Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].[NH:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[NH2:12].Cl>CCO>[NH2:8][C:7]1[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:12]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CC(C)(C#N)C(=O)CC#N
Reactant: NNc1cccc(O)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C#N)c1cc(N)n(-c2cccc(O)c2)n1
Yield: 53 %

Procedure:
2,2-Dimethyl-3-oxo-pentanedinitrile (WO 2008/034008, which is incorporated herein by reference in its entirety, 353 mg, 2.80 mmol) and Intermediate 20a (387 mg, 2.80 mmol) were suspended in EtOH (10 mL) and concentrated HCl was added (711 μL, 8.53 mmol) and the reaction was refluxed for 90 min. The reaction was cooled, concentrated in vacuo and partitioned between H2O and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo and the resulting oil was triturated with pentane/Et2O (9:1) to afford the title compound as a brown solid (363 mg, 53%). LCMS (Method 3): Rt 2.77 min, m/z 243.3 [MH+].
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:29])[CH3:28]>>[C:27]([NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:16]2[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14]=3[N:15]=2)[CH2:33][CH2:32]1)(=[O:29])[CH3:28]
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine and 4-acetylamino-piperidine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)C.C(O)CCC>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: ClCc1ccccn1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCO
Solvent: CCO
Product: c1ccc(Cn2ccnc2)nc1

Procedure:
A solution of 2-chloromethylpyridine hydrochloride (16.4 g, 0.1 mol) in ethanol (50 ml) was added dropwise to a stirred, boiling solution of potassium tert-butoxide (22.4 g, 0.2 mol) and imidazole (6.8 g, 0.1 mol) in dry butan-1-ol (100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 5 h. After removal of the solvents under reduced pressure, the resulting oil was dissolved in hydrochloric acid (150 ml, 2 M), and the acid solution was washed with ether (100 ml). The acid solution was then basified with sodium hydroxide solution (10 M), and the basic solution was extracted with chloroform (3×100 ml). The chloroform solutions were combined, dried (MgSO4 ), and the chloroform was then removed under reduced pressure. The residue was purified by using a silica-gel column and by elution with chloroform/methanol (9:1). The resulting solid was recrystallised from ethanol/light petroleum affording 1-(2-pyridylmethyl)imidazole as white cubes, m.p. 79°-80°.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[N:7][C:8](=[O:19])[C:9](=[O:18])[N:10]=2)[CH:5]=1)([O-:3])=[O:2].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[C:20]1([NH:26][C:27]([N:14]2[CH2:15][CH2:16][C:17]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]4[NH:7][C:8](=[O:19])[C:9](=[O:18])[NH:10][C:11]=4[C:12]=3[CH2:13]2)=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1N=c2cc([N+](=O)[O-])c3ncccc3c2=NC1=O
Reactant: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CN(C(=S)Nc1ccccc1)CC3
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of the 6-nitropyridoquinoxalinedione (0.1 g, 0.38 mmol), phenylisothiocyanate (70 μL), triethylamine (70 μL) in DMF (5 mL) was stirred at 60° C. for 24 hours. The mixture was poured onto water and allowed to stand. The precipitate was collected by filtration, washed with water and ether, and dried in vacuo to give product (130 mg) as a beige solid; mp 270-274° C., nmR, IR.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])[CH2:6][CH2:5][CH2:4]1)#[N:2].O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cccc(C(=O)O)c2)CCC1
Yield: 86.4 %

Procedure:
Using methyl 3-(1-cyanocyclobutyl)benzoate (0.9 g, 4.2 mmol), lithium hydroxide-monohydrate (0.26 g, 6.3 mmol), tetrahydrofuran (9.0 mL), methanol (3.0 mL) and water (4.0 mL) as starting materials and in the same manner as in Reference Example 37, the title compound (0.73 g, 86%) was obtained as a white powder.
Reaction SMILES: [Li].C#C.[Li].N.C#C.[C:8]([C:10]1([OH:30])[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:13]([CH3:29])[CH2:12][CH2:11]1)#[CH:9].[ClH:31]>>[ClH:31].[CH2:8]([C:10]1([OH:30])[C:15]2([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:13]([CH3:29])[CH2:12][CH2:11]1)[CH3:9]
Reactant: C#CC1(O)CCN(C)C(Cc2ccc(OC)cc2)C12CCCC2
Agent: C#C
Agent: Cl
Agent: N
Product: CCC1(O)CCN(C)C(Cc2ccc(OC)cc2)C12CCCC2

Procedure:
In a manner similar to the method described in example 47, 4.5 g of 6-(p-methoxybenzyl)-7-methyl-7-azaspiro [4.5] decan-10-one (obtained from 8 g of the picrate described in example 36) is reacted with acetylene lithium, prepared by dissolution of 1.1 g of lithium in 200 ml of liquid ammonia saturated with acetylene. The crude reaction product, 10-ethinyl-6-(p-methoxybenzyl)-7-methyl-7-azaspiro [4.5] decan-10-ol, is submitted to catalytic hydrogenation in the usual manner, giving the above-mentioned compound. The hydrochloride melts at 217°-220° C with decomposition. Yield 76%.
Reaction SMILES: [CH2:1]([OH:26])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][C:11]#[C:12][C:13]#[C:14][CH2:15][CH2:16][C:17]#[C:18][C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28].O1CC[CH2:34][CH2:33]1>>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30]([O:25][CH2:24][CH3:23])=[O:31])[CH3:28].[CH2:24]([OH:25])[CH2:23][CH2:22][CH2:21][C:20]#[C:19][C:18]#[C:17][CH2:16][CH2:15][C:14]#[C:13][C:12]#[C:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:26]
Reactant: CCN=C=O
Reactant: C1CCOC1
Agent: OCCCCC#CC#CCCC#CC#CCCC#CC#CCCCCO
Product: CCOC(=O)N(CC)CC

Procedure:
Following the general procedure of Example 1, 1.3 parts CF4 diol, 40 parts tetrahydrofuran, 1.42 parts ethyl isocyanate, 0.2 parts DBTE, and 4 parts TEA were mixed together and allowed to react at room temperature for 11/2 hours. The product was precipitated by the addition of 175 parts n-hexane and was quickly filtered and washed several times with additional n-hexane. After drying, the 2.3 parts of product XLV was obtained representing a 95.8% conversion. The product had a fluffy texture which changes blue very rapidly when exposed to daylight. The product was recrystallized by dissolving in 40 parts hot acetone followed by 20 parts hot petroleum ether. The precipitate turned blue during crystallization at about -8° C. The melting point of the material was 146.4° to 148.8° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:34]=[CH:33][C:21]2[CH:22]=[CH:23][C:24]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:25]=3[C:26](=O)[C:20]=2[CH:19]=1.O>C1COCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:34]=[CH:33][C:21]2[CH:22]=[CH:23][C:24]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:25]=3[C:26](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:20]=2[CH:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccc2c(=O)c3cc(F)ccc3ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C=C1c2ccc(C)cc2C=Cc2ccc(F)cc21
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Ethyl diethylphosphonoacetate (1.3 ml) was dissolved in 30 ml of THF, and 0.26 g of sodium hydride (60% oily) was added to the solution under ice cooling, followed by stirring under the same conditions for 30 minutes. To the mixture was added dropwise 20 ml of a solution of 0.3 g of 7-fluoro-2-methyl-5-oxo-5H-dibenzo[ a,d]cycloheptene in THF, and the mixture was heated under reflux for 2 hours. After cooling, water and ethyl acetate were added to the mixture, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (10/1)] to give 0.38 g (98%) of the product as a yellow oily substance.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:12]=2[C:13]=1[CH3:14]>N1C=CC=CC=1>[CH3:6][N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:24][CH:23]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc(N)cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc(NS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Methanesulphonyl chloride (0.21 g, 1.85 mmole) was added dropwise to a solution of N-methyl-N-(3-methyl-5-aminobenzofur-2-ylmethyl)-4-methanesulphonamidophenethylamine (see Preparation 10B--0.78 g, 1.68 mmole) in pyridine (7 ml) and the solution was then stirred at room temperature for 60 hours. The solvent was evaporated and the residue triturated with toluene. The toluene was decanted, the residue stirred with aqueous sodium bicarbonate, and the precipitate collected by filtration and recrystallised from methanol to give the title compound, yield 0.38 g, m.p. 142°-143.5°.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[CH:3]=[CH:2]1.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cccc2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc3occc23)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2.40 g (5.37 mmol) of 1-benzofuran-4-ol (from example XXI), 0.90 g (5.64 mmol) of 3,4-difluoronitrobenzene and 1.48 g (10.7 mmol) of potassium carbonate are suspended in 20 ml of anhydrous dimethylformamide, and the mixture is stirred at 50° C. for 5 hours. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude product is purified on a silica gel column (mobile phase: cyclohexane:ethyl acetate (10:1)).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])=[CH:27][CH:26]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-tolyl isocyanate (0.154 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 298 mg (96.8%) of the desired product as a solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:6][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CNCC[C@@H](O)c1ccccc1
Product: CNCC[C@@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
A process according to claim 6 comprising the additional step, following all preceding steps, of reacting (R)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (R)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](Cl)=[O:7].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of the product of Example 39A (13 mmol) in dichloromethane (100 mL) at 0° C. was added slowly tert-butyl piperazine-1-carboxylate (1.06 g, 13 mmol) and triethylamine (3.6 mL). After stirring for 2 hours, water was added slowly and the mixture was extracted with dichloromethane (3×200 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 100/1 dichloromethane/methanol to provide the title compound. MS: 388 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25].O.O.O.C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:25]=[C:24]([NH2:26])[N:23]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Yield: 54.5 %

Procedure:
A solution of 1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidine carbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate (32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17 hours and the solvent was removed in vacuo. The residue was diluted with water and the mixture was swirled for a few minutes. The undissolved white solid was collected and washed with water, followed by a small amount of cold ethyl acetate to give the title compound (4.10 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)=[C:4]([CH:3]=1)[C:10]([OH:9])=[O:11]
Reactant: O=C1OCc2ncc(Cl)cc21
Reactant: Oc1cccc(Cl)c1
Product: O=C(O)c1cc(Cl)cnc1COc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 3-chlorofuro[3,4-b]pyridin-5(7H)-one (Organic letters, 2001, 3, 209.) and 3-chloro phenol:
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([N:7]=[C:8]=[O:9])([F:6])[F:5]>>[CH3:1][NH:2][C:8]([NH:7][C:4]([F:6])([F:5])[F:3])=[O:9]
Reactant: O=C=NC(F)(F)F
Reactant: CN
Product: CNC(=O)NC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (3.1 grams; 0.1 mol) is placed into a glass ampule of 30 ml capacity and is cooled in an acetone-dry ice bath. Trifluoromethyl isocyanate (11.1 grams; 0.1 mol) is added to the ampule and the ampule is sealed. The reaction mixture is slowly warmed up to room temperature and is allowed to stand at this temperature for a period of about 1 hour. At the end of this time the ampule is opened and the contents removed and distilled under reduced pressure to yield N-methyl-N'-trifluoromethyl urea.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O.CCOC(C)=O>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:2]=[CH:3]2)#[N:11]
Reactant: CCOC(=O)CCBr
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Temperature: 80 °C

Procedure:
1H-indazole-5-carbonitrile (D1) (3.5 g, 24.45 mmol) was dissolved in N,N-dimethylformamide (60 ml). cesium carbonate (15.93 g, 48.9 mmol) and ethyl 3-bromopropanoate (4.68 ml, 36.7 mmol) were added. The mixture was heated at 80° C. for 4 hours. Diluted with EtOAc and washed with water (3×40 ml), dried over MgSO4 and evaporated. The mixture was purified by flash chromatography, eluting EtOAc/iso-Hexane 10-30% then 10-20% to give (3.682 g) for the first isomer (yellow oil) and (1.509 g) for the second isomer (pink solid). Analysis of the first isomer by 1H nmr indicated that is was the 1-isomer contaminated with the 2-isomer (ca. 20%) δH (d6-DMSO, 400 MHz) 1.05 (3H, t), 2.95 (2H, t), 3.97 (2H, q), 4.69 (2H, t), 7.74 (1H, dd), 7.92 (1H, dt), 8.28 (1H, d), 8.38 (1H, dd). MS (ES+): C13H13N3O2 requires 243; found (MH+) 244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:30][OH:31]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)CCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
Ethyl 3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propanoate (27 mg, 0.079 mmol) was suspended in benzene (1 mL) under an atmosphere of nitrogen and phosphorus pentachloride (18.0 mg, 0.086 mmol) was added. The solution was heated to reflux for 2.5 h. The solvent was removed in vacuo. The residue was dissolved in EtOH (1.0 mL) and hydroxylamine (100 μL, 2 mmol) (50% solution in water) was added to the reaction. After stirring 1 h, the solution was diluted with MeOH and purified by preparative LCMS to give the desired product (8.5 mg, 30%). 1H NMR (400 MHz, CD3OD): δ 7.03 (t, J=8.9 Hz, 1 H), 6.95 (dd, J=6.4, 2.7 Hz, 1 H), 6.71 (m, 1 H), 4.12 (q, J=7.2 Hz, 2 H), 3.11 (t, J=7.2 Hz, 2 H), 2.80 (t, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H); LCMS for C14H15ClFN4O1(M+H)+: m/z=357.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][N:15]=1
Reactant: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3ccnc(Cl)c3)cc2)o1

Procedure:
A mixture of 4-chloro-N-(2-chloro-4-pyridinyl)benzenesulfonamide (D3) (350 mg, 1 mmol), 5-methylfuran-2-boronic acid (150 mg, 1.2 mmol), sodium carbonate (230 mg, 2.2 mmol) and dichlorobis(triphenylphosphine) palladium(0) (20 mg, 15 mol %) in 1,2-dimethoxyethane (3 ml) and water (1 ml) was microwaved at 120° C. for 20 min. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml) and the organic phase was dried and evaporated. Purification by column chromatography eluting with 5-50% ethyl acetate in hexanes afforded the title compound (D4), MS (ES+) m/e 349, 351 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14]([C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[CH:21][C:22]([Cl:26])=[N:23]2)=[CH:18][C:17]=1[CH3:28])=[O:15])C.S([O-])([O-])(=O)=O.[Mg+2].[NH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[Cl-].[Li+]>O1CCCC1.C(OCC)(=O)C>[N:35]1([C:20]2[C:19]3[C:24](=[CH:25][C:16]([CH2:14][OH:15])=[C:17]([CH3:28])[CH:18]=3)[N:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCCNCC1
Reactant: CCOC(=O)c1cc2nc(Cl)cc(Cl)c2cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1CO
Temperature: 80 °C
Yield: 66.2 %

Procedure:
Diisobutylaluminum hydride (1 M in tetrahydrofuran, 4.9 mL, 4.9 mmol) was added dropwise to a solution of 2,4-dichloro-6-methyl-quinoline-7-carboxylic acid ethyl ester (example 81c, 200 mg, 0.704 mmol) in tetrahydrofuran (10 mL), then after 20 min the reaction was stopped by addition of 2.5 M aq. magnesium sulfate solution (2 mL). The precipitate that formed after a few seconds was removed by filtration, and the filtrate was washed with brine, dried (MgSO4), and evaporated. The residue ((2,4-dichloro-6-methyl-quinolin-7-yl)-methanol) was dissolved in 1-methylpyrrolidin-2-one (3 mL), then azepane (349 mg, 3.52 mmol) and lithium chloride (119 mg, 2.82 mmol) were added, and the solution was heated at 80° C. for 16 h. After cooling ethyl acetate was added and the solution was washed with sat. aq. ammonium chloride solution and brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) yielded the title compound (142 mg, 66%). Off-white solid, ISP-MS: m/e=305.3 ([M+H]+).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.CS[C:12](=[NH:14])[NH2:13].Cl>C(#N)C>[C:12]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)(=[NH:13])[NH2:14]
Reactant: CSC(=N)N
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Solvent: CC#N
Product: N=C(N)N1CCc2[nH]cnc2C1

Procedure:
A solution of 1.23 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 0.9 g of S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness, the residue is treated with one equivalent of ethanolic hydrogen chloride. After cooling, 1.4 g of 5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydrochloride, m.p. 310°, are collected.