Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][CH2:19][C:20]([N:9]2[CH2:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CNC2)cc1
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
A solution of 3-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 4-phenyl-1-(3-phenylazetidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 467 mg of colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1>>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]=1[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:14]=1)#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: N#Cc1ccc(O)cc1C(F)(F)F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-hydroxy-2-(trifluoromethyl)-benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:27]1[N:32]=[C:31]([S:33][C:34]#[N:35])[C:30]([N+:36]([O-:38])=[O:37])=[CH:29][N:28]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[N+:36]([C:30]1[C:31]([S:33][C:34]#[N:35])=[N:32][C:27]([NH:15][C:10]2[CH:9]=[C:8]([NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH:12][C:11]=2[CH3:14])=[N:28][CH:29]=1)([O-:38])=[O:37]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(3-amino-4-methylphenyl)carbamate (8.82 g, 39.7 mmol) in tetrahydrofuran (200 mL) were added N-ethyl-N-isopropylpropane-2-amine (10.4 mL, 59.8 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (9.49 g, 43.8 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 2×30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {3-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]-4-methylphenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: C([Li])(CC)C.[C:6]1([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[C:17]([F:23])[CH:16]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:24][C:25]([F:30])([F:29])[C:26]([CH3:28])=[O:27].O>C1COCC1>[OH:27][C:26]([CH3:28])([C:25]([F:30])([F:29])[F:24])[C:22]#[C:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[F:23]
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1F)C(F)(F)F
Temperature: 25 °C
Yield: 33.2 %

Procedure:
s-Butyllithium (0.24 ml of a 1.3M solution in hexanes) was added dropwise to a solution of 4-phenylsulphonyl-2-fluorophenylethyne (Method 28) (0.08 g) in dry THF (3 ml) at −50° C. After 25 minutes a solution of 1,1,1-trifluoroacetone (0.035 g) in dry THF (0.5 ml) was added and the mixture was allowed to warm to ambient temperature overnight. Water (10 ml) was added and THF was evaporated off under reduced pressure. The residue was diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-30% ethyl acetate/hexane then triturated with hexane to give the title compound (0.038 g) as a solid. NMR (CDCl3): 1.75 (s, 3H), 2.75 (s, 1H), 7.5-7.75 (m, 6H), 7.93 (d, 2H); EA: C17H12F4O3S requires C, 54.8; H, 3.3%; found: C, 54.4; H, 3.4%.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH2:16][CH2:17][C:18]4[NH:19][C:20](=[O:23])[CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH2:16][CH2:17][C:18]4[NH:19][C:20](=[O:23])[CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CNC
Reactant: CC(Cl)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Product: CC(c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1)N(C)C
Temperature: 80 °C

Procedure:
This compound was prepared from intermediate 245b and dimethylamine according to the procedure described in Example 171, with the exception of heating to 80° C. Received 69 mg (77%)
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH2:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(F)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylacetyl chloride (4.2 mL, 34.1 mL) was fast dropwise added to a solution of 2-bromo-5-fluorobenzenamine (4.31 g, 22.7 mmol) in CH2Cl2 (50 mL) at room temperature, followed by the addition of DIEA (7.9 mL, 45.4 mmol). The resulting mixture was stirred at room temperature for 2 hrs, and then partitioned between HCl (1N, 200 mL) and EtOAc(250 mL). After separation, the organic phase was washed with brine (50 mL), dried on MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (1200 mL) to afford the expected product, as a colorless oil (6.07 g, 98% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 9 H), 6.69 (ddd, J=8.81, 7.55, 3.02 Hz, 1 H), 7.45 (dd, J=8.81, 5.79 Hz, 1 H), 8.04 (s, 1 H), 8.28 (dd, J=11.08, 3.02 Hz, 1 H); Mass spec. 274.04 (MH+), Calc. for C11H13BrFNO 273.02.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20](=[O:22])[CH3:21])(=O)C.P(=O)(O)(O)O>C(O)(=O)C>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:1]2[CH2:6][CH2:5][CH:21]([C:20]([OH:19])=[O:22])[CH2:3][CH:2]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: O=C(O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
A mixture of 100 g (0.52 mol) of 2-phenylindole, 80.8 g (0.57 mol) of 4-cyclohexanonecarboxylic acid, 518 mL of acetic acid, 103.6 mL of acetic anhydride and 25.9 mL of 85% phosphoric acid was stirred at room temperature for 3 days and then chilled in an ice bath to 20° C. The precipitate that resulted was collected, washed with water, pressed dry, taken up in ether, and this solution was washed with water three times and with brine one time, dried over magnesium sulfate, charcoaled, evaporated at 200 mL, and let stand for 2 days to give a precipitate. This precipitate was collected and combined with a second crop to give 72.7 g (44%) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid, m.p. 178°-179° C. A small portion was recrystallized from acetonitrile, m.p. 180°-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].N([O-])=O.[Na+].[BrH:18]>>[Br:18][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In a round bottom flask, 4-cyano-3-trifluoromethylaniline (20 g, 107.5 mmol) was solubilized in 300 mL of 47% aq HBr. This solution was cooled to 0° C. in an ice bath and NaNO2 (22.2 g, 322 mmol) was added slowly. Then CuBr (46.3 g, 322.5 mmol) was added slowly. After the addition, the ice bath was removed and the mixture was stirred at 20° C. for 3 hr. The mixture was cooled to 0° C. in an ice bath and 500 mL of water were added to get a yellow precipitate. Solid was filtered and washed successively with 10% aq. HCl (50 mL) and water (100 mL), and dried to give the product (23.5 g, 87%), 1H NMR (300 MHz, Acetone-d6)δ: 8.19 (s, 1H, C3—H), 8.16 (d, 1H, J=8 Hz, C6—H), 8.05 (d, 1H, J=8 Hz, C5—H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccccn1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 5 mL of ethanol solution containing 5-chlorooxindole (167 mg, 1 mmol), 2-pyridine-carboxaldehyde (129 mg, 1.2 mmol) and 3 drops of piperidine was stirred at 80° C. for 6 hours. After cooling the solution to 5° C., yellow precipitate was obtained (200 mg, 78%). MS: m/z 257 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:17][CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:17][CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:12][CH2:11]1
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Cl)cc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1OCC1CCN(CCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5.85 g (0.020 mol) of 4-[(5-chloro-2-methoxyphenoxy)methyl]piperidine hydrochloride, 8.37 g (0.022 mol) of 3-bromo-N-(triphenylmethyl)propanamine and 6.91 g (0.050 mol) of K2CO3 in 50 ml of DMF are reacted. The reaction mixture is heated to 95°-100° C. It is cooled to room temperature, poured into 150 ml of water and extracted 3 times with ethyl acetate. The organic phases are combined, washed with water, dried over MgSO4, filtered and evaporated. The product is obtained after chromatography.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([N:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]=[CH2:11]
Reactant: OCCNc1ccccc1
Reactant: C=CCBr
Product: C=CCN(CCO)c1ccccc1

Procedure:
2-anilinoethanol (13.7 g, 0. 10 mol) is treated with allyl bromide (18.15 g, 0.15 mol), in the manner as set forth in Example 3, to provide N-allyl-N-(2-hydroxyethyl)benzenamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]1>CN(C=O)C.C(N(CC)CC)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
1,2-dichloro-4-(chloromethyl)benzene (390 mg, 1.99 mmol)) was added to a solution of tert-butyl 4-piperidinylcarbamate (400 mg, 2.0 mmol) in DMF (25 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 3 hrs and then concentrated in vacuo. To the solution of the solid in dichloromethane was added (30 ml) trifluoroacetic acid (6 ml) was added and stirred at room temperature for 2 hrs. The solution was diluted with dichloromethane and washed with two portions of water. The combined water washings were treated with 2M NaOH to pH 10 and extracted with ether. The ether was dried (Na2SO4), filtered and evaporated to leave a yellow residue (300 mg, 1.16 mmol).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24]>>[OH:27][C:26]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:23](=[O:24])[C:22]=1[S:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: Cc1ccccc1SC(C(=O)O)C(=O)O
Product: Cc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-methylphenyl)thio]propanedioic acid (1.43 g, 5.07 mmol). m.p. 210°-211° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 6.82 (s, 1H), 6.86 (d, 1H), 7.04 (m, 2H), 7.17 (d, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:16])[C:10]([CH3:15])=[C:11]([CH3:14])[CH:12]2[OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C)C(=O)N(c2cccc(C)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1=C(C)C(O)N(c2cccc(C)c2)C1=O
Yield: 9.2 %

Procedure:
To 20 g (0.93 mole) of the resulting N-(3-methylphenyl)dimethyl-maleimide in 180 ml of methanol is added at 20° 7.2 g (0.185 mole) of sodium borohydride in portions so small that the temperature does not exceed 40°. An intense evolution of gas is observed. The reaction mixture is initially a clear colourless solution, but soon becomes a white suspension, which is poured after one hour into water. The white substance which has precipitated out is filtered off, washed well with methanol and dried under reduced pressure to obtain 18.6 g of white crystals (92.1% of theory), which melt at 170°-172° (compound No. 9, Table I).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: O=[N+]([O-])c1cccc(C=NNC(=S)NC2CC3C=CC2C3)c1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 3-nitrobenzaldehyde (85 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (68 mg, 38%). 1H NMR (CDCl3): 9.82 (s, 1H), 8.48 (t, J=1.8 Hz, 1H), 8.28-8.25 (m, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 6.26-6.16 (m, 2H), 4.32-4.25 (m, 1H), 3.09 (s, 1H), 3.00 (s, 1H), 1.97-1.90 (m, 1H), 1.70 (d, J=9.0 Hz, 1H), 1.53 (d, J=9.3 Hz, 1H), 1.49-1.43 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C>[CH3:14][C:2]1([CH3:1])[CH2:10][C:9]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.8 %

Procedure:
To a solution of 6,6-dimethyl 3-ethyl-4,5,6,7-tetrahydro-1H-indol-4-one (50 mg, 0.26 mmol) in DMF (4 mL) at 0° C., was added NaH (11 mg of a 60% dispersion in mineral oil, 0.29 mmol). The cooling bath was removed and the mixture stirred at room temperature for 20 min. After this time 2-fluoropyridine (26 μl, 0.29 mmol) was added and the residue heated at 90° C. for 6 h. The solvent was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed an silica gel, eluting with hexane:EtOAc (2:1), to give the title pyrrole (18 mg, 26%) as a colourless solid. mp 125-127° C. 1H NMR (360 MHz, CDCl3) δ 1.10 (6H,s), 1.23 (3H,t,J=7.4 Hz), 2.38 (2H,s), 2.83 (2H,d of q, J=7.4 and 1.0 Hz), 2.92 (2H,s), 6.88 (1H,s), 7.25-7.27 (1H,m), 7.30 (1H,d,J=8.0 Hz), 7.82 (1H,d of t, J=7.7 and 1.9 Hz), 8.51-8.57 (1H,m). MS (ES+) 269 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:14])[CH2:4][CH2:5][CH:6]=[C:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:14])[CH2:4][CH2:5][CH:6]1[O:23][C:7]1([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC(C)=CCCC(=O)CBr
Solvent: ClCCl
Product: CCCCCC1(C)OC1CCC(=O)CBr
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 95.9 %

Procedure:
1-Bromo-6-methyl-2-oxo-undec-5-ene (10.4 g, 0.04 mole) is dissolved in methylene chloride (100 ml). The solution is cooled to 0° C. and m-chloroperbenzoic acid (7.9 g, 0.04 mole of 85% pure substance) in methylene chloride (180 ml) is added while stirring at +5°-10° C. within 25 minutes. After stirring for 3 hours at 0° C., the reaction mixture is stored at +5° C. for 16 hours. It is then filtered through a sintered glass funnel, and the filtrate is washed first with saturated aqueous sodium bicarbonate, and then 5 times with sodium sulfite (60 g in 500 ml of H2O). The solution is washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered, and evaporated in vacuo to give 1-bromo-5,6-epoxy-6-methyl-undecan-2-one (10.63 g).
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]13[C:25]2[C:16](=[CH:17][C:18]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[CH:24]=2)[O:15][CH2:14]1.N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:39]4[O:44][CH2:43][CH2:42][O:41][C:40]=4[CH:45]=3)OC2)C1=O>>[CH3:39][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:45][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:8]1=[O:13]
Reactant: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (37%): mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ8.77 (s, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.56 (s, 1H), 6.23 (s, 1H), 4.83 (ABq, 2H), 4.23-4.04 (m, 6H), 3.85-3.77 (m, 2H), 3.67-3.61 (m, 2H), 3.52-3.46 (m, 1H), 3.32 (s, 3H); MS (ES+) m/z 455.1 (M+1).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([CH3:21])[C:8]=2[C:9]#[N:10])[CH2:3]1.N.S(=O)(=O)(O)[OH:24]>>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=[C:11]([CH3:21])[C:8]=2[C:9]([NH2:10])=[O:24])[CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C#N
Agent: N
Product: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C(N)=O
Yield: 68 %

Procedure:
A solution of 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile (0.18 g, 0.62 mmol) in sulphuric acid (8 ml) is heated at 100° C. for 1 h. After completion of the reaction (monitored by TLC), the mixture is poured onto ice water. The aqueous layer is basified with aqueous ammonia to pH 10 and extracted with ethyl acetate (3×20 ml). The combined organic layers are washed with water (10 ml), dried over sodium sulfate and concentrated in vacuo yielding 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide (0.13 g, 0.423 mmol, 68%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][CH:20]([OH:25])[CH2:21]3)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.Cl.[NH:27]1[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28]1.C(N(CC)CC)C>C(#N)C>[OH:25][CH:20]1[CH2:19][CH:18]2[N:17]([C:4]3[C:5]4[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:9][S:8][C:6]=4[N:7]=[C:2]([N:27]4[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28]4)[N:3]=3)[CH:22]([CH2:23][CH2:24]2)[CH2:21]1
Reactant: OC1CC2CCC(C1)N2c1nc(Cl)nc2scc(-c3ccccc3)c12
Reactant: NC(=O)C1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)C1CCN(c2nc(N3C4CCC3CC(O)C4)c3c(-c4ccccc4)csc3n2)C1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
8-(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (44 mg, 0.12 mmol) was suspended in acetonitrile (3 mL). Pyrrolidine-3-carboxamide hydrochloride (36 mg, 0.24 mmol) and triethylamine (0.067 mL, 0.47 mmol) were added and the mixture was heated to 150° C. for 30 min in a microwave (twice). Further batches of pyrrolidine-3-carboxamide hydrochloride (36 mg, 0.24 mmol) and triethylamine (0.067 mL, 0.47 mmol) were added and the mixtures were heated to 150° C. for 30 min in a microwave. The solvent was evaporated and the residue was purified by LCUV (acidic method 1) to give the target compound as a white solid (44 mg). m/z [M+H]+450.1. Retention time 3.75 min (LCMS method+ve 6 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[C:21](OCC)(OCC)(OCC)[CH3:22]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:21]([CH3:22])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: NNc1cc(-c2ccccc2F)c2cc(Cl)ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3F)c3cc(Cl)ccc3n12

Procedure:
In the manner given in Example 2, 6-chloro-4-(o-fluorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-chloro-1-methyl-5-(o-fluorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]1[CH2:5][O:4]1.[CH3:8][C:9]([NH2:12])([CH3:11])[CH3:10]>CO>[CH3:8][C:9]([NH:12][CH2:5][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])([CH3:11])[CH3:10]
Reactant: ClC(Cl)(Cl)C1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)C(Cl)(Cl)Cl

Procedure:
The preparation of 2-(trichloromethyl)oxirane is reported by H. Gilman and R. K. Abbott, Jr., J. Org. Chem. 8, 224 (1943). 2-(Trichloromethyl)oxirane can be reacted with 1,1-dimethylethylamine at about -30° to +50° C. in a solvent such as methanol to produce 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol.