.360 mmol) and N-methylmorpholine (0.519 mL, 4.72 mmol) were suspended in Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Added 25 mL of water and let stir for 10 minutes. The contents were filtered and dried. The product was collected as 455 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.22 (m, 4 H), 2.12 (s, 3 H), 2.22 (s, 3 H), 2.36 (s, 3 H), 3.74-3.87 (m, 1 H), 4.33 (d, J=5.05 Hz, 2 H), 5.88 (s, 1 H), 7.19 (s, 1 H), 8.79 (t, J=4.67 Hz, 1 H), 11.53 (br. s., 1 H). MS(ES) [M+H]+385.9
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].[NH2:14][OH:15]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])/[C:5](=[N:14]/[OH:15])/[NH2:6]
Reactant: NO
Reactant: CC(C)Oc1ccc(C#N)cc1Br
Solvent: CCO
Product: CC(C)Oc1ccc(/C(N)=N/O)cc1Br
Temperature: 65 °C
Yield: 98.2 %

Procedure:
3-bromo-4-isopropoxybenzonitrile (0.68 g, 2.83 mmol) and hydroxylamine (0.208 ml, 3.12 mmol) were combined in EtOH (20 ml). The reaction mixture was heated at 65° C. for 16 hr. The reaction mixture was concentrated to afford (Z)-3-bromo-N′-hydroxy-4-isopropoxybenzimidamide (0.76 g, 2.78 mmol, 98% yield) as pale yellow solid. LC/MS (Table 1, Method a) Rt=2.89 min.; MS m/z: 275.00 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([OH:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)[NH2:24].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([NH:24][NH:23][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cycloheptanecarboxylic acid (0.10 g, 0.33 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.07 g, 0.39 mmol), NMM (0.10 g, 1.0 mmol) and HOAt (0.053 g, 0.39 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.075 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 72%). MH+466.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([CH2:52]Br)[CH:51]=1)[C:47]#[N:48]>CC#N>[Br:43][C:44]1[CH:51]=[C:50]([CH:49]=[C:46]([C:47]#[N:48])[CH:45]=1)[CH2:52][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: N#Cc1cc(Br)cc(CBr)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cc(Br)cc(C#N)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 79.7 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 3-bromo-5-(bromomethyl)benzonitrile (503 mg, 1.829 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively with dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (616 mg, 80% yield). 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J=8.6 Hz, 2H), 7.57-7.52 (m, 2H), 7.49 (s, 1H), 6.85 (d, J=9.3 Hz, 1H), 4.49 (s, 2H), 3.82 (s, 2H), 2.81 (t, J=6.7 Hz, 2H), 1.84 (t, J=6.7 Hz, 2H), 1.36 (s, 9H), 1.36 (s, 6H). LRMS [ESI, MH+] m/z calcd for C25H30BrN2O5S 549.11, found 549.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1>ClC(OCC)=O>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:8]([O:7][CH2:6][CH3:5])=[O:9])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: CCOC(=O)Cl
Product: CCCCC1OC(=O)c2cc(NC(=O)OCC)ccc21

Procedure:
A mixture of 3.08 g (0.015 mol) of compound obtained in Example 4 and 10 ml of ethyl chloroformate is heated for 10 minutes. The excess ethyl chloroformate is removed in vacuo and the residue is washed with water and crystallised from dilute ethanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[C:27](=[O:28])[CH:26]=[C:25]([CH3:29])[NH:24][C:23]=1[CH3:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22]1[C:27](=[O:28])[CH:26]=[C:25]([CH3:29])[NH:24][C:23]=1[CH3:30])=[O:9]
Reactant: Cc1c(OC2CCOCC2)cc(Cl)cc1C(=O)O
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCOCC3)c2C)c(C)[nH]1
Reaction time: 16 h
Yield: 45.5 %

Procedure:
A 20 mL vial was charged with 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (72.0 mg, 0.266 mmol), 3-(aminomethyl)-2,6-dimethylpyridin -4(1H)-one hydrochloride (60.2 mg, 0.319 mmol), EDC (76 mg, 0.399 mmol), HOAt (61.5 mg, 0.399 mmol), N,N-dimethylformamide (3 mL) and N-methylmorpholine (0.351 mL, 3.19 mmol). The reaction was stirred for 16 h, at which time it was added drop-wise to a rapidly stirred solution of saturated NaHCO3 (25 mL) and water (10 mL) and stirred at room temperature 1 h. The solid was collected via vacuum filtration and dried under vacuum. Purification of the residue by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18; Eluent: 20-55% acetonitrile/0.1% formic acid in water, 5 min gradient) gave a sticky, glassy solid. This residue was dissolved with DCM (20 mL) and washed with a saturated NaHCO3 (6 mL) and water (3 mL). The aqueous was extracted with DCM (2×20 mL) and the combined organic layers were filtered through MgSO4 and Na2SO4 and concentrated to give 5-chloro-N-((2,6-dimethyl-4-oxo -1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (49 mg, 0.121 mmol, 45.5% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.21 (t, J=4.93 Hz, 1H), 7.15 (d, J=2.02 Hz, 1H), 6.80 (d, J=2.02 Hz, 1H), 5.87 (s, 1H), 4.66 (tt, J=4.04, 7.96 Hz, 1H), 4.19 (d, J=5.05 Hz, 2H), 3.73-3.89 (m, 2H), 3.51 (ddd, J=3.03, 8.59, 11.62 Hz, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.07 (s, 3H), 1.86-2.00 (m, 2H), 1.49-1.66 (m, 2H). MS(ES) [M+H]+ 405.1.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][CH2:22][CH2:23]C#N>>[OH:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][CH2:22][CH2:23][C:13]1[NH:2][C:3](=[O:12])[C:4]2[C:5]([CH:11]=1)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Reactant: N#CCCCN1CCC[C@@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCCN3CCC[C@@H]3CO)cc12
Yield: 7 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (5.8040 g) and (R)-4-(2-hydroxymethylpyrrolidin-1-yl)butyronitrile (2.75 g), (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-1-one (344.1 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27][OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(Br)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (5.7:1) as a white foam, MS (ESI+): m/z=409.0895 ([M+H]+, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4](=[O:7])[O:5][CH:6]=1.[C:8](O)([CH3:11])([CH3:10])[CH3:9].S(=O)(=O)(O)O>O>[C:8]([CH:3]1[C:2]([OH:1])=[CH:6][O:5][C:4]1=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1CC(O)=CO1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)C1C(=O)OC=C1O
Temperature: 40 °C
Yield: 7.4 %

Procedure:
To 4-hydroxy-2-furanone (50 g, 0.5 mol) in tert-butanol (50 ml, 0.53 mol) was added concentrated sulfuric acid (25 ml). The mixture was heated at 40° C. for 20 h then allowed to cool. Water (250 ml) was added and the mixture was extracted with diethyl ether (3×250 ml), the diethyl ether layers were combined, washed with brine (250 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a brown solid. The solid was purified by silica gel chromatography with 0%→100% ethyl acetate/isohexane as eluent followed by two recrystallisations from ethyl acetate/isohexane (1:1) to afford the required product (5.75 g). Data for the title compound: 1H NMR (400 MHz, DMSO) δ 1.21 (9H, s), 4.48 (2H, s), 11.40 (1H, s); MS (ES+) m/e 156 [MH]+.