Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[F:27]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][C:21]=1[F:27]
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(Cl)c(F)c1

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (5.32 mL, 30.9 mmol), pyridine (3.33 mL, 41.2 mmol) and 4-chloro-3-fluoroaniline (3.00 g, 20.6 mmol). The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(4-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=274.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)c1
Yield: 97.1 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0095 mL (0.072 mMol) 3-methylbenzoyl chloride, 0.022 gm (99%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.Cl>ClCCl>[CH3:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=1.[CH3:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=1
Reactant: COC(=O)c1ccc(C)cc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C)cc1N(S(C)(=O)=O)S(C)(=O)=O
Product: COC(=O)c1ccc(C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methanesulphonyl chloride (12.2 ml) was added to a stirred, cooled solution of methyl 2-amino-4-methylbenzoate (10.3 g) and triethylamine (19.5 ml) in dichloromethane while maintaining the temperature below 0° C. The mixture was stirred at room temperature for 4 hours. Hydrochloric acid solution (2M) was added and the layers were separated. The organic layer was washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give a mixure of methyl 4-methyl-2-[N,N-bis(methylsulphonyl)amino]benzoate and methyl 4-methyl-2-(N-methylsulphonylamino)benzoate (18.26 g) as a yellow solid which was not further purified.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(OC)(O[CH3:18])(=O)=O>>[CH3:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: COc1ccc(-c2ccccc2)cc1

Procedure:
Methylation of 4-hydroxybiphenyl is carried out with dimethyl sulphate according to a conventional method.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39](=[O:48])[N:40]([CH3:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][CH:33]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39](=[O:48])[N:40]([CH3:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:36][CH:37]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(C(=O)NCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
A solution of 1-methylpiperidine-4-carboxylic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 5% yield as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[S:53][C:54]([CH:63]([NH2:71])[CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1>CN(C=O)C>[CH3:51][C:52]1[S:53][C:54]([C@@H:63]([NH:71][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1
Reactant: Cc1nc(-c2ccccc2)c(C(N)Cc2ccccc2)s1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c([C@H](Cc2ccccc2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)s1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 15B (29.4 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.02 (d, J=7.8 Hz, 1H), 7.46-7.26 (m, 4H), 7.13 (t, J=6.1 Hz, 3H), 6.99 (d, J=7.7 Hz, 2H), 5.37 (dd, J=14.8, 7.3 Hz, 1H), 4.68 (t, J=12.7 Hz, 2H), 2.99 (ddd, J=20.2, 13.5, 7.3 Hz, 2H), 2.63 (s, 3H), 2.45-2.19 (m, 4H), 1.61 (d, J=5.5 Hz, 4H); MS (m/z) 525 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20]([NH2:22])=[O:21].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][N:11]([CH2:27][NH:22][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([CH3:26])[CH:25]=[C:17]([CH3:16])[CH:18]=2)[CH2:12][CH:13]=1
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: Cc1cc(C)cc(C(N)=O)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C)cc(C(=O)NCN2CC=C(c3ccccn3)CC2)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), 3,5-dimethylbenzamide (75 mg, 0.5 mmol), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 18 mg (56%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ2.33 (s, 6H), 2.56 (m, 2H), 2.78 (t, J=4 Hz, 2H), 3.28 (m, 2H), 4.18 (d, J=5 Hz, 2H), 6.71 (m, 1H), 7.18 (s, 1H), 7.22 (m, 1H), 7.50 (m, 3H), 7.75 (t, J=6 Hz, 1H), 8.52 (d, J=5 Hz, 1H), 8.62 (t, J=5 Hz, 1H), MS (ESI/APCI−) m/e 320 (M−H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[C:55]([C:66]([F:69])([F:68])[F:67])[CH:54]=1>CN(C=O)C.O>[F:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:65]2)=[C:55]([C:66]([F:69])([F:67])[F:68])[CH:54]=1
Reactant: Fc1ccc(NC2CCNCC2)c(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccc(F)cc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 36 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (140 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (97 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol). After 2 minutes (4-fluoro-2-trifluoromethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (prepared according to the method used for the synthesis of Intermediate 3) (150 mg, 0.6 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 105 mg (36% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 490.18, 95.36%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.0 (t, 1H), 7.8 (m, 2H), 7.4 (m, 6H), 7.1 (m, 2H), 4.6 (d, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.5 (m, 2H), 1.4 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]#[N:50])[CH:40]=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:37](=[O:36])[NH:38][C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]#[N:50])[CH:40]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C#N)cc(C(F)(F)F)c3)c2)C1
Reaction time: 24 h

Procedure:
4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 31-F (140 mg, 0.38 mmol) is dissolved in THF (5 mL) and NaH (31 mg, 0.76 mmol, 60% in mineral oil) is added followed by (3-cyano-5-trifluoromethyl-phenyl)-carbamic acid phenyl ester (428 mg, 1.15 mmol). After 24 h, the reaction is concentrated and then partitioned between DCM and water. The crude residue is purified via FCC (5-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 579.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.[I-].[Na+].[F:52][C:53]([F:57])([F:56])[CH2:54][O-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[C:20]([CH2:22][O:23][CH2:54][C:53]([F:57])([F:56])[F:52])[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]CC(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(CO)c(-c3ccc(F)cc3F)o2)CC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3F)o2)CC1
Temperature: 0 °C

Procedure:
To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet and dropping funnel is added 4-[5-(2,4-Difluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, methane sulfonic anhydride (5.87 g, 33.7 mmol), and 150 mL of dry tetrahydrofuran. The mixture is stirred and cooled to 0° C., followed by dropwise addition of diisopropyl ethylamine (8.4 mL, 48 mmol). The mixture is stirred for 1 hour at 0° C. and then allowed to warm to room temperature. To the resultant mixture is then added sodium iodide (7.75 g, 51.7 mmol), and the mixture is stirred for an additional three hours. The sodium 2,2,2-trifluoroethoxide (0.151 mmol in 80 mL of dry tetrahydrofuran) is added dropwise over a 15 minute period and the resulting mixture is stirred for an additional 1 hour. The mixture is cooled to 0° C. and carefully quenched with 125 mL of water. After the addition was complete, the mixture is extracted with water and methylene chloride. The aqueous is washed with an additional three portions of methylene chloride, using 300 mL volumes. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue. The residue is purified by preparative medium performance liquid chromatography to give upon concentration the desired fractions of the title compound.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:12]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[C:11]=1[CH3:29])=[O:9])[CH3:6].[N-:30]=[N+:31]=[N-].[Na+]>O.Cl>[CH2:5]([O:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:12]([C:22]2[CH:23]=[CH:24][C:25]([N:28]=[N+:30]=[N-:31])=[CH:26][CH:27]=2)[C:11]=1[CH3:29])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(N)cc2)c1C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(N=[N+]=[N-])cc2)c1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of NaNO2 (0.015 g, 0.216 mmol) in water (1.5 mL) was added to an ice-cold solution of Example 26 (0.075 g, 0.212 mmol) in HCl (3 mL, 37% w/v) over 10 minutes. A solution of NaN3 (0.138 g, 2.12 mmol) in water (0.5 mL) was added drop wise with stirring at 0° C. over 10 minutes, and the temperature of the mixture was allowed to rise to 25° C. After stirring for another 20 minutes at room temperature, the mixture was extracted with DCM (3×25 mL), and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (ESI) m/z 381 (M+H); IR: 2097 cm−1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH:46]([CH:57]([CH3:59])[CH3:58])[C@@H:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH3:48]>C1COCC1>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[C@H:46]([CH:57]([CH3:59])[CH3:58])[C@@H:47]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH3:48]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)C(O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@H]([C@H](C)NC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
Phthalimide (4.3 g), triphenylphosphine (9.6 g), and DIAD (19.2 ml) were added to a THF (40 ml) solution containing tert-butyl ((2S)-3-hydroxy-4-methylpentan-2-yl)carbamate (5.3 g) obtained in the 4th step, followed by stirring at room temperature for 16 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 5:1). Yellow oily matter of tert-butyl ((2S,3R)-3-(1,3-dioxoisoindolin-2-yl)-4-methylpentan-2-yl)carbamate (3 g) was thus obtained.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+]>C(O)(=O)C>[C:6]([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: ClCC1CO1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(O)CCl
Reaction time: 8 h
Yield: 131.1 %

Procedure:
A suspension of epichlorhydrin (27.8 g) and sodium acetate (12.3 g) in acetic acid (36 g) is heated at 50°-55° C. for 8 hours. The reaction mixture is allowed to stand overnight and concentrated in vacuum. The residue is neutralized with aqueous sodium hydrogencarbonate and shaken with ether. The ethereal layer is dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is distilled in vacuum to give 1-acetoxy-3-chloro-2-propanol (30 g) as an oil boiling at 115°-116° C./13 mm Hg. The yield is 65.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[CH3:21][N:22]=[C:23]=[S:24].NC(N)=S>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]([NH:22][CH3:21])=[S:24])=[CH:16][CH:15]=1
Reactant: CN=C=S
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Agent: NC(N)=S
Product: CNC(=S)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1

Procedure:
Proceeding in analogy to the method described in example 19 and starting from 500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (see example 17) and 220 mg (3.0 mmol) of methyl isothiocyanate allowed 245 mg of the desired thiourea to be isolated.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[I:11][CH3:12]>C(O)C>[I-:11].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:12]
Reactant: Cc1nc2ccccc2s1
Reactant: CI
Solvent: CCO
Product: Cc1sc2ccccc2[n+]1C
Product: [I-]

Procedure:
14.9 g (12.7 ml, 0.10 mol) 2-methyl-benzothiazole and 28.4 g (12.5 ml, 0.20 mol) iodomethane were boiled for 7 h in 20 ml ethanol. The residue was filtrated and washed with ethanol.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:9]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:9]=1
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 140 °C

Procedure:
In a 2-5 mL microwave vial was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4k, 300 mg, 0.45 mmol), phenylboronic acid (108 mg, 0.89 mmol), K3PO4 (189 mg, 0.89 mmol), and Pd(PPh3)4 (52 mg, 0.045 mmol). To this was added 3:1 1,4-dioxane:H2O (4 mL). The vial was flushed with argon and sealed. The reaction was heated to 140° C. for 20 minutes in a microwave synthesizer. The reaction was then diluted with DCM (30 mL) and washed with H2O. The organic phase was dried over Na2SO4 and the residue was purified via silica gel chromatography to yield the title compound. Yield=265 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[C:19]([SiH2:23][O:24][C:25]([CH3:39])([CH3:38])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[C:34]([CH:36]=O)=[CH:33][CH:32]=[CH:31]2)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([SiH2:23][O:24][C:25]([CH3:39])([CH3:38])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[C:34]([CH2:36][N:15]1[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][NH:10][C:11]3=[O:18])[CH2:17][CH2:16]1)=[CH:33][CH:32]=[CH:31]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(C=O)c12
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(CN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.056 g, 0.22 mmol) and 8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde (0.067 g, 0.22 mmol) were dissolved in dry 1,2-dichloroethane (5 mL). To the reaction mixture was added crashed 4A Molecular Sieve (0.028 g), a catalytic amount of glacial acetic acid. The reaction mixture was stirred at room temperature for 1 hr and it was then added at room temperature sodium triacetoxyborohydride (0.071 g, 0.33 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with water and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via semi-preparative HPLC (aqueous 0.5% TFA/acetonitrile) to yield crude 8-[8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalen-1-ylmethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one which was directly used to the next step.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[C-:23]#[N:24].[K+]>O.CO>[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C:12]([N:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)([C:23]#[N:24])[CH2:11][CH2:10]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: C1CCNC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(C#N)(N2CCCC2)CC1
Reaction time: 1 h

Procedure:
A mixture of methanol (50 ml) and water (50 ml) was acidified with hydrochloric acid (37%, 0.2 ml) and mixed with pyrrolidine (7.5 ml, 91 mmol) with ice cooling and stirring. 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) was then added to the solution. The batch was stirred for 10 min to dissolve the ketone as completely as possible. KCN (1.6 g, 24.6 mmol) was then added. The ice cooling was removed and the batch stirred for 2 d at RT, during which white solid separated out. The batch was brought to approx. 0° C. again for 1 h by ice cooling to complete the precipitation. The precipitate was then separated by means of a fritted glass filter and dried in a vacuum at a bath temperature of 40° C. A diastereoisomer mixture of the title compound was obtained with a yield of 2.7 g (90%) and with a melting point of 136-142° C.