Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A158) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:11][C:10]([O:14][Si](C)(C)C)([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>ClCCl>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:11][C:10]([OH:14])([C:12]([NH2:13])=[O:26])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(Diphenylmethyl)azetidin-3-one (600 mg, 2.53 mmol), was dissolved in dichloromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59 mmol) and trimethylsilylcyanide (0.8 mL, 6.01 mmol) at ambient for 2 h and then the mixture was concentrated in vacuo to afford 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (774 mg, 2.30 mmol, 91% yield) as a yellow solid. 1-(diphenylmethyl)-3[(trimethylsilyl)oxy]azetidine-3-carbonitrile (250 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) at 0° C. and concentrated sulfuric acid (0.2 mL) was added dropwise. The mixture was stirred at ambient for 2 h and then was cooled to 0° C. and 25% ammonium hydroxide solution was added carefully dropwise to pH ˜10-11. The mixture was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a residue which was triturated with hexanes/ether to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (160 mg, 0.567 mmol, 76% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3): 7.92 (br s, 1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (br s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS (EI) for C17H18N2O2: 283 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([N:14]=[C:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1COCC1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:15]([NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccccc1)Nc1nccs1

Procedure:
A 2-amino-thiazole derivative is condensed with a benzylisocyanate by heating with a basic catalyst (typically DMAP) in an inert organic solvent (typically THF or NMP) to afford the corresponding 1-(thiazol-2-yl)-3-benzyl-urea, which is purified by silica gel chromatography.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][C:15]2([Cl:18])[Cl:17])[CH:6]=1)=[O:3].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>C(OCC)C>[S:19]1[CH2:23][CH2:22][N:21]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]3[CH2:16][C:15]3([Cl:18])[Cl:17])[CH:6]=2)=[O:3])[CH2:20]1
Reactant: C1CSCN1
Reactant: O=C(Cl)Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1)N1CCSC1
Yield: 88 %

Procedure:
1.00 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenyl chloroformate was dissolved in 20 ml of diethyl ether and, to the solution, there were added 0.32 g of thiazolidine and 0.37 g of triethylamine. The mixture was stirred at 0° to -5° C. for an hour and then washed with water. The ether was distilled off from the ether layer and the oily residue was purified by silica gel column chromatography to give 1.02 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenyl 3-thiazolidinecarboxylate [Compound (7)], which had the melting point of 74°-79.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[C@@H:12]2[CH2:17][CH2:18][C@H:9]1[CH2:10][C@H:11]2[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]([NH2:27])=[O:26].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[NH2:27][C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:14]([C@@H:13]1[C@@H:12]2[CH2:17][CH2:18][C@@H:9]([CH2:10][C@H:11]2[OH:19])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[O:26]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H]([C@H](O)C2)[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid obtained in Example 2-5 (4.05 g), (2S)-2-pyrrolidinecarboxamide (1.77 g) and 1-hydroxybenzotriazole hydrate (1.68 g), were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15 g) and N,N-diisopropylethylamine (5.2 mL) with cooling on an ice bath. After 5 minutes, the ice bath was removed and the mixture was stirred overnight at room temperature.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[NH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:29]4[CH:34]=[C:33]([NH2:35])[C:32]([F:36])=[CH:31][C:30]=4[CH3:37])[C:22](=[O:28])[N:23]3[CH2:26][CH3:27])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:29]3[CH:34]=[C:33]([NH2:35])[C:32]([F:36])=[CH:31][C:30]=3[CH3:37])[C:22](=[O:28])[N:23]2[CH2:26][CH3:27])=[CH:18][N:17]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NCc3ccc(OC)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(N)cc21
Temperature: 50 °C
Yield: 46 %

Procedure:
TFA (2 mL, 26.9 mmol) was added to a solution of 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one in DCM (10 mL) and the reaction mixture was refluxed at 50° C. for 2 h. After cooling to RT, the reaction mixture was washed with water and the combined aqueous layers were neutralized with satd. NaHCO3. The aqueous layer was extracted with EtOAc (3×) and the extracts were dried (Na2SO4) and concentrated to give 7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (0.9 g, 46% yield, over 2 steps). 1H NMR (300 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.56 (s, 1H), 6.83 (d, J=12.3 Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.40 (s, 2H), 6.32 (s, 1H), 4.85 (s, 2H), 4.07 (q, J=6.9 Hz, 2H), 1.94 (s, 3H), 1.19 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 313.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([CH3:16])=C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:20]CC1>O.CCOC(C)=O.O=[Os](=O)(=O)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](=[O:20])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C(C)CC1CCN(Cc2ccccc2)C1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)CC1CCN(Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
To a rapidly stirred solution of 1-4 (7.0 g, 33 mmol) in THF (200 mL) and H2O (150 mL) was added NaIO4 (21 g, 100 mmol) followed by addition of OsO4 (10 mL; 2.5% solution). After 16 hrs, an additional amount of OsO4 (10 mL) was added, and the reaction was stirred for 6 hrs. The reaction was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 1-5 as a brown oil.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 411.84 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.N1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C)C=O>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([N:1]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCCCC2)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
5.8 g of 2,6-dinitrobenzonitrile was dissolved in 30 ml of dimethylformamide, and 10.2 ml of piperidine was added to the solution. The mixture was stirred at 50° C. for 30 minutes while externally cooling because of heat generation. The reaction mixture was poured into water, and the precipitate thus formed was collected, washed with water and then with methanol, and dried to obtain 6.7 of 2-nitro-6-piperidinobenzonitrile (melting point: 122°-123° C.).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O.O>CN(C=O)C>[C:32]([O:31][C:29]([N:7]1[C:6]2[N:1]=[CH:2][N:3]=[C:4]([N:10]3[CH2:17][C:14]4([CH2:16][CH2:15]4)[N:13]([S:18](=[O:20])(=[O:19])[NH2:21])[CH2:12][CH2:11]3)[C:5]=2[CH:9]=[CH:8]1)=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid amide (intermediate 1) (1.5 g, 4.86 mmol) was dissolved in dry DMF (20 ml), added Cs2CO3 (1.59 g, 4.86 mmol) and cooled to 0° C. A solution of BOC2O (1.06 g, 4.86 mmol) in dry DMF (10 mL) was added and the reaction mixture was allowed to warm up to rt and stirred at rt for 16 h. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4])[CH3:2].[CH:13](S(C1C=CC=CC=1)(=O)=O)(C)C>>[CH:1]([S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4])([CH3:13])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(N)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1
Product: CC(C)S(=O)(=O)c1cccc(N)c1

Procedure:
3-Isopropylsulfonylaniline was synthesized in analogy to 3-ethylsulfonylaniline starting with 3-(isopropylsulfonyl)-benzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[C:16]([F:33])=[C:17]([NH:21][S:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35]>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[C:16]([F:33])=[C:17]([NH:21][S:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CCc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-ethyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.196 mmol) and ammonium hydroxide (3 mL, 77 mmol), the title compound was obtained as an off-white solid (52 mg, 51% yield). MS (ESI): 492 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([C:13]([NH:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[O:14])=[N:3]1.FC(F)(F)C(O)=O.[ClH:33]>>[ClH:33].[NH2:18][CH2:17][CH2:16][NH:15][C:13]([C:4]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:14]
Reactant: Cn1cc(-c2ccccc2)c(C(=O)NCCNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccccc2)c(C(=O)NCCN)n1
Yield: 90.4 %

Procedure:
In an analogous manner to that described in Examples 16 and 17 from 4.6 g (13.4 mmol) of t-butyl [2-(1-methyl-4-phenyl-3-pyrazolecarboxamido)ethyl]carbamate there were obtained, after cleavage of the t-butoxycarbonyl group with trifluoroacetic acid and working-up, 4.8 g of the crude hydrochloride. Recrystallization from ethanol/diethyl ether yielded 3.4 g (90%) of N-(2-aminoethyl)-1-methyl-4-phenyl-3-pyrazolecarboxamide hydrochloride as white crystals, melting point 182°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-ethyl 3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (1.00 g, 285 mmol, EXAMPLE 33 Step 1) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) at room temperature. After being stirred at room temperature for 8 h, the volatile was evaporated to afford 1.36 g (quant.) of the title compound that was used directly in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:14]3[N:13]=[CH:12][NH:11][C:10]=3[C:9](=[O:15])[NH:8][C:7]2=[O:16])[CH2:5][CH2:4]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[CH2:17]([N:11]1[C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH:3]3[CH2:5][CH2:4]3)[C:14]=2[N:13]=[CH:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=O)n(C2CC2)c2ncn(Cc3ccccc3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
10.4 g (0.26 mol) of sodium hydroxide dissolved in 110 ml of water were added to a suspension of 50 g (0.26 mol) of 3-cyclopropylxanthine in 300 ml of methanol and the reaction mixture was stirred for one hour at 70° C., then treated dropwise at the same temperature with 44.5 g (0.26 mol) of benzyl bromide and kept between 70° and 80° C. for 4 hours. 1.04 g (0.026 mol) of sodium hydroxide and 4.45 g (0.026 mol) of benzyl bromide were then added. After a further hour, the mixture was cooled and filtered cold on a suction filter and the product was washed with water on the suction filter. The crude product thus obtained could be employed without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1
Reactant: Oc1cc(F)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ncc3c(O)cc(F)cc32)cc1F
Yield: 91.1 %

Procedure:
A solution of 6-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D8) (470 mg, 1.34 mmol) in ethanol (20 mL) and ethyl acetate (20 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated to yield the title compound (E4) (320 mg).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][N:51]1[CH2:56][CH2:55][C:54]([CH3:63])([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:60]3[CH2:61][CH2:62][N:57]([C:54]4([CH3:63])[CH2:55][CH2:56][N:51]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:52][CH2:53]4)[CH2:58][CH2:59]3)=[O:41])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: CCOC(=O)CN1CCC(C)(N2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(C)(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 mL (1.18 mmol) triethylamine were added to a mixture of 250 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 250 mg (0.50 mmol) ethyl(4-methyl-4-piperazin-1-yl-piperidin-1-yl)-acetate (Example A7f) and 160 mg (0.50 mmol) TBTU in 2 mL DMF and the reaction mixture was stirred for 4 h at RT. It was evaporated down i. vac. and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[OH:14].[F:15][C:16]1[CH:23]=[C:22](F)[C:21]([F:25])=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:15][C:16]1[CH:23]=[C:22]([O:14][C:4]2[CH:5]=[CH:6][C:7]([O:9][C:10]([F:12])([F:11])[F:13])=[CH:8][C:3]=2[O:2][CH3:1])[C:21]([F:25])=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: COc1cc(OC(F)(F)F)ccc1O
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(OC(F)(F)F)ccc1Oc1cc(F)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethoxy)phenol (Preparation 54, 331 mg, 1.59 mmol) in dimethylsulfoxide (10 mL) was added 2,4,5-trifluorobenzonitrile (250 mg, 1.59 mmol) and potassium carbonate (220 mg, 1.59 mmol) This suspension was stirred for 18 hours at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL), and extracted with dichloromethane (3×40 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a clear oil (549 mg, 100%). This was used in the next reaction with no further purification.
Reaction SMILES: C1([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:9]([C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[N:8]2)C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:9]3[N:8]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:7]=[CH:11][C:10]=3[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:19]=2)=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Nc1cccc(-c2nn(-c3ccccc3)cc2-c2ccncc2)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2c(-c3ccncc3)cnn2-c2ccccc2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
3-(1-Phenyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (as regioisomeric mixture) was dissolved in dry dichloromethane (1 mL) under nitrogen atmosphere, 4-chloro-3-trifluoromethylphenylisocyanate (61 mg, 0.275 mmol, 1.4 eq) was added and the reaction mixture was stirred at room temperature for 3 hours. The solution was concentrated to dryness and purified by chromatography on silica gel (SP1, gradient n-hexane/ethyl acetate 1:1 to pure ethyl acetate). Two pools of fractions containing the two separated regioisomers were obtained, together with some mixed fractions (total yield 78%). 55 mg of 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(2-phenyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-urea were obtained as colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[NH3:14]>C(O)(C)C>[CH3:12][S:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[CH:3][C:2]([NH2:14])=[N:13][C:6]=2[N:7]=1
Reactant: CSc1ncc2ccc(Cl)nc2n1
Reactant: N
Solvent: CC(C)O
Product: CSc1ncc2ccc(N)nc2n1
Temperature: 40 °C
Yield: 74.2 %

Procedure:
A suspension of 2.95 g (13.9 mmol) of 7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (Example 6) in 200 mL of isopropanol saturated with ammonia is sealed and heated at 40° C. for 65 hours. The suspension is resaturated with ammonia and heated for another 18 hours at 40° C. The solid is collected by filtration and triturated with water to give 1.98 g (74.2%) of the product, mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]=[CH:7]2.[CH3:15]O>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2
Reactant: CO
Reactant: Nc1cccc2cnc(C(=O)O)cc12
Product: COC(=O)c1cc2c(N)cccc2cn1

Procedure:
5-Aminoisoquinoline-3-carboxylic acid (25 g) is added to methanol (2 liters). The mixture is heated to the reflux temperature and a stream of dry hydrogen chloride is bubbled through for 3 hours. The mixture is heated under reflux for a further 3 hours and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue is dissolved in water (200 cc) and the solution is washed with ethyl acetate (2×100 cc). The aqueous solution is rendered alkaline to pH 9 by adding potassium carbonate. The precipitate formed is filtered off, washed with water and dried to yield 5-amino-3-methoxycarbonylisoquinoline (20.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33](O)=[O:34]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COCCOCCOCC(=O)O
Product: COCCOCCOCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and [2-(2-methoxy-ethoxy)-ethoxy]-acetic acid to yield (3aR,4S,7aR)-4-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 474; RT=7.747 min; HPLC Method I