Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: BrCCCC1CC1
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCC1CC1)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react will 1-bromo-3-cyclopropylpropane (Step IV) to give the titled product, a compound of Formula I'. The high resolution FAB mass spectrum had (M+H)+ at m/z 369. Theory for C19H33N2O3S: 369.2212; measured: 369.2207.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[CH3:21]I.[OH-].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:21])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:8]([CH3:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)n(C)n1
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
In analogy to the procedure described for example 2 a], 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (PCT Int. Appl. (2003), WO 2004000785 A2) was reacted with methyl iodide in the presence of potassium hydroxide to give 2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester and 1-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester, both as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: NCCCN1CCOCC1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(NCCCN3CCOCC3)c2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
0.162 g (0.00041 mol) of 4-(2,6-dibrompyridine-4-sulphonyl)-phenylamine was dissolved in 6 ml of dioxane and treated with 0.60 ml of 4-(3-aminopropyl)morpholine. The mixture was stirred at 60° C. for 24 hrs., the solvent was removed and the residue was chromatographed on silica gel with 3% methanol in dichloromethane. There was obtained 0.15 g (80%) of [4-(4-aminobenzenesulphonyl)-6-brompyridin-2-yl]-(3-morpholin-4-ylpropyl)amine as a white, amorphous solid. MS (ISP): me/e=457, 455 (C18H24BrN4O3S+).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:5].[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>CO>[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[S:26][CH:2]=[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[N:27]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ccccc1C(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCCNC(N)=S
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1csc(NCCCNC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
A mixture of 2.55 g (10.6 mmol) 3-Bromo-1-o-tolyl-propane-1,2-dione, 1.9 g (8.1 mmol) (3-thioureido-propyl)-carbamic acid tert-butyl ester and 5.66 ml (40.6 mmol) NEt3 in 100 ml methanol was heated to 80° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purifier by flash column chromatography on silica eluting with a gradient of heptane and ethyl acetate. Evaporation of the product fractions yielded 2.17 g (71%) of the title compound as dark red oil.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:6]([N:13]1[C:14]([CH2:17][OH:18])([CH3:19])[CH2:15][O:16][CH2:2][C:3]1=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CO)(CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC1(CO)COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (14.0 ml) was added dropwise to a mixture of 2-benzylamino-2-methyl-1,3-propanediol (28.5 g), potassium carbonate (30.3 g) in dichloromethane (150 ml) and water (150 ml) at 0° C., and the whole was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane and the extract was washed successively with water, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tert-butanol (400 ml) and the solution was added potassium tert-butoxide (16.38 g) portionwisely and the whole was refluxed for 30 minutes. After cooling, the solvent was removed by evaporation and ethyl acetate and water were added thereto. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give 4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.89 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[C:14](Cl)(Cl)=[O:15].C1C=CC=CC=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[O:7][C:14](=[O:15])[NH:9][N:8]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
The reactions of Equation 37 above can be run according to similar procedures described in U.S. 4,259,104; Golfier and Milcent, J. Heterocycl. Chem., 10, 989 (1973); and R. Madhavan and V. Srinivasan, Indian J. Chem. 7, 760 (1969). Thus, in reaction 37a, a 2-nitrobenzhydrazide XLVIII is reacted with phosgene in an aprotic solvent such as benzene at ambient temperature for about 10 hours, followed by addition of two mole equivalents of triethylamine and heating at reflux for about 2 hours to form 2-(2-nitrophenyl)-1,3,4-oxadiazolin-5-one of Formula (LI). In reaction 37b, LI is reacted with phosphorus pentachloride in phosphorus oxychloride or with phosphorus pentabromide in phosphorus oxybromide at 25° to 80° C. for about 5 hours to form (Xk'"). And in reaction 37c, Xk'" is reacted with sodium methoxide or sodium ethoxide in a solvent such as methanol or tetrahydrofuran at 0° to 30° C. for about 0.5 to 5 hours to form Xk"".
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:3]1=2.[CH2:19](O)[CH3:20]>>[O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:3]1=2
Reactant: CCO
Reactant: O=C(O)c1ccc2oc3ncccc3c(=O)c2c1
Product: CCOC(=O)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 10.5 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid and 150 ml of ethanol is allowed to absorb 10 g of hydrogen chloride gas, and then refluxed for 16 hours. The ethanol is distilled off, and water is added to the crystalline residue. The mixture is extracted with chloroform, and the chloroform layer is washed with aqueous potassium carbonate solution and dried. The chloroform is distilled off, and the residue is recrystallized from ethanol to give ethyl 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylate melting at 131°-132°C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].CCN(C(C)C)C(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH3:11])=[N:7]1)(=[O:14])[CH3:13]
Reactant: Cc1n[nH]c2cc(F)ccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)n1nc(C)c2ccc(F)cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
6-Fluoro-3-methyl-1H-indazole (2.79 g, 18.6 mmol) in CH2Cl2 (50 mL) was treated with acetic anhydride (2.8 g, 30 mmol), Hunig's base (5.2 mL, 30 mmol) and DMAP (0.2 g, 1.7 mmol). The mixture was stirred 1 h at 20° C., poured into water (100 mL) and extracted with CH2Cl2 (2×100 mL). The extracts were dried (Na2SO4), concentrated and the residue recrystallised from hexane to give the title compound (3.41 g, 96%) as a white crystalline solid; mp 89°-91° C. (from hexane); 1H NMR (360 MHz, CDCl3) δ 8.05 (dd, J=9.4, 2.2 Hz, 1H, indazole), 7.51 (dd, J=8.7, 5.1 Hz, 1H, indazole), 7.03 (dt, J=8.8, 2.2 Hz, 1H, indazole), 2.67 (s, 3H, Me), 2.49 (s, 3H, Ac); MS (CI+) m/e 193 (M+H+); Anal. calcd for C10H9FN2O: C, 62.49; H, 4.72; N, 14.58. Found: C, 62.50; H, 4.79; N, 14.63.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.Cl>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Reactant: Clc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(Cl)c21
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 17.1 %

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 1.85 mmol) in DMF (5 mL) was added Cs2CO3 (1.51 g, 4.62 mmol) at room temperature, followed by 2-chloropyrazine (254 mg, 2.22 mL). The resulting mixture was stirred at 90° C. for 40 min. The mixture was poured into ice-water and acidified to pH=2 with diluted hydrochloric acid. The resulting mixture was extracted with EtOAc (2×25 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the product (110 mg, yield: 32%). MS (ESI) m/z=349 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[Cl:8][S:9](O)(=[O:11])=[O:10]>>[Cl:1][C:2]1([S:9]([Cl:8])(=[O:11])=[O:10])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1
Reactant: Clc1csc(Cl)n1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1

Procedure:
can be prepared in a process in which, in a first step, 2,4-dichloro-thiazole is reacted with chlorosulphonic acid to give 2,4-dichloro-thiazole-sulphonyl chloride, in which, in a second step, the 2,4-dichloro-thiazole-sulphonyl chloride is reacted with primary amines or with a primary and a secondary amine to give 2-amino-4-chloro-thiazole-sulphonamides, and in which, in a third step, the sulphonamides mentioned are reacted with dichlorohalogenomethylsulphenyl chlorides to give the substances of the formula (I).
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH2:6]C#N)[CH2:3][C:4]#[N:5].[OH:10]O.[CH:12]([O-:14])=[O:13]>[OH-].[Na+].O>[OH:1][C:2]([CH3:9])([CH2:6][C:12]([OH:14])=[O:13])[CH2:3][C:4]([NH2:5])=[O:10]
Reactant: CC(O)(CC#N)CC#N
Reactant: O=C[O-]
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)(CC(N)=O)CC(=O)O

Procedure:
A solution of 12.4 g (0.10 moles) of 3-hydroxy-3-methylglutaronitrile in 107 ml of 1.3 M sodium hydroxide is stirred at room temperature while 17.4 ml (0.20 moles) of 30% hydrogen peroxide is slowly added. After the addition of peroxide, the mixture is heated to boiling and boiling is maintained for 2 hours. Thereafter the mixture is cooled, diluted to 1 liter with water and passed through a 200 ml column of Dowex 2 resin in the formate form. The column is then washed with 1 liter of water. Thereafter the product is eluted with 1 liter of 0.1 N formic acid and the eluate evaporated to dryness to afford 3-hydroxy-3-methylglutaric acid monoamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2)[CH3:12].N1CCCCC1>C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:20]2)[CH3:29]
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of oxindole (26 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 50 mg (67%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]1.C1COCC1.O.[Li+].[OH-]>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1
Reactant: COC(=O)C1(c2nc3ccccc3o2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1(c2nc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred solution of methyl 1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylate (0.132 g, 0.6077 mmol) in 3 mL 3:2 THF:H2O at room temperature under nitrogen was added LiOH (0.02911 g, 1.215 mmol). After stirring at ambient temperature overnight the reaction was diluted to 30 mL with ethyl acetate and washed with 2N HCl, water and brine. The organics were dried (MgSO4), filtered and concentrated to a white solid (100 mg, 81% yield).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH2:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>ClC(Cl)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([NH:18][CH2:20][C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: N#Cc1ccc(CNC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (20 mg, 80 μmol) in dichloroethane (2 ml) was added 4-(bromomethyl)benzonitrile (17 mg, 87 μmol) and DIPEA (15 μl, 87 μmol). The reaction was heated at 100° C. for 16 hours, concentrated at reduced pressure and purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound as colourless oil (10 mg, 33%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([NH:11][CH2:12][CH2:13][NH2:14])([CH3:10])[CH3:9].Cl[CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19]>C(N(CC)CC)C>[CH:8]([NH:11][CH2:12][CH2:13][NH:14][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19])([CH3:10])[CH3:9]
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Reactant: CC(C)NCCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)CCNCCNC(C)C
Yield: 63.2 %

Procedure:
Three hundred milliliters of a toluene solution of a mixture of N-isopropyl-1,2-ethylenediamine (20.0 g), 3-chloro-2',6'-dimethylpropionanilide (13.9 g) and triethylamine (10 ml) is treated as in Example 1 to provide a pale yellow powder. Recrystallization from n-hexane provides a colorless needle in an amount of 11.5 g (yield: 63.2%). m.p. 69.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1cn(-c2ccccc2)nc1OCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 42.8 %

Procedure:
Using [3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.79 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.51 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.51 g, 43%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:19])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([NH:14]3)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.C(N(C(C)C)CC)(C)C.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:19])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: BrCC1CC1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2CC1CC1
Yield: 32 %

Procedure:
To a stirred solution of 2.2 g of 10-chloro-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 40 ml of dimethylformamide was added 3.2 ml of diisopropylethyl amine and 1.07 ml of cyclopropylmethyl bromide, under nitrogen. The reaction mixture was warmed in an oil bath maintained at 70°-77° C. Additional cyclopropylmethyl bromide (0.16 ml) was added, warming continued for a total of 3 hr, and the solution was poured into dilute aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/0-5% methanol/ethyl acetate) followed by recrystallization from ether/dichloromethane/pentane to afford 0.97 g (32%) of product. The product was combined with products from two other reactions. The combined material was recrystallized from dichloromethane and the sublimed (175°-180° C., about 0.2 mm) to give the analytical sample, mp 187°-190° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([F:13])([F:24])[F:25]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccccc1C(F)(F)F
Yield: 61.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-(trifluoromethyl)benzoyl chloride (80 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 63 mg of N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide as a brown oil (Yield: 61%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].NC(CS)C(O)=O>C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (452 mg, 0.981 mmol) was added to a solution of 2-amino-3-mercaptopropanoic acid (214 mg, 1.767 mmol) in TFA (5 mL) and was stirred at room temperature for 15 min. The reaction mixture was poured into ice water. The white precipitate was collected by filtration to provide the title compound (342 mg). LCMS m/z=405.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.40 (d, J=6.1 Hz, 6H), 2.26-2.36 (m, 1H), 2.66 (dd, J=16.4, 8.5 Hz, 1H), 2.85-2.97 (m, 2H), 3.72-3.80 (m, 1H), 3.98-4.06 (m, 1H), 4.10-4.17 (m, 1H), 4.65 (septet, J=6.1 Hz, 1H), 5.00 (s, 2H), 6.12 (s, 1H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.8, 2.4 Hz, 1H), 7.64 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[S:8]1)=[O:4]
Reactant: CCCCOc1nc(O)ns1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 17.5 g of 3-hydroxy-5-n-butoxy-1,2,4-thiadiazole in 125 ml of tetrahydrofuran containing 0.5 ml of triethylamine and after stirring for 2 hours at 20° C, the mixture was evaporated to dryness. The residue was empasted with isopropyl ether and was vacuum filtered and dried to obtain 21 g of 2-(N-methylcarbamoyl)-5-n-butoxy-1,2,4-thiadiazole-3-one melting at 108° C.