Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:14][CH2:12][CH3:13])=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCN
Product: CCNC(=S)Nc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Chloro-2-methylphenyl isothiocyanate (18.3 g; 0.1 mol) was added dropwise to aqueous ethylamine (200 mL of 70% solution). The mixture was stirred for 18 hour at ambient temperature. Excess ethylamine was removed under a stream of nitrogen. The residue was diluted with water. The solids were collected by filtration, washed with water and dried to give N-(5-chloro-2-methylphenyl)-N ′-ethylthiourea (18.9 g). A sample crystallized from ethyl acetate afforded a solid, m.p. 120–122° C. Mass spectrum;; FAB (M+H)+ m/z 228. 1H-NMR (DMSO-d6; 300 MHz): δ 9.01 (br s, 1H), 7.67 (br s, 1H), 7.35 (br s, 1H), 7.25–7.16 (m, 2H), 3.44 (m, 2H), 2.13 (s, 3H), and 1.08 ppm (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)=[O:4].[NH2:15][CH2:16][C:17]([N:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)[C:22]=1[Cl:48])[CH3:20])=[O:18].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:48][C:22]1[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:19]([CH3:20])[C:17](=[O:18])[CH2:16][NH:15][C:12](=[O:14])[CH2:11][N:8]1[CH2:7][CH2:6][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CNC(=O)C1CCN(CC(=O)O)CC1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CNC(=O)C1CCN(CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CC1

Procedure:
2-(4-(methylcarbamoyl)piperidin-1-yl)acetic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide were combined as described for compound 1 to give 13. LCMS (+ESI) 682 (M+). 1H-NMR (CDCl3, δ): 8.58 (m, 1H), 7.88 (bt, 1H), 7.58 (t, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.20 (d, J=2.8 Hz, 3H), 3.82 (dd, 1H), 3.56 (dd, 1H), 3.24 (s, 3H), 2.94 (m, 4H), 2.81 (d, J=4.8 Hz, 3H), 2.18 (m, 3H), 1.85 (m, 5H). Calcd. for C33H37Cl2N7O5+3.1H2O: C, 53.67; H, 5.90; N, 13.28. Found: C, 53.29; H, 5.52; N, 12.92.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](N)[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1N
Reactant: Cc1cccc2nc(C(C)N)c(-c3ccccc3)c(=O)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2nc(C(C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)c(=O)n12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-aminoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.178 g, 0.637 mmol) and 4,6-diaminopyrimidine-5-carbonitrile (0.090 g, 0.67 mmol) in butan-1-ol (4 mL) was added diisopropylethyl amine (0.33 mL, 1.91 mmol). After stirring at 120° C. for 3 h, the solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-8% MeOH in DCM) to afford 4-amino-6-(1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethylamino)pyrimidine-5-carbonitrile as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.65 Hz, 3 H) 2.91 (s, 3 H) 5.09 (quin, J=6.85 Hz, 1 H) 6.97 (d, J=7.04 Hz, 1 H) 7.03 (d, J=7.24 Hz, 1 H) 7.32 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.72 (dd, J=8.80, 6.85 Hz, 1 H) 7.98 (s, 1 H) Mass Spectrum (ESI) m/e=398.1 (M+1). The racemic mixture (0.210 g) was separated by chiral separation using SFC to give 2 fractions. First-eluting enantiomer on AD-H column: 4-amino-6-(((1S)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (d, 3 H) 2.90 (s, 3 H) 5.09 (qd, J=6.89, 6.72 Hz, 1 H) 6.97 (d, J=6.85 Hz, 1 H) 7.04 (d, J=7.34 Hz, 1 H) 7.33 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.71 (dd, J=8.93, 6.97 Hz, 1 H) 7.97 (s, 1H) Mass Spectrum (ESI) m/e=398.1 (M+1). Second-eluting enantiomer on AD-H column: Concentration of product fractions gave a solid that was triturated in water and filtered to afford 4-amino-6-(((1R)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. Mass Spectrum (ESI) m/e=398.1 (M+1).
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[CH2:10]([NH2:13])[CH2:11][NH2:12].C(N(CC)CC)C>CO>[C:5]([C:4]([NH:12][CH2:11][CH2:10][NH2:13])=[O:9])([F:6])([F:7])[F:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: CO
Product: NCCNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
N-1-trifluoroacetylethyldiamine (CF3CONH(CH2)2NH2 is prepared by adding ethyltrifluoroacetate (1.2 ml, 10 mmol) dropwise over one hour to a stirred mixture of ethylenediamine (0.6 g; 10 mmol) and triethylamine (1 ml; 7 mmol) in 20 ml methanol. The solution is stirred overnight. After removal of solvents, the reaction mixture is flash chromatographed on silica using 0-25% methanol in dichloromethane. The fractions containing the desired product are pooled and concentrated to give a colorless product.
Reaction SMILES: [NH2:1][CH:2]([C:5]([F:8])([CH3:7])[CH3:6])[CH2:3][OH:4].C1C[O:12][CH2:11]C1>C(Cl)Cl>[F:8][C:5]([CH:2]1[CH2:3][O:4][C:11](=[O:12])[NH:1]1)([CH3:7])[CH3:6]
Reactant: C1CCOC1
Reactant: CC(C)(F)C(N)CO
Solvent: ClCCl
Product: CC(C)(F)C1COC(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-carbonyldiimidazole (530 mg, 3.27 mmol in THF (5 mL) was added slowly a solution of 2-amino-3-fluoro-3-methylbutan-1-ol (360 mg, 2.97 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 18 hr, was diluted with DCM and stirred for additional 30 min. The separated organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] to provide 4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 148.0 (M+H)+; Rt-0.32 min. 1H NMR (400 Mhz, CDCl3) δ ppm 6.30 (br. s., 1H), 4.39-4.54 (m, 1H), 4.26 (dd, J=8.9, 5.1 Hz, 1H), 3.84-3.99 (m, 1H), 1.29-1.45 (m, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C@@H:16]4[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]4)[NH:13][N:12]=3)[CH:9]=2)[N:4]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:3]=1.[N:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[N:48]1[CH:53]=[CH:52][C:51]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]5)[NH:13][N:12]=4)[CH:9]=3)[N:4]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:3]=2)=[CH:50][CH:49]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(Br)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Yield: 86.8 %

Procedure:
Stirred a mixture of (R)-tert-butyl 3-(3-(3-bromo-1-trityl-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (500 mg, 0.72 mmol), pyridine 4-boronic acid (150 mg, 1.22 mmol), PdCl2dppf (30 mg, 0.036 mmol) and Cesium carbonate (400 mg, 1.23 mmol) in dioxane (9 mL) and water (1 mL) at 100° C. in a microwave oven for 2 hours. After cooling, diluted with water (50 ml), then extracted with DCM (100 ml). The combined organic layer was dried (Na2SO4), filtered and evaporated to yield crude product, which chromatographed on silica gel eluting with 30% v/v EtOAc/Hexanes to yield (R)-tert-butyl 3-(3-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (430 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2)=O.[OH-].[Na+].O>CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Reaction time: 18 h

Procedure:
A mixture of 25.8 g. of 6-methoxycarbonyl-2-naphthyl-α-methylacetic acid, 4 g. of sodium hydroxide, 10 ml. of water, and 500 ml. of methanol are heated to 50° C, cooled, and evaporated. The residue is taken up in 500 ml. of diethylene glycol dimethyl ether and diborane is bubbled through. The resulting mixture is saturated with diborane and then is allowed to stand for 18 hours. The reaction mixture is acidified by the addition of aqueous 1N hydrochloric acid. The mixture is extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-hydroxymethyl-2-naphthyl-α-methylacetic acid.
Reaction SMILES: O([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1C(COC)=C(C3C=CON=3)N=CC=1N2)C1C=CC=CC=1.ClC1C=CC([O:34][C:35]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:36]=2[C:37]2[C:38]([CH2:56][O:57][CH3:58])=[C:39]([C:48]4[CH:52]=[C:51]([CH2:53][O:54][CH3:55])[O:50][N:49]=4)[N:40]=[CH:41][C:42]=2[NH:43]3)=CC=1>>[CH2:10]([O:34][C:35]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:36]=1[C:37]1[C:38]([CH2:56][O:57][CH3:58])=[C:39]([C:48]3[CH:52]=[C:51]([CH2:53][O:54][CH3:55])[O:50][N:49]=3)[N:40]=[CH:41][C:42]=1[NH:43]2)[C:9]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:8]=1
Reactant: COCc1c(-c2ccon2)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reactant: COCc1cc(-c2ncc3[nH]c4cccc(Oc5ccc(Cl)cc5)c4c3c2COC)no1
Product: COCc1cc(-c2ncc3[nH]c4cccc(OCc5ccccc5)c4c3c2COC)no1

Procedure:
5-phenoxy-4-methoxymethyl-3-(3-isoxazolyl)-β-carboline, 5-(4-chlorophenoxy)-3-(5-methoxymethyl-3-isoxazolyl)-4-methoxymethyl-β-carboline;
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Br:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1[nH]nc(N)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography ethyl acetate afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.94–7.02 (m, 2H), 6.82–6.88 (t, 2H), 4.84 (s, 2H), 4.1 (s, 2H), 3.72–3.78 (m, 4H), 3.04–3.08 (m, 4H), 2.16 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+H expected 396.27, found 396.
Reaction SMILES: [OH:1][C:2]([CH3:20])([C:9]([CH3:19])=[CH:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:23]Br>CO.C(=O)([O-])O.[Na+].O.CO>[OH:1][C:2]1([CH3:20])[C:9]([CH3:19])([Br:23])[CH:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(O)C(C)=CC=Cc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(O)CC(=O)OC(C=Cc2ccccc2)C1(C)Br
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
The carboxylic acid (1.09 g) prepared by hydrolyzing 12.20 g of ethyl 3-hydroxy-3,4-dimethyl-7-phenyl-4,6-heptadienoate with 4 N sodium hydroxide solution in 60 ml of methanol, was dissolved in a solution of 700 mg of sodium hydrogen carbonate in 40 ml of a solvent mixture of water-methanol (1:1) and a solution of 1.06 g of bromine in 1 ml of methanol was dropwise added thereto under cooling at -30°~35° C. After stirring for 30 minutes, the crystals produced were collected by filtration, washed with water, dried, and recrystallized from a mixture of n-hexane and ethyl acetate (5:1) to give 750 mg of the desired compound melting at 121°-123° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CC(C)=O.O>[C:18]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)ccc1NC(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
8.2 g of potassium carbonate was added to a suspension of 3.0 g of 4-amino-3-methylbenzoic acid in 60 ml of acetone and 60 ml of water. Thereto was dropwise added, with ice-cooling, a solution of 4.0 g of cinnamoyl chloride in 30 ml of acetone. The mixture was stirred at the same temperature for 30 minutes to give rise to a reaction. The reaction mixture was poured into ice water, and the mixture was made acidic with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 2.9 g of 4-cinnamoylamino-3-methylbenzoic acid as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16]CC[CH2:13]2)[NH:11][CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1(C(N)(C)CN)C[CH2:21]1.CC(C)(O)C#N>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]([CH3:13])([CH3:16])[NH:11][CH2:10][C:9]1([CH:18]1[CH2:21][CH2:20]1)[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(N)(CN)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Agent: CC(C)(O)C#N
Product: CC1(C)CN(C(=O)OC(C)(C)C)C(C)(C2CC2)CN1

Procedure:
2-Cyclopropyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 2-cyclopropyl-propane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[CH3:35][CH:34]([C:33]1[N:37]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:30][N:32]=1)[CH3:36]
Reactant: CC(C)C(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 31 mg (0.306 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 60 mg (80% of theory)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10](O)=[O:11])[CH:8]=1)[CH3:2].CN(C=O)C.S(Cl)([Cl:21])=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10]([Cl:21])=[O:11])[CH:8]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(I)c(CC(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(I)c(CC(=O)Cl)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
5-Ethyl-2-iodophenylacetic acid is dissolved in methylene chloride (400 ml) and DMF (1 ml) is added. Thionyl chloride (21 ml, 300 mmol) is then added dropwise over 20 minutes. The mixture is heated to reflux and heating continued for 3.5 hours when the mixture is cooled and ice-water (400 ml) and methylene chloride (300 ml) are added. The layers are separated, the organic layer is washed with a sodium bicarbonate solution, saturated brine, dried (magnesium sulfate), and evaporated under reduced pressure to yield 5-ethyl-2-iodophenylacetyl chloride.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:26][N:27]([CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C.[ClH:39].O1CCOCC1>C(O)C>[ClH:39].[CH3:38][O:37][CH2:36][CH2:35][N:27]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:3]=2[CH:2]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1C(=O)C2=CO
Reactant: COCCN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COCCn1ncc2c1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of tert-butyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (200 mg, 0.58 mmol) and tert-butyl N-amino-N-(2-methoxyethyl)carbamate (130 mg, 0.70 mmol) in ethanol (5 mL) was allowed to stir at rt for 2 h. A solution of hydrogen chloride in 1,4-dioxane (150 μL of 4.0 M, 0.60 mmol) was added and the mixture was stirred at 50° C. for 1.5 h before it was concentrated in vacuo to give 1-(2-methoxyethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (85 mg, 44%). ESI-MS m/z calc. 299.2. found 300.3 (M+1)+; Retention time: 0.95 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.[OH-].[K+].[CH3:17][C:18](OC)(C)C>O>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:18][CH2:17]3)=[CH:10][C:4]=2[O:3]1
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Reactant: COC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 70 °C

Procedure:
A mixture of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (1.0 eq), 50 wt % aqueous KOH (5.0 eq) 1-bromo-2-chloroethane (1.5 eq), and Oct4NBr (0.02 eq) was heated at 70° C. for 1 hour. The reaction mixture was cooled, then worked up with MTBE and water. The organic phase was washed with water and brine. The solvent was removed to afford (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5 %

Procedure:
A mixture of 5.0 g (50 mmol) 2-aminothiazole, 10.0 g (50 mmol) tert-butyl 4-aminopiperidine-1-carboxylate, 21.2 g (100 mmol) sodium triacetoxyborohydride and 5.7 ml (100 mmol) acetic acid in THF (100 ml) was stirred for 24 h at RT. Subsequently, a further 10.6 g (50 mmol) sodium triacetoxyborohydride and 2.85 ml (50 mmol) acetic acid were added and stirring took place for a further 2 d at RT. The solvent was removed in vacuo and the residue was taken up by chloroform and washed a plurality of times with 10% aq. NaOH soln and water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, Chloroform/EtOH 20:1) was carried out on the residue, yielding 712 mg (2.5 mmol, 25%) tert-butyl-4-(thiazol-2-ylamino)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([C:9]1[CH:39]=[CH:38][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=O)=[CH:17][CH:16]=2)=[C:11]([CH3:40])[C:10]=1[OH:41])(=[O:8])[CH3:7].[OH-].[K+].Cl>CC(C)=O.O>[OH:41][C:10]1[C:11]([CH3:40])=[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([C:22]3[CH:30]=[CH:29][CH:28]=[C:24]([C:25]4[NH:5][C:3]([SH:4])=[N:2][N:1]=4)[CH:23]=3)[O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[CH:17][CH:16]=2)[CH:38]=[CH:39][C:9]=1[C:6](=[O:8])[CH3:7]
Reactant: NNC(N)=S
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O

Procedure:
Heat a solution of 3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid thiosemicarbazide (1.20 g, 2.04 mmol) and potassium hydroxide (0.228 g, 4.08 mmol) in acetone (5.0 mL) and water (5.0 mL) overnight. Acidify with 2N hydrochloric acid and extract with ethyl acetate (5×). Combine organic layers and wash with brine, dry, and concentrate to afford the title compound which was used without further purification (1.12 g, 2.04 mmol, 99%). MS (m/z): 544 (M−H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1

Procedure:
Using cyclohexyl{3-ethyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.55 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.37 g) synthesized in Example 1(2) and in the same manner as in Example 1 (7), the title object compound (0.32 g, 38%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:15][C:16]1[CH:17]=[C:18]([CH3:19])[N:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:2]2[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1c(N)[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2ccccc2n2c(C)cc(C)nc12
Yield: 75.6 %

Procedure:
A stirred solution of methyl 2-aminoindole-3-carboxylate (I. Forbes et al, J. Chem. Soc. Perkin 1, 1992, 275) (0.25 g, 0.0013 mole) in xylene (5 ml) was treated with 2,4-pentanedione (0.13 g, 0.0013 mole) and a few crystals of 4-toluenesulphonic acid and heated under reflux for 2 h. The mixture was concentrated in vacuo and the residue dissolved in chloroform (20 ml), washed with water (2×20 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid (0.25 g, 75%).