Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[N:11]1[CH2:15][CH:14]([C:16]([N:18]2[CH2:22]C[CH2:20][CH2:19]2)=[O:17])[CH2:13][C:12]1=[O:23])([CH3:3])[CH3:2].C(C1CCC(C)CC1N1C(=O)CC(C(O)=O)C1)(C)C>>[N:18]1([C:16]([CH:14]2[CH2:15][N:11]([CH:5]3[CH2:6][CH:7]([CH3:10])[CH2:8][CH2:9][CH:4]3[CH:1]([CH3:2])[CH3:3])[C:12](=[O:23])[CH2:13]2)=[O:17])[CH2:19][CH2:20][CH2:22]1
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCC3)CC2=O)C1
Agent: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Product: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCC3)CC2=O)C1

Procedure:
1-(2-Isopropyl-5-methyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one was similarly prepared as described in Examples I, II, and III. 1-(2-Isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 10 g, 37.5 mmol) was used to provide 4-(azetidine-1-carbonyl)-1-(2-isopropyl-5-methyl-cyclohexyl)-pyrrolidin-2-one (10.2 mg, 32 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: N#CCCCCCCl
Product: N#CCCCCCN1CCCCC1

Procedure:
Using piperidine and 6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 181 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=O.[NH2:29][OH:30]>CO.O>[OH:30][N:29]=[CH:1][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: NO
Solvent: O
Solvent: CO
Product: Cc1c(C=NO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a slurry of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (37 mg, 0.1 mmol) in MeOH (1 ml) was added H2NOH (50% wt. in H2O, 14 μl 0.2 mmol) at rt. The heterogeneous mixture was stirred overnight, then diluted with H2O (5 ml) and filtered, the solid was dissolved in MeOH, which was concentrated to give title compound (30 mg, 78%) as a yellow powder. It has a retention time of 6.18 min (standard LCl method, 8 min run). MS Found: (M+H)+=384.2
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:33][C:31]([F:32])([F:34])[C:23]1[CH:24]=[C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])[CH:26]=[CH:27][C:22]=1[F:21]
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(C(F)(F)F)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-fluoro-3-(trifluoromethyl)phenyl isocyanate (0.21 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for twenty-four hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a beige solid (0.18 g, 48% yield), mp=96–98° C.; MS (−) ESI m/z=384 (M−H)−; [α]D25=+22.1° (c=1, EtOH).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([F:11])[CH:13]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1cc(F)cc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: COc1cc(F)cc(-c2cc(F)c(N)c(F)c2)c1
Yield: 42 %

Procedure:
The title compound (51 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-fluoro-5-methoxyphenylboronic acid (106 mg, 0.62 mmol) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.35 (dd, J 2.1, 8.1, 2H), 7.06 (d, J10.2, 1H), 7.01 (s, 1H), 6.71 (dd, J 2, 8.8, 1H), 5.42 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:5]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[C:4]([C:23](=O)[CH3:24])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:5]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[C:4]([CH:23]([NH2:32])[CH3:24])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2ccncc2)c1-c1cc(F)cc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1-c1ccncc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethanone (0.013 g, 0.036 mmol), ammonium acetate (0.028 g, 0.36 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.091 mL, 0.091 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product. LCMS calculated for C20H18ClF2N2 (M+H)+: m/z=359.1. found: 359.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[C:8](=[O:12])[NH:9][C:10]([CH3:11])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCCCc1ccc(=O)[nH]c1C
Agent: O=S(=O)(O)O
Product: CCCCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 5-butyl-6-methylpyridin-2(1H)-one (562 mg, 3.40 mmol) in concentrated sulfuric acid (4.3 mL) was cooled in an ice bath and 70% nitric acid (0.4 mL) was added dropwise. After one hour, the reaction mixture was poured into ice/water and the yellow product extracted into methylene chloride. This solution was dried, filtered and evaporated. The residue (468 mg) was chromatographed on silica gel eluting with 1-2% methanol/chloroform to yield 293 mg (41%) of pure product.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[C:48]2[CH:49]=[CH:50][NH:51][C:47]=2[CH:46]=[C:45]([CH3:52])[N:44]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:40][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[C:48]5[CH:49]=[CH:50][NH:51][C:47]=5[CH:46]=[C:45]([CH3:52])[N:44]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Cc1cc2[nH]ccc2c(Br)n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1cc2[nH]ccc2c(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)n1
Temperature: 150 °C
Yield: 22.9 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]isobutyramide (100 mg, 0.14 mmol), 4-bromo-6-methyl-1H-pyrrolo[3,2-c]pyridine (20 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (6 mg, 20 mol %) in dioxane (1.5 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The cooled reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PPC, 2 M NH3 in MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 90:10 to 02:98) to give 170 as an off-white solid (11 mg, 22%). LCMS RT 5.14 min, [M+H]+ 535. 1H NMR (CDCl3, 400 MHz) δ 7.41 (s, 1 H), 7.29-7.25 (m, 2 H), 7.14 (s, 1 H), 7.09 (d, J=5.3 Hz, 1 H), 5.36 (d, J=5.3 Hz, 1 H), 4.07 (t, J=4.6 Hz, 4 H), 3.88 (t, J=4.6 Hz, 4 H), 3.83 (s, 2 H), 2.70 (s, 3 H), 2.58 (m, 8 H), 1.23 (s, 6 H)
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)(=[O:24])[CH3:23]
Reactant: CN(O)C(=O)c1ccc(CCCCc2ccncc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ON(C)C(=O)c1ccc(CCCCc2ccncc2)cc1
Reaction time: 20 h

Procedure:
A solution of 200 mg of N-hydroxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide in dry pyridine (3.0 ml) was mixed with acetic anhydride (0.5 ml) and was allowed to stand at room temperature for 20 hours. The mixture was then concentrated in vacuo, diluted with dichloromethane, washed with a dilute Na2CO3 solution and water, dried (MgSO4 anhydrous), evaporated and the residue was purified by column chromatography on silica gel to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]([CH3:25])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:14]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:26])[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(OCC(=O)O)cc1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ccc(OCC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 30 mg, 0.085 mmol) in 1 mL methylene chloride was added 4-isopropylphenoxyacetic acid (33 mg, 0.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 35 mg (78%) of 2-(3-{1-[(4-Isopropyl-phenoxy)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester as a clear oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH:11]([N+:17]([O-])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:17][CH:11]([CH:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C(N)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 67.1 %

Procedure:
The nitro compound of Example 18 (2.1 g, 5.42 mmol) is dissolved in 50 mL of ethyl acetate aided by a few drops of methanol. A catalytic amount of 20% palladium-on-carbon is added and the reaction mixture is stirred under one atmosphere of hydrogen at room temperature for 2 hours. The catalyst is removed by filtration through Celite and washed with ethyl acetate. The solvent is evaporated to provide 1.3 g (67%) of product as a thick oil;
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][NH2:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([CH:31]=O)=[C:26]([Cl:33])[N:25]=1>O>[Cl:33][C:26]1[N:25]=[C:24]([Cl:23])[N:29]=[C:28]2[N:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[N:12]=[CH:31][C:27]=12
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: NNC1CCC2(CC1)OCCO2
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)c2cnn(C3CCC4(CC3)OCCO4)c2n1
Reaction time: 0.07 h
Yield: 70.8 %

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-yl)-hydrazine (46 g, 368 mL of above solution) was cooled in an ice bath, then triethylamine (47 mL) and ethanol (368 mL) were added. When the internal temperature reached 7.6° C., 2,4,6-trichloro-pyrimidine-5-carbaldehyde (32 g, synthesized by method of WO 02/066482) was added as a solid over 1.5 min. The internal temperature jumped to 12.6° C., and continued to rise to 17° C. during 4 min. After stirring a total of 28 min, water (367 mL) was added and the slurry was filtered. The cake was washed well twice with water (300 mL), then hexane (300 mL) and air dried over house vacuum overnight. This gave a damp cake that was washed twice with hexane (400 mL). Air-drying over house vacuum over weekend gave 35.29 g (70.8%) of 4,6-dichloro-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine, containing ˜6.5% of 2,4,6-Trichloro-pyrimidine-5-carbaldehyde. It was important to have a minimal amount of 2,4,6-trichloro-pyrimidine-5-carbaldehyde, which consumes 2 equivalents of 8-oxa-3-aza-bicyclo[3.2.1]octane in the next step.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13]C)=O)[CH2:6]1)(=[O:3])[CH3:2].[NH3:15]>>[C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([NH2:15])=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)[C@H]1CCC[C@@H](NC(C)=O)C1
Product: CC(=O)N[C@@H]1CCC[C@H](C(N)=O)C1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of cis-methyl 3-acetamidocyclohexanecarboxylate (350 mg, 1.75 mmol) and methanolic ammonia (20 ml) was stirred for 72 h at 90° C. in a steel bomb. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude product which was washed with n-pentane to afford 200 mg (57.1%) of cis-3-acetamidocyclohexanecarboxamide as white color solid.
Reaction SMILES: [Na].[CH2:2]([N:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][C:11]([C:13]1[CH:21]=[C:17]([C:18]([NH2:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[O:32]([CH2:39][CH2:40]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:23]([N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:40][CH2:39][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:17]([CH:21]=1)[C:18]([NH2:20])=[O:19])=[O:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCCOc1ccccc1

Procedure:
A solution of the sodium salt from 5-(N,N-dibenzylglycyl)-salicylamide (10 g) and sodium hydride (0.7 g) in dimethylformamide (50 ml) was heated at 100° for 2 hours with 2-phenoxyethyl bromide (6 g. ). The solution was evaporated under reduced pressure gave a yellow residue that was dissolved in ethyl acetate and water. The organic solution was washed three times with water, dried (MgSO4) and evaporated to leave the crude ether as a yellow oily solid, which was recrystallised from ethanol (150 ml) to give colourless plates (4.6 g) m.p. 146°-147°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH2:15].[N+:16]([O-])([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][NH2:16]
Reactant: Nc1cc([N+](=O)[O-])ccc1SCCCCl
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1cc([N+](=O)[O-])ccc1SCCCCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
2-[(3-Chloropropyl)sulfanyl]-5-nitrophenylamine (100 mg, 0.44 mmol) was dissolved in hydrochloric acid (1.8 mL) in an ice bath, 1 M aqueous sodium nitrate (0.5 mL) was added dropwise. This was stirred at 0° C. for 1.5 hours. 0.25 M tin (II) chloride in hydrogen chloride (3.28 mL) was added dropwise. After addition the reaction was allowed to warm to room temperature, and stirred for 1.5 hours. The reaction was basified with 50% sodium hydroxide until pH of 14 and extracted with ethylacetate (3×50 mL). The solution was concentrated to a residue, taken up in minimal chloroform and 1 M hydrogen chloride in ether was added until percipitation. The solution was filtered and dried to give 1-{2-[(3-chloropropyl)sulfanyl]-5-nitrophenyl}hydrazine (100 mg, 85%). 1H NMR (CDCl3, 300 MHz): δ7.94 (d, 1H, J=2.5 Hz), 7.3 (dd, 1H, J=8.5 Hz, J=8.4 Hz ), 7.38 (d, 1H, J=8.4 Hz), 6.28 (s-broad, 1H), 3.73 (s-broad, 2H), 3.63 (t, 2H, J=6.3 Hz ), 3.00 (t, 2H, J=7 Hz), 2.01 (q, 2H, J=6.5 Hz) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[CH3:33][O:34][C:35]1[C:36]([NH2:41])=[CH:37][CH:38]=[CH:39][CH:40]=1.NC1C=C(O)C(C)=CC=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH3:33])=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1N
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccccc3OC)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with o-anisidine according to the procedure from Example 137C substituting o-anisidine for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (120 mg, 67%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 3.12-3.28 (m, 1H), 3.78 (s, 3H), 3.81 (s, 3H), 6.92-7.05 (m, 4H), 7.05-7.12 (m, 1H), 7.13-7.23 (m, 1H), 7.40 (d, J=8.82 Hz, 2H), 7.64 (d, J=8.46 Hz, 1H), 7.71 (d, J=7.72 Hz, 1H), 7.81 (d, J=8.82 Hz, 1H), 7.99 (s, 1H), 8.59 (s, 1H), 8.86 (d, J=8.46 Hz, 1H), 9.44 (s, 1H), 9.44 (s, 1H); MS (APCI) m/z 553 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]12[N:20]([C:21](=[O:32])[CH:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:23][CH2:24]Br)[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15][CH2:14]2.C(N(C(C)C)CC)(C)C.[I-].[K+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C)C=O>[CH:17]12[N:20]([C:21](=[O:32])[CH:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:23][CH2:24][N:10]3[CH2:9][CH2:8][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12][CH2:11]3)[CH:13]([CH2:19][CH2:18]1)[CH2:14][CH2:15][CH2:16]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(C(CCBr)c1ccccc1)N1C2CCCC1CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(CCN1CCN(c2ccccn2)CC1)c1ccccc1)N1C2CCCC1CC2

Procedure:
The title compound was prepared from 4-(pyridin-2-yl)-piperazine (1.0 g, 6.0 mmole), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-bromo-2-phenyl-butan-1-one (1.6 g, 4.76 mmole), diisopropylethylamine (0.9 g, 7.0 mmole) and potassium iodide (0.8 g, 5.0 mmole) in dimethylformamide (30 mL) in the manner described in example 2 to yield 1.1 g of product as the dihydrochloride, m.p. 196°-236° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)SC)#[N:2].[CH2:20]([NH2:22])[CH3:21]>C(O)C>[C:1]([N:3]=[C:4]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[NH:22][CH2:20][CH3:21])#[N:2]
Reactant: COc1ccc2c(c1)C(N=C(NC#N)SC)CCC2
Reactant: CCN
Solvent: CCO
Product: CCNC(=NC#N)NC1CCCc2ccc(OC)cc21

Procedure:
A solution of 5.5 g of N-cyano-N'-(1,2,3,4-tetrahydro-7-methoxy-1-naphthyl)-S-methylisothiourea and 10 ml of 70 percent aqueous ethylamine in 100 ml of ethanol was heated at reflux for 37 hours. The solvent was removed by evaporation in vacuo, and the residue was chromatographed on silica gel, using ethyl acetate as eluent. The ethyl acetate was removed from the eluate by evaporation in vacuo, and the residue was crystallized from toluene to give N"-cyano-N-ethyl-N'-(1,2,3,4-tetrahydro-7-methoxy-1-naphthyl)guanidine as 2.7 g of white, crystalline solid, mp 130°-131°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:19]=4[S:20][C:3]=1[C:4]=23.Br.[Br:28][CH2:29][CH2:30][NH2:31]>CCO>[BrH:28].[CH2:16]([N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:29][CH2:30][NH2:31])=[C:3]3[S:20][C:19]4[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:17]
Reactant: NCCBr
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1c(OC)cccc1-2
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1c(OC)cccc1-2
Yield: 34.2 %

Procedure:
Reaction of a solution of 3.5 g (0.0095 mol) of 5-amino-N,N-diethyl-7-methoxy-2H[1]benzothiopyrano-[4,3,2-cd]indazole-2-ethanamine and 5.8 g (0.0283 mol) of 2-bromoethylamine, hyrobromide, in 30 ml of EtOH as described in Example 38 gave 1.6 g of product.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22]/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Product: O=C1/C(=C(\NC2CC2)c2ccccc2)Sc2ccccc21
Yield: 25 %

Procedure:
Prepared as in Example 31 with a yield of 25% of theory from 2-benzoyl-benzo[b]thiophen-3-ol and cyclopropylamine. Egg-yellow crystals, m.p. 131°-132° C. (petroleum ether/ethyl acetate 1:1).