Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.C(Cl)Cl.CSC.C[OH:23]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:23])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)ccc2ccc(F)cc21
Reactant: CO
Solvent: CSC
Solvent: ClCCl
Product: O=CCn1c(=O)ccc2ccc(F)cc21
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone (5.0 g, 0.025 mmol) in 3:1 CH2Cl2:MeOH (500 mL) was cooled to −70° and 03 was bubbled through the solution for 20 min. Dimethyl sulfide (19 mL, 0.25 mol) were added and the reaction was stirred for 90 min at −70° C., then allowed to warm to room temperature overnight. The solvents were removed under reduced pressure yielding a thick orange oil. Purification by column chromatography on silica gel (1% to 100% hexane:ethyl acetate gradient) yielded a dark yellow solid (4.2 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C(N(CC)CC)C.[CH2:24]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCOCC>[C:7]([C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=1)#[N:8]
Reactant: N#Cc1ccccc1Oc1ccccc1N
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Oc2ccccc2C#N)cc1
Yield: 77.3 %

Procedure:
In 20 ml of ether was dissolved 2.0 g of 2-(2-aminophenoxy)benzonitrile followed by addition of 2.04 g of triethylamine. Then, with ice-cooling and stirring, a solution of 2.67 g of 4-hexyloxybenzoyl chloride in 5 ml of ether was added dropwise. The mixture was further stirred at the same temperature for 1 hour. The reaction mixture was then washed with diluted hydrochloric acid and aqueous sodium hydrogen carbonate solution in that order, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate-n-hexane as the eluent and the relevant fraction was crystallized from diisopropyl ether to give 3.05 g of the title compound as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:8]1[O:10][CH2:9]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(OCC2CO2)cc1
Product: COc1ccc(OCC(O)CN2CCNCC2)cc1
Yield: 50.7 %

Procedure:
Following the procedure of part A of Example 1, 9.56 g of piperazine is allowed to react with 10 g of p-methoxyphenyl glycidyl ether to obtain 7.5 g of N-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-piperazine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.O>C1COCC1>[C:17]1(=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of triethyl phosphono acetate (35.2 g) in 100 mL THF, at 0° C., was added slowly via a syringe a solution of NaH (6.2 g) in 60 mL THF. The mixture was stirred at 0° C. for 10 minutes, cyclobutanone (10 g) was added by a syringe, and the resulting mixture was stirred at room temperature for 2 hours, followed by addition of distilled water to quench the reaction. The aqueous solution was extracted by ethyl acetate (3×20 mL), the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude residue was eluted by column chromatography (10% ethyl acetate/hexane), to give ethyl 2-cyclobutylideneacetate (20 g). 1HNMR (300 MHz, CDCl3) δ=5.57 (s, 1H), 4.13 (q, 2H), 3.11 (m, 2H), 2.81 (m, 2H), 2.08(m, 2H), 1.26 (t) ppm. MS: m/z 370 (100, M+H)+
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=[O:3].[CH2:9]([O:11][C:12](=[O:30])[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[N:15][C:14]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)C>O1CCOCC1>[F:19][C:17]1[CH:16]=[N:15][C:14]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:9](=[O:3])[O:11][C:12](=[O:30])[C:13]=2[CH:18]=1
Reactant: CCOC(=O)c1cc(F)cnc1NCc1ccc(OC)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cc(F)cnc32)cc1
Yield: 90.2 %

Procedure:
Trichloromethyl chloroformate (11.41 mL, 94.63 mmol) was added slowly to a solution of 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester (68) (24 g, 78.86 mmol) in dioxane and refluxed for 4 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was recrystallized by ether to yield 21.5 g (90%) of 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (69) as white solids. MP: 143° C.; 1H-NMR (DMSO-d6): δ 3.71 (s, 3H), 5.27 (s, 2H), 6.85 (m, 2H), 7.35 (m, 2H), 8.40 (dd, J=2.8, 6.8 Hz, 1H), 8.82 (d, J=2.8 Hz, 1H); EIMS: 303 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1>>[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH:34][C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=3)=[CH:31][CH:32]=2)[CH:27]=[N:26]1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N(C)C
Yield: 72.9 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol) and 1-(3-fluorobenzyl)-1H-indazol-5-amine (193 mg, 0.8 mmol) were reacted to give the title compound as a pale solid (272 mg, 74%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.59 (s, 2H), 6.81 (d, 1H), 6.87 (d, 1H), 6.96 (m, 2H), 7.25 (m, 1H), 7.34 (d, 1H), 7.47 (d, 1H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.07 (s, 1H), 8.42 (s, 1H), 8.62 (s, 1H); Mass spectrum 485.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH:38][CH3:39])[CH2:23][CH2:22]1.Cl>CC(C)=O.C(O)(C)C>[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][N:38]([CH3:39])[C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:23][CH2:22]1
Reactant: CNCCN1CCCCC1CNC[C@H]1CC[C@H](O)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CN(CCN1CCCCC1CNC[C@H]1CC[C@H](O)CC1)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 24 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and trans-2-[2-[[(4-hydroxy-cyclohexyl)methylamino]methyl]-piperidin-1-yl]-N-methyl-ethanamine in a yield of 24% of theory. Colourless, substantially amorphous solid substance with an approximate m.p. 105°-120° C. M.p. of the hydrochloride 210°-213° C. (D.) (acetone/isopropanol).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[I-].[K+].[CH3:30][CH:31]=[CH:32][CH2:33][NH2:34]>O1CCCC1>[F:26][C:2]([F:27])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:34][CH2:33][CH2:32][CH:31]=[CH2:30])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: CC=CCN
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-(trifluoromethyl)-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:13][C:14]1[O:18][C:17]([CH2:19][CH2:20]O)=[CH:16][CH:15]=1.CC1C=CC(S([O-])(=O)=O)=CC=1>CC(C)=O>[CH3:13][C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(CCO)o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(CCNS(=O)(=O)c2ccccc2)o1
Temperature: 90 °C
Yield: 23 %

Procedure:
Benzenesulfonamide (157 mg, 1.00 mmol) was added to a 10% aqueous solution of sodium hydroxide (0.40 mL, 1.0 mmol). A solution of compound 24A (280 mg, 1.00 mmol) in acetone (1 mL) was then added. The reaction mixture was heated at 90° C. for 8 h then cooled to room temperature. Ice was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water, dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel, eluting with CH2Cl2 gave 60 mg (0.23 mmol, 23%) of compound 24B as yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)(O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([C:4]1[CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(O)(c2cccc(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1=CCC(c2cccc(F)c2)CC1
Temperature: 30 °C
Yield: 61.7 %

Procedure:
The compound (18) (13.5 g), p-toluenesulfonic acid (0.4 g) and toluene (250 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (300 ml) and toluene (500 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder and dried, giving 7.7 g of 4-propyl-1-(3-fluorophenyl)-3-cyclohexene (19). The yield based on the compound (18) was 61.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](O)(C(F)(F)F)=O>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=[N:22][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Product: c1ccc(COc2ccc3ncn(-c4ccccc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(Benzyloxy)-N2-phenylpyridine-2,3-diamine (60 mg, 0.21 mmol) was dissolved in trimethyl orthformate (5.0 mL), and TFA (10 μL) was added. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a red solid (58 mg). 1H NMR (500 MHz, CDCl3) δ ppm 5.40 (s, 2H), 7.15 (d, J=9.0 Hz, 1H), 7.31-7.42 (m, 5H), 7.62-7.72 (m, 5H), 8.32 (d, J=9.0 Hz, 1H), 9.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23])=S)[CH:2]=[CH2:3].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[N:13]=[C:14]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)ccc1NC(=S)Nc1ccccc1Br
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reaction time: 0.25 h
Yield: 146 %

Procedure:
To a stirred solution of N-(2-Allyloxy-4-cyanophenyl)-N′-(2-bromophenyl)-thiourea (900 mg, 2.32 mmol) and triethylamine (1 ml, 6.95 mmol) in methylene chloride was added dropwise at 0° methanesulfonyl chloride (360 μL, 4.64 mmol) under Ar. The reaction was stirred for 15 minutes at 0° and tlc showed no starting material present. The reaction mixture was chromatographed on silica gel eluting with methylene chloride to afford the title compound as a yellow solid (1.2 g, >100%). This was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.O[CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(=O)([O-])O.[K+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(C)=O>[C:25]([CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]2[CH2:13][CH2:12][O:10][CH:7]([C:5]3[N:6]=[C:2]([Cl:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:29])=[CH:18][CH:19]=1)([O:27][CH3:28])=[O:26]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(Cl)n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1

Procedure:
Prepared by analogy to Example 32 by reaction of 5 g (0.0208 mol) of 2-chloro-4-bromoacetyl-thiazole with 5.6 g (0.021 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in 200 ml of acetone and 6.3 g (0.063 mol) of potassium hydrogen carbonate over 20 hours at room temperature. The reduction is carried out in 41 ml of trifluoroacetic acid using 3.5 g (0.029 mol) of triethylsilane for 24 hours. The crude product is purified on a silica gel column using methylene chloride/methanol=20:1 as eluant.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:24][CH2:23][C:13]3([CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:24][CH2:23][C:13]3([CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]3)[C:12]2=[O:25])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 133 step 5 from 10-(4-tert-butyl-phenyl)-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 343, step 1) by treatment with 2M HCl. Off-white solid (90%). MS (m/e): 300.4 [MH+].
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19](Cl)=[O:20])=[CH:12]2)[CH3:8].O>N1C=CC=CC=1>[CH2:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)=[O:20])=[CH:12]2)[CH3:8]
Reactant: Nc1nnn[nH]1
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Solvent: c1ccncc1
Solvent: O
Product: CCc1ccc2nnc(C(=O)Nc3nnn[nH]3)cc2c1
Reaction time: 8 h

Procedure:
A solution of 5-amino-1,2,3,4-tetrazole (0.425 g.) in dry pyridine (10 ml.) was added to 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.). The resulting solution was kept at room temperature overnight, and water (50 ml.) and N-hydrochloric acid (50 ml.) were then added. The mixture was filtered, and the solid residue washed with water and crystallised from aqueous dimethylformamide to give 6-ethyl-N-(1,2,3,4-tetrazol-5-yl)cinnolin-3-yl carboxamide, m.p. over 250° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([Cl:35])=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)Cl)c(F)c3)c2CC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.95 g, 4.21 mmol) in DCM (20 mL) at 0° C. under nitrogen, add three drops of DMF and oxalyl chloride (1.06 g, 8.41 mmol). Stir for 2 h and concentrate in vacuo to afford the desired intermediate as a yellow oil (1.93 g, 95%).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[C:37]=1[S:44](Cl)(=[O:46])=[O:45]>CN(C)C=O>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:44]([C:37]1[C:38]([CH3:43])=[CH:39][C:40]([CH3:42])=[CH:41][C:36]=1[CH3:35])(=[O:46])=[O:45])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)OC(C)(C)C)s1
Reaction time: 5 h
Yield: 83.8 %

Procedure:
0.490 g (1.38 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonyl-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) were dissolved in 15 ml of anhydrous dimethylformamide. Under stirring, 0.47 ml of N,N-diisopropyl-N-ethylamine and 0.302 g of 2,4,6-trimethylphenylsulfonyl chloride were added. Stirring was continued for 5 hours until the reaction was complete (thin layer chromatography). The solvents were removed in vacuo, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and with brine. After drying with anhydrous magnesium sulfate and filtration, the solvents were removed in vacuo to give 0.623 g of a yellow oil which was sufficiently pure for use in the subsequent step.
Reaction SMILES: C(OC(N1C2C=CC=CC=2N=C1CN(C[C:30](=C)[CH2:31][CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43])C1C2N=CC=CC=2CCC1)=O)(C)(C)C.O.NN.[CH2:48]([OH:50])[CH3:49]>>[OH:50][CH2:48][CH2:49][C:31](=[CH2:30])[CH2:32][N:33]1[C:34](=[O:43])[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]1=[O:42]
Reactant: CCO
Reactant: C=C(CCN1C(=O)c2ccccc2C1=O)CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Agent: NN
Solvent: O
Product: C=C(CCO)CN1C(=O)c2ccccc2C1=O
Yield: 55 %

Procedure:
To a solution of 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.239 g, 0.40 mmol) in ethanol (8 mL) was added hydrazine monohydrate (0.40 mL, 8.26 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 86 mg (55%) of the free base of the title compound as a yellow oil.
Reaction SMILES: C([O:5]C(NOCC(O)=O)=O)(C)(C)C.C(OCC)(=O)C.[CH:20]1([N:26]=[C:27]=[N:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.ON1C(=O)CCC1=O>C(#N)C>[CH:29]1([NH:28][C:27]([NH:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:5])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1.C[Si]([C:40]#[CH:41])(C)C>N1CCCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:26]2[C:27]([CH3:28])=[C:23]([C:21]([NH:20][C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:13][CH2:12][CH:11]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH2:10][CH2:9]4)=[C:2]([C:40]#[CH:41])[CH:3]=3)=[O:22])[CH:24]=[N:25]2)=[CH:30][CH:31]=1
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Br)c2)cnn1-c1ccc(Cl)cc1
Reactant: C#C[Si](C)(C)C
Solvent: C1CCNCC1
Product: C#Cc1cc(NC(=O)c2cnn(-c3ccc(Cl)cc3)c2C)ccc1N1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
A suspension of N-[3-bromo-4-(4-morpholinopiperidin-1-yl)phenyl]-1-(4-chlorophenyl)-5-methylpyrazole-4-carboxamide (1 g), bistriphenylphosphinepalladium dichloride (0.38 g), cuprous iodide (0.06 g), trimethylsilylacetylene (0.53 g) and piperidine (50 ml) was refluxed under heating for 15 h. The solvent was evaporated and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane). The resulting residue was dissolved in methanol (10 ml) and potassium carbonate (170 mg) was added. The mixture was stirred at room temperature for 1 h. After the reaction, potassium carbonate was filtered off. The filtrate was purified by silica gel column chromatography (mobile phase: chloroform/methanol) and recrystallized from a mixed solvent of chloroform-diisopropyl ether to give the title compound (27 mg), melting point: 203–205° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH:9]1[CH3:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][C:17]1[CH:18]=[C:19]([CH3:21])[N:20]=[C:15]([NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]2[CH3:23])[N:16]=1
Reactant: Cc1cc(C)nc(NC2CCCN(C(=O)OC(C)(C)C)C2C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(N[C@@H]2CCCN[C@H]2C)n1
Yield: 102.6 %

Procedure:
To the title compound from Step A (75 mg, 0.23 mmol) in DCM (4 mL) was added TFA (4 mL). Upon completion (˜3 h), the reaction was concentrated, neutralized with 5% Na2CO3 (aq) and extracted with DCM (3×). The combined organics were dried (Na2SO4) to give the title compound (52 mg) which was used without further purification. MS (ESI) mass calcd. for C12H20N4, 220.2; m/z found 221.1 [M+H]+.