Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[N:10]([S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:8]>C1(C)C=CC=CC=1.C1COCC1.[NH4+].[Cl-]>[CH3:25][N:23]([CH3:24])[S:22]([N:10]1[C:9]([C:7](=[O:8])[CH3:1])=[CH:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:11]1)(=[O:26])=[O:27]
Reactant: CON(C)C(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A 1.4M solution of methylmagnesium bromide in toluene and THF (3.88 mL, 5.43 mmol) was added to a solution of 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide (1.54 g, 4.17 mmol) in THF (20 mL) at −78° C. and under nitrogen. The mixture was stirred at −78° C. for 1 hour and then at room temperature for 16 hours. Then, a second portion of methylmagnesium bromide in toluene and THF (3.58 mL, 5.01 mmol) was added at 0° C. and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide (1.2 g, 89% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:19][NH2:20]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:20][N:19]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Solvent: CCO
Solvent: O
Product: Oc1cccc(C2CC(c3ccccc3)=NN2)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a 250 ml round bottom flask equipped with magnetic stirrer and reflux condenser was charged 3.2 g (0.0143 moles) of 3-hydroxychalcone, 50 mls of ethanol and 0.7 g (0.0143 moles) of hydrazine monohydrate. The reaction was refluxed for a total of 2 hours, after which it was cooled to ambient temperature. The resulting solid was collected by vacuum filtration, washed with hexane, and dried in vacuuo at 40° C. overnight to afford 3.4 g of the title compound, 3-phenyl-5-(3-hydroxyphenyl)-2-pyrazoline as a tan solid in a 99% isolated yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:8][CH2:7]2)=[O:4].[Cl:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=1[C:36]1[CH:40]=[C:39]([CH2:41]O)[O:38][N:37]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:41][C:39]3[O:38][N:37]=[C:36]([C:29]4[C:30]([F:35])=[CH:31][CH:32]=[C:33]([F:34])[C:28]=4[Cl:27])[CH:40]=3)=[CH:16][CH:17]=1)[CH2:8][CH2:7]2)=[O:4]
Reactant: COC(=O)C1=C(c2ccc(O)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Reactant: OCc1cc(-c2c(F)ccc(F)c2Cl)no1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of compound B4 (6.80 g, 18.9 mmol), [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-methanol (6.97 g, 28.3 mmol), ADDP (9.55 g, 37.8 mmol) and PBu3 (85%, 13.8 mL, 56.6 mmol) in toluene (280 mL) was heated to reflux for 1 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:1) yielded the title compound (11.0 g, 99%). LC-MS: tR=1.14 min; ES+: 587.30.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][NH:10][C:9](=[O:12])[C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[CH3:31]NN>>[CH3:31][N:10]1[C:9](=[O:12])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=2)=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=c1[nH][nH]c(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CNN
Product: Cn1[nH]c(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1=O
Yield: 15 %

Procedure:
Following the procedure for the preparation of 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one using methyl hydrazine provided the title compound. Yield: 15%. 1H NMR (500 MHz, d6-DMSO): δ 8.44-8.36 (m, 2H), 8.04-7.96 (m, 2H), 7.82-7.74 (m, 2H), 7.72-7.56 (m, 2H), 7.38-7.22 (m, 1H), 7.18-7.12 (m, 2H), 7.10-7.06 (m, 1H), 7.01-6.98 (m, 2H), 5.36 (s, 2H), 3.69 (s, 1H), 3.59 (s, 3H). MS: M+H: m/z=409.1.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[Cl:15][C:10]1[NH:9][C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH2:1][CH2:2][CH3:3])[C:12]=2[N:11]=1
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 5 h
Yield: 43.2 %

Procedure:
3-Propyl-3,7-dihydro-1H-purine-2,6-dione (J. Med. Chem., 1993, 36 (10), 1380-6) (0.3 g, 1.5 mmol) and N-chlorosuccinimide (0.21 g, 1.5 mmol) were dissolved in DMF (5 ml) and the solution stirred for 5 h. The solution was concentrated and the solid residues washed with methanol and filtered to provide the product as a white solid (0.148 g, 42%). NMR; δH (400 MHz, d6-DMSO) 0.85 (t, 3H, J=7 Hz), 1.65 (m, 2H), 3.8 (t, 2H, J=7 Hz), 11.2 (s, 1H), one exchangeable not observed to δH 13; m/z 229 [MH+]
Reaction SMILES: [CH2:1]([O:4]N1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C(C)(C)C)(C)C)C=C.[CH2:24]([O:27][NH:28][C@@H:29]1[C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][C@@H:32]([CH2:39][O:40][CH3:41])[NH:31][CH2:30]1)[CH:25]=[CH2:26]>>[CH2:24]([O:27][N:28]1[C:1](=[O:4])[N:31]2[CH2:30][C@H:29]1[C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][C@H:32]2[CH2:39][O:40][CH3:41])[CH:25]=[CH2:26]
Reactant: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)NC
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C(=O)NC)=C[C@H]2COC
Yield: 68 %

Procedure:
The title compound (0.28 g, 68%) was prepared according to the procedure described for Intermediate 13, starting from (3R,6S)-3-(allyloxyamino)-6-(methoxymethyl)-N-methyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 258, 0.52 g)
Reaction SMILES: [N:1]([C@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][NH:6][C:5]1=[O:17])=[N+:2]=[N-:3].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+]>>[N:1]([C@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]1=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1CC[C@@H](c2ccccc2)CNC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@H](N=[N+]=[N-])C1=O

Procedure:
Using a similar procedure to that described in Example 1(h), 1.21 g of 3(S*)-azido-6(S*)-phenylperhydroazepin-2-one (Isomer B) [prepared as described in Example 1(g)], 1 ml of t-butyl bromoacetate and 252 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) afforded 1.9 g of the title compound as a syrup.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:6]2=[N:19]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)[C:6]2=[NH:19])=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
HCl (4M in 1,4-dioxane, 3.38 mL, 13.51 mmol) was added to a solution of N-(5′-bromo-4,4-difluorospiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 27 Step 1, 565 mg, 1.35 mmol) in anhydrous 1,4-dioxane (4 mL). The resulting mixture was stirred under a nitrogen atmosphere at r.t. for 90 min. Et2O (2 mL) was added and the precipitate was filtered off and washed with Et2O. The solid was partitioned between DCM (8 mL) and sat. aq. NaHCO3 (8 mL). The phases were separated and the organic layer was dried over MgSO4 and concentrated to give 6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (418 mg, 99% yield), that was used directly in the next step. MS (ES+) m/z 314 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO.[H][H]>C1COCC1>[Br:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)[CH:24]([CH3:26])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)N(C(=O)CCOCCCBr)C1CCN(Cc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(CCCOCCCBr)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a stirred solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 3-(bromopropoxy)propionamide (28.2 g, 66 mmol) in THF (300 mL) was added BH3-THF (100 mL, 2.0 M in THF, 200 mmol) and the reaction mixture was refluxed for 48 h. The reaction mixture was then allowed to cool to room temperature and methanol was added dropwise until evolution of hydrogen gas stopped. The mixture was then concentrated under reduced pressure and dissolved in dichloromethane (500 mL). The reaction mixture was washed with 1 N hydrochloride acid (500 mL) and the organic layer removed. The aqueous layer was then made basic to pH 12 using 1 N sodium hydroxide and extracted with dichloromethane (500 mL). The combined organic layers were washed with water (400 mL), brine (400 mL), dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The resulting crude product was purified by silica gel chromatography (dichloromethane/methanol/aqueous ammonia: 9/0.5/0.05) to afford 20.5 g of the title intermediate (76% yield).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH2:16])[CH2:6]1)(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21](Cl)=[O:22]>>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:18]([CH3:17])[CH:19]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CC(=O)OC1CCN([C@H]2CCCC[C@H]2N)C1
Product: CC(=O)OC1CCN([C@H]2CCCC[C@H]2NC(=O)c2cc(C)cc(C)c2)C1

Procedure:
Following the procedure of Example 1b, using cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]amine and 3.5-dimethylbenzoyl chloride there is obtained as product cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]-3,5-dimethylbenzamide.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].O>N1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([O:9][C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=c1cccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=c1cccccc1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 71 %

Procedure:
2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (1.1 g, 4.9 mmol) in 5 mL of pyridine. Addition of 10 mL of water allowed for precipitation of PZBG-4c in 71% yield (0.38 g, 1.2 mmol) without the need for further purification. 1H NMR (400 MHz, DMSO) δ=8.45 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.8 Hz, 2H), 7.52 (d, J=9.2 Hz, 1H), 7.46 (dd, J1=10.2 Hz, J2=3.6 Hz, 1H), 7.31 (dd, J1=9.8 Hz, J2=2 Hz, 1H), 7.15 (dd, J1=10.6 Hz, J2=3.6 Hz, 1H). 13C (100 MHz, CDCl3) δ=179.09, 154.86, 151.50, 141.95, 141.27, 138.59, 136.87, 132.06, 131.48, 130.42, 125.42. ESI-MS(+): m/z 308.01 [M+H]+, 324.73 [M+NH4]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:21][CH2:20][C:15]2(OCC[O:16]2)[CH2:14][CH2:13]1.O.Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCC3(CC2)OCCO3)c(F)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
The crude 8-(2,6-difluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane from the preceding procedure was dissolved in 4:1 acetone:water (100 mL). Concentrated HCl (5 mL) was added, and the resulting mixture was stirred at 50° C. for 8 hours and then cooled to room temperature. The mixture was concentrated in vacuo to approximately 20 mL, which was carefully added to concentrated aq. NaHCO3 (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with Et2O and hexanes to give a bright-yellow solid that was collected and dried to provide the title compound (7.13 g, 81%).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>CS(C)=O>[C:16]([NH:20][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Product: CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Temperature: 65 °C
Yield: 91.3 %

Procedure:
To a stirred solution of 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (13 g, 63.7 mmol) in DMSO (100 mL) was added t-BuNH2 (33.7 mL, 318 mmol). The reaction mixture was heated in an oil bath at 65° C. for 4 h. It was cooled to RT, treated with 100 mL of ice cold water. The precipitated light orange solid was collected, washed with water (2×15 mL), dried in a vacuum oven at 35° C. for 18 h to give 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (14.96 g, 91% yield) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (dd, J=8.12, 1.66 Hz, 1H), 7.76 (dd, J=7.34, 1.66 Hz, 1H), 7.35 (t, J=7.73 Hz, 1H), 4.81 (br., 1H), 2.88 (s, 3H), 2.53 (s, 3H), 1.57 (s, 9H). m/z (ESI, +ve) 258.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)=[C:15]=[O:16]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]([NH:14][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[CH:22]4)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
1-(4-Chlorophenyl)piperazine (197 mg, 1.01 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, 1H, J=1.0 Hz), 8.83 (s, 1H), 8.49 (d, 1H, 6.1 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.77 (m, 1H), 7.61-7.72 (m, 2H), 7.26-7.29 (m, 2H), 7.01-7.04 (m, 2H), 3.68 (m, 4H), 3.23 (m, 4H); MS (ESI+) m/z 367 (M+H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[O:11][C@@H:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[O:11][C@@H:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21

Procedure:
Methyl [(2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate (70a) (175 mg, 0.410 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (4 mL) and kept at ambient temperature for 30 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated and the residue used immediately in the next step.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7]CC)=[O:6])[NH2:3].CN(C)/[CH:12]=[CH:13]/[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl>CCO.CC(=O)OCC>[C:16]1([C:14]2[N:2]([CH2:4][C:5]([OH:7])=[O:6])[N:3]=[CH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CNN
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)Cn1nccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
To a solution of ethyl hydrazinoacetate hydrochloride (866 mg) in EtOH (20 mL) was added (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (981 mg) and K2CO3 (774 mg). The reaction mixture was stirred at 80° C. for 20 h, cooled down and the pH was brought to 2-3 by adding 1M HCl. EA was added and the phases were separated. The org. layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 720 mg of white solid. LC-MS (B): tR=0.63 min; [M+H]+: 203.43.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC#N>[CH3:1][N:2]1[C:6]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])=[N:5][CH:4]=[N:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cncn1
Solvent: CC#N
Product: Cn1ncnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 1-methyl-1H-1,2,4-triazole (5.0 g, 60.17 mmol, 1 eq.) in 250 ml of MeCN cooled to −5° C. were added Benzoyl chloride (8.45 g, 60.17 mmol, 1 eq.) and TEA (6.39 g, 8.8 ml, 63.18 mmol, 1.05 eq.) dropwise. Upon complete addition the temperature was raised to r.t. and the reaction stirred overnight. The white solid was removed by filtration and the solvent evaporated. The yellow residue was triturated in EtOAc and the white solid removed by filtration. The solvent was evaporated and the resulting brown solid was recrystalised in EtOAc/IPE to give (1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methanone (6.5 g, 58% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=1>>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:27]([F:33])[CH:26]=1
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Product: COC(=O)c1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-bromomethyl-3-fluoro-benzoic acid methyl ester analogous to Example 2c to yield 4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester: MS: m/e=497.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O.C(#N)C>C(OCC)(=O)C>[I:13][C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccnn1-c1ccccn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(I)cnn1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-(5-methyl-1H-pyrazol-1-yl)pyridine (100 mg, 0.63 mmol) and N-iodosuccinimide (212 mg, 0.942 mmol) were added to acetonitrile (5 ml). The reaction mixture was heated to 60° C. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford 2-(4-iodo-5-methyl-1H-pyrazol-1-yl)pyridine. LRMS (ESI) calculated for C9H9IN3 [M+H]+, 286.0; found 286.0.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+]>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:12]([CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:13]
Reactant: ClCc1cccc2nnsc12
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CCc1cccc2nnsc12
Reaction time: 8 h

Procedure:
18.4 g of 7-chloromethylbenzo-1,2,3-thiadiazole are dissolved in 50 ml of chloroform, 0.5 g of tetrabutylammonium iodide are added, the mixture is heated to 50°-55° C. and treated dropwise in the course of 0.5 hours with a solution of 5.6 g of sodium cyanide in 20 ml of water, with stirring. Heating is continued overnight at the same temperature, on the following day the mixture is cooled, treated with water and extracted several times using dichloromethane. The extracts are washed with water, dried over sodium sulfate and filtered over Hyflo, and the filtrate is evaporated. The residue is purified on silica gel (hexane/ethyl acetate) resulting in the title compound of m.p. 78°-80° C.
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([CH2:26][C:27]([N:13]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:27](=[O:28])[CH2:26][C:16]45[CH2:25][CH:20]6[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]6)[CH2:23]4)[CH2:17]5)[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]3)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2
Reactant: C1COCCNCCOCCOCCN1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCN(C(=O)CC23CC4CC(CC(C4)C2)C3)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and (1-adamantyl) acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[C:12]([C:14]([C:29]#[N:30])=[C:15](SC)[NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:13]>>[C:12]([C:14]([C:29]#[N:30])=[C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)[NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:13]
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Reactant: NCCSCc1nnc(N)s1
Product: Cc1nc[nH]c1CSCCNC(NCCSCc1nnc(N)s1)=C(C#N)C#N

Procedure:
By the procedure of Example 24(iii) reacting 2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole with 1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene, gives the title compound.